Genomics and epigenomics: new promises of personalized medicine for cancer patients

Recent years have brought about a marked extension of our understanding of the somatic basis of cancer. Parallel to the large-scale investigation of diverse tumor genomes the knowledge arose that cancer pathologies are most often not restricted to single genomic events. In contrast, a large number of different alterations in the genomes and epigenomes come together and promote the malignant transformation. The combination of mutations, structural variations and epigenetic alterations differs between each tumor, making individual diagnosis and treatment strategies necessary. This view is summarized in the new discipline of personalized medicine. To satisfy the ideas of this approach each tumor needs to be fully characterized and individual diagnostic and therapeutic strategies designed. Here, we will discuss the power of high-throughput sequencing technologies for genomic and epigenomic analyses. We will provide insight into the current status and how these technologies can be transferred to routine clinical usage

evolution, structure and function of metazoan splicing factor PRPF39

In the yeast U1 snRNP the Prp39/Prp42 heterodimer is essential for early steps of spliceosome assembly. In metazoans no Prp42 ortholog exists, raising the question how the heterodimer is functionally substituted. Here we present the crystal structure of murine PRPF39, which forms a homodimer. Structure-guided point mutations disrupt dimer formation and inhibit splicing, manifesting the homodimer as functional unit. PRPF39 expression is controlled by NMD-inducing alternative splicing in mice and human, suggesting a role in adapting splicing efficiency to cell type specific requirements. A phylogenetic analysis reveals coevolution of shortened U1 snRNA and the absence of Prp42, which correlates with overall splicing complexity in different fungi. While current models correlate the diversity of spliceosomal proteins with splicing complexity, our study highlights a contrary case. We find that organisms with higher splicing complexity have substituted the Prp39/Prp42 heterodimer with a PRPF39 homodimer

The Effect of Flow at Maud Rise on the Sea Ice Cover - Numerical Experiments

The role of seamounts in the formation and evolution of sea ice isinvestigated in a series of numerical experiments with a coupled seaice-ocean model. Bottom topography, stratification and forcing areconfigured for the Maud Rise region in the Weddell Sea. The specificflow regime that develops at the seamount as the combined response tosteady and tidal forcing consists of free and trapped waves and aTaylor column, which is caused by mean flow and tidal flowrectification. The enhanced variability through tidal motion inparticular is capable of modifying the mixed layer above the seamountenough to delay and reduce sea ice formation throughout the winter.The induced sea ice anomaly spreads and moves westward and affects anarea of several 100~000 km$^{2}$. Process studies reveal the complexinteraction between wind, steady and periodic ocean currents: allthree are required in the process of generation of the sea ice andmixed layer anomalies (mainly through tidal flow), their detachmentfrom the topography (caused by steady oceanic flow), and the westwardtranslation of the sea ice anomaly (driven by the time-mean wind)

Correction to: The hidden therapist: evidence for a central role of music in psychedelic therapy.

The article The hidden therapist: evidence for a central role of music in psychedelic therapy, written by Mendel Kaelen, Bruna Giribaldi, Jordan Raine, Lisa Evans, Christopher Timmerman, Natalie Rodriguez, Leor Roseman, Amanda Feilding, David Nutt, Robin Carhart-Harris, was originally published electronically on the publisher's internet portal

Nonlinear dimensionality reduction in climate data

Linear methods of dimensionality reduction are useful tools for handling and interpreting high dimensional data. However, the cumulative variance explained by each of the subspaces in which the data space is decomposed may show a slow convergence that makes the selection of a proper minimum number of subspaces for successfully representing the variability of the process ambiguous. The use of nonlinear methods can improve the embedding of multivariate data into lower dimensional manifolds. In this article, a nonlinear method for dimensionality reduction, Isomap, is applied to the sea surface temperature and thermocline data in the tropical Pacific Ocean, where the El Niño-Southern Oscillation (ENSO) phenomenon and the annual cycle phenomena interact. Isomap gives a more accurate description of the manifold dimensionality of the physical system. The knowledge of the minimum number of dimensions is expected to improve the development of low dimensional models for understanding and predicting ENSO

Data-Efficient Iterative Training of Gaussian Approximation Potentials: Application to Surface Structure Determination of Rutile IrO₂ and RuO₂

Machine-learning interatomic potentials like Gaussian Approximation Potentials (GAPs) constitute a powerful class of surrogate models to computationally involved first-principles calculations. At similar predictive quality but significantly reduced cost, they could leverage otherwise barely tractable extensive sampling as in global surface structure determination (SSD). This efficiency is jeopardized though, if an a priori unknown structural and chemical search space as in SSD requires an excessive number of first-principles data for the GAP training.To this end, we present a general and data-efficient iterative training protocol that blends the creation of new training data with the actual surface exploration process. Demonstrating this protocol with the SSD of low-index facets of rutile IrO2 and RuO2 , the involved simulated annealing on the basis of the refining GAP identifies a number of unknown terminations even in the restricted sub-space of (1×1) surface unit-cells. Especially in an O-poor environment, some of these, then metal-rich terminations, are thermodynamically most stable and are reminiscent of complexions as discussed for complex ceramic materials

Sensitivity of the Atlantic meridional overturning circulation to South Atlantic freshwater anomalies

The sensitivity of the Atlantic Meridional Overturning Circulation (AMOC) to changes in basin integrated net evaporation is highly dependent on the zonal salinity contrast at the southern border of the Atlantic. Biases in the freshwater budget strongly affect the stability of the AMOC in numerical models. The impact of these biases is investigated, by adding local anomaly patterns in the South Atlantic to the freshwater fluxes at the surface. These anomalies impact the freshwater and salt transport by the different components of the ocean circulation, in particular the basin-scale salt-advection feedback, completely changing the response of the AMOC to arbitrary perturbations. It is found that an appropriate dipole anomaly pattern at the southern border of the Atlantic Ocean can collapse the AMOC entirely even without a further hosing. The results suggest a new view on the stability of the AMOC, controlled by processes in the South Atlantic. <br/

Interferometry of direct photons in Pb+Pb collisions at 158 AGeV

We present final results from the WA98 experiment which provide first measurements of Bose-Einstein correlations of direct photons in ultrarelativistic heavy ion collisions. Invariant interferometric radii were extracted in the range $100<K_T<300$ MeV/c and compared to interferometric radii of charged pions. The yield of direct photons for $100<p_T<300$ MeV/c was extracted from the correlation strength parameter and compared to the yield of direct photons measured in WA98 at higher $p_T$ with the statistical subtraction method, and to predictions of a fireball model.Comment: 4 pages, 3 figures, proceedings for Quark Matter 200