Exome sequencing of liver fluke-associated cholangiocarcinoma

Opisthorchis viverrini-related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini-related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 (mutated in 44.4% of cases), KRAS (16.7%) and SMAD4 (16.7%), we identified somatic mutations in 10 newly implicated genes in 14.8-3.7% of cases. These included inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%) and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%). These genes have functions that can be broadly grouped into three biological classes: (i) deactivation of histone modifiers, (ii) activation of G protein signaling and (iii) loss of genome stability. This study provides insight into the mutational landscape contributing to O. viverrini-related CCA.     

Perceiving distance accurately by a directional process of integrating ground information

By itself, the absolute distance of an object cannot be accurately judged beyond 2-3 m (refs 1-3). Yet, when it is viewed with reference to a flat terrain, humans accurately judge the absolute distance of the object up to 20 m, an ability that is important for various actions. Here we provide evidence that this is accomplished by integrating local patches of ground information into a global surface reference frame. We first show that restricting an observer's visual field of view to the local ground area around the target leads to distance underestimation, indicating that a relatively wide expanse of the ground surface is required for accurate distance judgement. Second, as proof of surface integration, we show that even with the restricted view, the observer can accurately judge absolute distance by scanning local patches of the ground surface, bit by bit, from near to far, but not in the reverse direction. This finding also reveals that the surface integration process uses the near-ground-surface information as a foundation for surface representation, and extrapolation to the far ground surface around the target for accurate absolute distance computation.     

Imaging the vortex-lattice melting process in the presence of disorder

General arguments suggest that first-order phase transitions become less sharp in the presence of weak disorder, while extensive disorder can transform them into second-order transitions; but the atomic level details of this process are not clear. The vortex lattice in superconductors provides a unique system in which to study the first-order transition on an inter-particle scale, as well as over a wide range of particle densities. Here we use a differential magneto-optical technique to obtain direct experimental visualization of the melting process in a disordered superconductor. The images reveal complex behaviour in nucleation, pattern formation, and solid-liquid interface coarsening and pinning. Although the local melting is found to be first-order, a global rounding of the transition is observed; this results from a disorder-induced broad distribution of local melting temperatures, at scales down to the mesoscopic level. We also resolve local hysteretic supercooling of microscopic liquid domains, a non-equilibrium process that occurs only at selected sites where the disorder-modified melting temperature has a local maximum. By revealing the nucleation process, we are able to experimentally evaluate the solid-liquid surface tension, which we find to be extremely small.     

A one-dimensional chain state of vortex matter.

Magnetic flux penetrates isotropic type II superconductors in flux-quantized vortices, which arrange themselves into a lattice structure that is independent of the direction of the applied field. In extremely anisotropic high-transition-temperature (high-Tc) superconductors, a lattice of stacks of circular 'pancake' vortices forms when a magnetic field is applied perpendicular to the copper oxide layers, while an orthogonal elongated lattice of elliptical Josephson vortices forms when the applied field is parallel to the layers. Here we report that when a tilted magnetic field is applied to single crystals of Bi2Sr2CaCu2O8+delta, these lattices can interact to form a new state of vortex matter in which all stacks of pancake vortices intersect the Josephson vortices. The sublattice of Josephson vortices can therefore be used to manipulate the sublattice of pancake vortices. This result explains the suppression of irreversible magnetization by in-plane fields as seen in Bi2Sr2CaCu2O8+delta crystals, a hitherto mysterious observation. The ability to manipulate sublattices could be important for flux-logic devices, where a 'bit' might be represented by a pancake vortex stack, and the problem of vortex positioning is overcome through sublattice interactions. This also enables the development of flux transducers and amplifiers, considerably broadening the scope for applications of anisotropic high-Tc superconductors.     

