Mouse ooplasm confers context-specific reprogramming capacity

Enucleated oocytes have the distinctive ability to reprogram somatic nuclei back to totipotency. Here, we investigate genome-scale DNA methylation patterns after nuclear transfer and compare them to the dynamics at fertilization. We identify specific targets for DNA demethylation after nuclear transfer, such as germline-associated promoters, as well as unique limitations that include certain repetitive element classes.     

Chimaeric sounds reveal dichotomies in auditory perception

By Fourier's theorem, signals can be decomposed into a sum of sinusoids of different frequencies. This is especially relevant for hearing, because the inner ear performs a form of mechanical Fourier transform by mapping frequencies along the length of the cochlear partition. An alternative signal decomposition, originated by Hilbert, is to factor a signal into the product of a slowly varying envelope and a rapidly varying fine time structure. Neurons in the auditory brainstem sensitive to these features have been found in mammalian physiological studies. To investigate the relative perceptual importance of envelope and fine structure, we synthesized stimuli that we call 'auditory chimaeras', which have the envelope of one sound and the fine structure of another. Here we show that the envelope is most important for speech reception, and the fine structure is most important for pitch perception and sound localization. When the two features are in conflict, the sound of speech is heard at a location determined by the fine structure, but the words are identified according to the envelope. This finding reveals a possible acoustic basis for the hypothesized 'what' and 'where' pathways in the auditory cortex.     

Interception of comet Hyakutake's ion tail at a distance of 500 million kilometres

Remote sensing observations and the direct sampling of material from a few comets have established the characteristic composition of cometary gas. This gas is ionized by solar ultraviolet radiation and the solar wind to form 'pick-up' ions, ions in a low ionization state that retain the same compositional signatures as the original gas. The pick-up ions are carried outward by the solar wind, and they could in principle be detected far from the coma (Sampling of pick-up ions has also been used to study interplanetary dust, Venus' tail and the interstellar medium.) Here we report the serendipitous detection of cometary pick-up ions, most probably associated with the tail of comet Hyakutake, at a distance of 3.4 AU from the nucleus. Previous observations have provided a wealth of physical and chemical information about a small sample of comets, but this detection suggests that remote sampling of comet compositions, and the discovery of otherwise invisible comets, may be possible.     

Synthetic biology: engineering Escherichia coli to see light

We have designed a bacterial system that is switched between different states by red light. The system consists of a synthetic sensor kinase that allows a lawn of bacteria to function as a biological film, such that the projection of a pattern of light on to the bacteria produces a high-definition (about 100 megapixels per square inch), two-dimensional chemical image. This spatial control of bacterial gene expression could be used to 'print' complex biological materials, for example, and to investigate signalling pathways through precise spatial and temporal control of their phosphorylation steps.     

Serum glutamic oxaloacetic transaminase after hepatic artery ligature

Zusammenfassung Bei Hunden verursacht die Ligatur der Arteria hepatica einen starken Anstieg der Serum-Glutaminsäure-Oxalessigsäure-Transaminase-Werte mit Maxima am dritten oder vierten Tag. Der Anstieg wird auf die bioptisch feststellbare Nekrose von Leberzellen zurückgeführt, die mit und ohne Verabreichung von Achromycin gleich stark ausgeprägt war.Die Wirkungsweise des Achromycins wird diskutiert und auf Parallelergebnisse an Patienten hingewiesen.     

Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.