CCAAT/enhancer binding protein-alpha (C/EBP alpha) induces transdifferentiation of B cells into macrophages at high efficiencies and enhances reprogramming into induced pluripotent stem (iPS) cells when co-expressed with the transcription factors Oct4 (Pou5f1), Sox2, Klf4 and Myc (hereafter called OSKM)(1,2). However, how C/EBP alpha accomplishes these effects is unclear. Here we find that in mouse primary B cells transient C/EBP alpha expression followed by OSKM activation induces a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population. During this conversion, pluripotency and epithelial-mesenchymal transition genes become markedly upregulated, and 60% of the cells express Oct4 within 2 days. C/EBP alpha acts as a 'path-breaker' as it transiently makes the chromatin of pluripotency genes more accessible to DNase I. C/EBP alpha also induces the expression of the dioxygenase Tet2 and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated after OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM-induced B-cell reprogramming. Because the enzyme is also required for efficient C/EBP alpha-induced immune cell conversion(3), our data indicate that Tet2 provides a mechanistic link between iPS cell reprogramming and B-cell transdifferentiation. The rapid iPS reprogramming approach described here should help to fully elucidate the process and has potential clinical applications.

Genome-wide association studies (GWAS) have reproducibly associated variants within introns of FTO with increased risk for obesity and type 2 diabetes (T2D)(1-3). Although the molecular mechanisms linking these noncoding variants with obesity are not immediately obvious, subsequent studies in mice demonstrated that FTO expression levels influence body mass and composition phenotypes(4-6). However, no direct connection between the obesity-associated variants and FTO expression or function has been made(7-9). Here we show that the obesity-associated noncoding sequences within FTO are functionally connected, at megabase distances, with the homeobox gene IRX3. The obesity-associated FTO region directly interacts with the promoters of IRX3 as well as FTO in the human, mouse and zebrafish genomes. Furthermore, long-range enhancers within this region recapitulate aspects of IRX3 expression, suggesting that the obesity-associated interval belongs to the regulatory landscape of IRX3. Consistent with this, obesity-associated single nucleotide polymorphisms are associated with expression of IRX3, but not FTO, in human brains. A direct link between IRX3 expression and regulation of body mass and composition is demonstrated by a reduction in body weight of 25 to 30% in Irx3-deficient mice, primarily through the loss of fat mass and increase in basal metabolic rate with browning of white adipose tissue. Finally, hypothalamic expression of a dominant negative form of Irx3 reproduces the metabolic phenotypes of Irx3 deficient mice. Our data suggest that IRX3 is a functional long-range target of obesity-associated variants within FTO and represents a novel determinant of body mass and composition.

The next generation of radar (radio detection and ranging) systems needs to be based on software-defined radio to adapt to variable environments, with higher carrier frequencies for smaller antennas and broadened bandwidth for increased resolution(1-4). Today's digital microwave components (synthesizers and analogue-to-digital converters) suffer from limited bandwidth with high noise at increasing frequencies(5-7), so that fully digital radar systems can work up to only a few gigahertz, and noisy analogue up-and downconversions are necessary for higher frequencies. In contrast, photonics provide high precision and ultrawide bandwidth(8,9), allowing both the flexible generation of extremely stable radio-frequency signals with arbitrary waveforms up to millimetre waves(10-22), and the detection of such signals and their precise direct digitization without downconversion(23-26). Until now, the photonics-based generation and detection of radio-frequency signals have been studied separately and have not been tested in a radar system. Here we present the development and the field trial results of a fully photonics-based coherent radar demonstrator carried out within the project PHODIR27. The proposed architecture exploits a single pulsed laser for generating tunable radar signals and receiving their echoes, avoiding radio-frequency up-and downconversion and guaranteeing both the software-defined approach and high resolution. Its performance exceeds state-of-the-art electronics at carrier frequencies above two gigahertz, and the detection of non-cooperating aeroplanes confirms the effectiveness and expected precision of the system.

The key to explaining and controlling a range of quantum phenomena is to study how information propagates around many-body systems. Quantum dynamics can be described by particle-like carriers of information that emerge in the collective behaviour of the underlying system, the so-called quasiparticles(1). These elementary excitations are predicted to distribute quantum information in a fashion determined by the system's interactions(2). Here we report quasiparticle dynamics observed in a quantum many-body system of trapped atomic ions(3,4). First, we observe the entanglement distributed by quasiparticles as they trace out light-cone-like wavefronts(5-11). Second, using the ability to tune the interaction range in our system, we observe information propagation in an experimental regime where the effective-light-cone picture does not apply(7,12). Our results will enable experimental studies of a range of quantum phenomena, including transport(13,14), thermalization(15), localization(16) and entanglement growth(17), and represent a first step towards a newquantum-optic regime of engineered quasiparticles with tunable nonlinear interactions.

A central feature of quantum mechanics is that a measurement result is intrinsically probabilistic. Consequently, continuously monitoring a quantum system will randomly perturb its natural unitary evolution. The ability to control a quantum system in the presence of these fluctuations is of increasing importance in quantum information processing and finds application in fields ranging from nuclear magnetic resonance(1) to chemical synthesis(2). A detailed understanding of this stochastic evolution is essential for the development of optimized control methods. Here we reconstruct the individual quantum trajectories(3-5) of a superconducting circuit that evolves under the competing influences of continuous weak measurement and Rabi drive. By tracking individual trajectories that evolve between any chosen initial and final states, we can deduce the most probable path through quantum state space. These pre- and post-selected quantum trajectories also reveal the optimal detector signal in the form of a smooth, time-continuous function that connects the desired boundary conditions. Our investigation reveals the rich interplay between measurement dynamics, typically associated with wave function collapse, and unitary evolution of the quantum state as described by the Schrodinger equation. These results and the underlying theory(6), based on a principle of least action, reveal the optimal route from initial to final states, and may inform new quantum control methods for state steering and information processing.

Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2-20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 6005,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics.