Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia

Effective targeted cancer therapeutic development depends upon distinguishing disease-associated 'driver' mutations, which have causative roles in malignancy pathogenesis, from 'passenger' mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis. Abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts.     

DNA media storage

In 1994, University of Southern California computer scientist Dr. Leonard Adleman solved the Hamiltonian path problem using DNA as a computational mechanism. He proved the principle that DNA computing could be used to solve computationally complex problems. Because of the limitations in discovery time, resource requirements, and sequence mismatches, DNA computing has not yet become a commonly accepted practice. However, advancements are continually being discovered that are evolving the field of DNA computing. Practical applications of DNA are not restricted to computation alone. This research presents a novel approach in which DNA could be used as a means of storing files. Through the use of multiple sequence alignment combined with intelligent heuristics, the most probabilistic file contents can be determined with minimal errors.     

Global azimuthal seismic anisotropy and the unique plate-motion deformation of Australia

Differences in the thickness of the high-velocity lid underlying continents as imaged by seismic tomography, have fuelled a long debate on the origin of the 'roots' of continents. Some of these differences may be reconciled by observations of radial anisotropy between 250 and 300 km depth, with horizontally polarized shear waves travelling faster than vertically polarized ones. This azimuthally averaged anisotropy could arise from present-day deformation at the base of the plate, as has been found for shallower depths beneath ocean basins. Such deformation would also produce significant azimuthal variation, owing to the preferred alignment of highly anisotropic minerals. Here we report global observations of surface-wave azimuthal anisotropy, which indicate that only the continental portion of the Australian plate displays significant azimuthal anisotropy and strong correlation with present-day plate motion in the depth range 175-300 km. Beneath other continents, azimuthal anisotropy is only weakly correlated with plate motion and its depth location is similar to that found beneath oceans. We infer that the fast-moving Australian plate contains the only continental region with a sufficiently large deformation at its base to be transformed into azimuthal anisotropy. Simple shear leading to anisotropy with a plunging axis of symmetry may explain the smaller azimuthal anisotropy beneath other continents.     

Development of DArT markers for a linkage map of flue-cured tobacco

Tobacco(Nicotiana tabacum) is one of the most economically important nonfood crops,and flue-cured tobacco accounts for approximately 80% of world tobacco production.An extremely narrow genetic diversity in the tobacco pool has led to a low efficiency of PCR-based molecular markers(such as AFLP and SSR).Diversity Arrays Technology(DArT) is a high-throughput hybridisation-based marker system that has been developed in many plants including wheat,which,like tobacco,has a complex genome.In this study,we developed a tobacco DArT chip that included 7680 representative sequence tags based on typical tobacco accessions.The 1076 DArT markers of flue-cured tobacco were identified and most(82.1%) of their polymorphism information contents(PICs) were greater than 0.4.An integrated linkage map that included 851 markers(238 DArT and 613 SSR),which is the highest density map of flue-cured tobacco to date,was constructed.This chip-based DArT system provides an alternative in high-throughput marker genotyping for tobacco.     

Alignment of the stellar spin with the orbits of a three-planet system

The Sun's equator and the planets' orbital planes are nearly aligned, which is presumably a consequence of their formation from a single spinning gaseous disk. For exoplanetary systems this well-aligned configuration is not guaranteed: dynamical interactions may tilt planetary orbits, or stars may be misaligned with the protoplanetary disk through chaotic accretion , magnetic interactions or torques from neighbouring stars. Indeed, isolated 'hot Jupiters' are often misaligned and even orbiting retrograde. Here we report an analysis of transits of planets over starspots on the Sun-like star Kepler-30 (ref. 8), and show that the orbits of its three planets are aligned with the stellar equator. Furthermore, the orbits are aligned with one another to within a few degrees. This configuration is similar to that of our Solar System, and contrasts with the isolated hot Jupiters. The orderly alignment seen in the Kepler-30 system suggests that high obliquities are confined to systems that experienced disruptive dynamical interactions. Should this be corroborated by observations of other coplanar multi-planet systems, then star-disk misalignments would be ruled out as the explanation for the high obliquities of hot Jupiters, and dynamical interactions would be implicated as the origin of hot Jupiters.     

HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus

Early treatment of acute HIV-1 infection followed by treatment interruptions has shown promise for enhancing immune control of infection. A subsequent loss of control, however, allows the correlates of protective immunity to be assessed. Here we show that sudden breakthrough of plasma viraemia occurred after prolonged immune containment in an individual infected with HIV-1 at a time when 25 distinct CD8+ T-cell epitopes in the viral proteins Gag, RT, Integrase, Env, Nef, Vpr, Vif and Rev were being targeted. Sequencing of the virus in plasma and cells showed that superinfection with a second clade-B virus was coincident with the loss of immune control. This sudden increase in viraemia was associated with a decline in half of the CD8+ T-cell responses. The declining CD8+ T-cell responses were coupled with sequence changes relative to the initial virus that resulted in impaired recognition. Our data show that HIV-1 superinfection can occur in the setting of a strong and broadly directed virus-specific CD8+ T-cell response. The lack of cross-protective immunity for closely related HIV-1 strains, despite persistent recognition of multiple CD8 epitopes, has important implications for public health and vaccine development.     

Glyoxalase 1 and glutathione reductase 1 regulate anxiety in mice

Anxiety and fear are normal emotional responses to threatening situations. In human anxiety disorders--such as panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, social phobia, specific phobias and generalized anxiety disorder--these responses are exaggerated. The molecular mechanisms involved in the regulation of normal and pathological anxiety are mostly unknown. However, the availability of different inbred strains of mice offers an excellent model system in which to study the genetics of certain behavioural phenotypes. Here we report, using a combination of behavioural analysis of six inbred mouse strains with quantitative gene expression profiling of several brain regions, the identification of 17 genes with expression patterns that correlate with anxiety-like behavioural phenotypes. To determine if two of the genes, glyoxalase 1 and glutathione reductase 1, have a causal role in the genesis of anxiety, we performed genetic manipulation using lentivirus-mediated gene transfer. Local overexpression of these genes in the mouse brain resulted in increased anxiety-like behaviour, while local inhibition of glyoxalase 1 expression by RNA interference decreased the anxiety-like behaviour. Both of these genes are involved in oxidative stress metabolism, linking this pathway with anxiety-related behaviour.