Selective antiproliferative effects of thymidine

A substance with antiproliferative bioactivity in an aqueous extract ofCordyline terminalis was purified and identified by mass spectrometry to be the natural nucleoside, thymidine. 10^–5M Thymidine inhibited EL4 cell replication and decreased cell viability after 12–24 h. The effect was highly specific for this nucleoside. Treated cell cultures showed a significant increase in S phase cells and a corresponding decrease in G₁ phase cells. Nitrobenzylthioinosine (which prevented facilitated entry of thymidine) protected cells from the antiproliferative action of thymidine. A human breast cancer cell line (MCF7) was also growth-inhibited by 10^–5M thymidine but a murine lymphoma cell line (K36) was not. Thus, submillimolar thymidine has effects on cell proliferation which are selective both with respect to specificity for the compound and for different tumour cell lines.     

Antiviral activities of extracts from Hong Kong seaweeds

We extracted six Hong Kong brown seaweed species with hot water for their antiviral properties. The cytotoxicity and antiviral activity of these extracts were tested by MTT [3-（4,5-dimethylthiazol-2-yl）-2,5-diphenlytetrezolium bromide] method, cytopathic effect reduction assay, and plaque reduction assay. The antiviral effect was further determined by flow cytometric analysis. The results showed that most of these extracts inhibited the propagation of herpes simplex virus types 1 and 2 （HSV-1 and HSV-2） standard strains with very low cytotoxicity to the host cells. The extracts ofHydroclathrus clathratus and Lobophora variegata showed more potential anti-HSV activities than the extracts of the other four seaweeds. They also had moderate antirespiratory syncytial virus （RSV） activities but could not inhibit influenza A virus. Hydroclathrus clathratus was further extracted by diluted acid and alkali and the antiviral effects of the extracts were also detected. The result showed that the hot water extract contained the main carbohydrate components that exhibited the antiviral activities against various strains of HSV, including the acyclovir-resistant strain. HI-3, a compound fractionated from this hot water extract, showed a dose-dependent anti-HSV activity in flow cytometric analysis and plaque reduction assay.     

Fatty acid modulation of antiestrogen action and antiestrogen-binding protein in cultured lymphoid cells

Summary Nonsteroidal antiestrogens reversibly and specifically inhibited the proliferation of two estrogen receptornegative lymphoid cell lines (EL4 and Raji) in a dose-dependent manner. [³H]Thymidine incorporation of concanavalin A-stimulated primary splenocytes was also inhibited by 10^–6 M clomiphene (1-[4-(2-diethylaminoethoxy)phenyl]-1,2-diphenyl-2-chloroethylene). The antiproliferative effect could be prevented by the simultaneous presence in the growth medium of 10^–5 M linoleic acid or 10^–5 M arachidonic acid but not by 10^–6 M estradiol. Both lymphoid cell lines had high affinity antiestrogen-binding sites whose affinity could be altered by conditions of growth. Growth of EL4 cells in RPMI 1640 medium supplemented with charcoal-pretreated 5% fetal calf serum (charcoal-stripped medium) resulted in significantly higher affinity (K_d 0.54 nM±0.11 nM; n=6) than growth in medium supplemented with untreated serum (complete medium) (K_d=1.68 nM±0.48 nM; n=6) (p<0.001). This change in affinity was partly due to removal of fatty acids from the growth medium by charcoal pretreatment, since addition of 10^–5 M linoleic acid or 10^–5 M gamma-linolenic to charcoal-stripped medium decreased the affinity of the antiestrogen-binding protein. In contrast, growth in 10^–5 M stearic acid or 10^–5 M oleic acid did not significantly alter the affinity of the antiestrogen-binding protein, whereas 10^–5 M palmitic acid significantly increased its affinity. The same fatty acids were also tested for their intrinsic effects on EL4 cell proliferation. Oleic, linoleic and gamma-linolenic acids were growth stimulatory while stearic and palmitic acids were not. Thus linoleic and gamma-linolenic acids whose presence in the growth medium was associated with decreased affinity of [³H]tamoxifen (1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut-1(Z)-ene) binding to the intracellular antiestrogen-binding protein were also growth stimulatory. Unsaturated fatty acids have previously been shown to inhibit binding of [³H]tamoxifen to the antiestrogen-binding protein in a cell-free system. The present observations demonstrate that unsaturated fatty acids also modify the affinity of the antiestrogen-binding protein in intact cells.