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An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Activation of the aryl hydrocarbon receptor (AHR) by environmental xenobiotic toxic chemicals, for instance 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), has been implicated in a variety of cellular processes such as embryogenesis, transformation, tumorigenesis and inflammation. But the identity of an endogenous ligand activating the AHR under physiological conditions in the absence of environmental toxic chemicals is still unknown. Here we identify the tryptophan (Trp) catabolite kynurenine (Kyn) as an endogenous ligand of the human AHR that is constitutively generated by human tumour cells via tryptophan-2,3-dioxygenase (TDO), a liver- and neuron-derived Trp-degrading enzyme not yet implicated in cancer biology. TDO-derived Kyn suppresses antitumour immune responses and promotes tumour-cell survival and motility through the AHR in an autocrine/paracrine fashion. The TDO-AHR pathway is active in human brain tumours and is associated with malignant progression and poor survival. Because Kyn is produced during cancer progression and inflammation in the local microenvironment in amounts sufficient for activating the human AHR, these results provide evidence for a previously unidentified pathophysiological function of the AHR with profound implications for cancer and immune biology.     

Tree-ring based PDSI reconstruction since AD 1842 in the Ortindag Sand Land, east Inner Mongolia

epartment of Wood Science, University of Hamburg, Hamburg D-21031, GermanyBased on three Chinese pine (Pinus tabulaeformis Carr.) and one Meyer spruce (Picea meyeri Rehd. et Wils.) ring-width chronologies, a 163-year drought history was reconstructed in the eastern Ortindag Sand Land. All tree-ring chronologies show large inter-annual variations and strong common signals and fairly consistent variation between different chronologies, indicating that they are excellent proxy of regional climate. A regional chronology (RC) was established by averaging the four standard chronologies and further employed for the analysis and climatic reconstruction. The analysis revealed that tree growth is primarily limited by low precipitation in February-March and June-July and high temperature in May-July. In addition, RC has high correlations with the monthly Palmer drought severity index (PDSI) prior to and during the growing season because the PDSI considers the accumulation of the droughts. Response function analysis revealed that RC only exhibits significant correlations with the PDSI in June and July (close to the 95% significance level in May). Because May―July is a critical period for tree growth, the average May-July PDSI (PDSI5-7) was reconstructed back to 1842 using RC in the Ortindag Sand Land. The reconstruction can explain 52% of the PDSI variance and the equation was rather stable over time. It agrees well with the variation of the average dryness/wetness indices in North China,and captures the decline process of the East Asian summer monsoon since the mid-1960s. It is worth noting that the Ortindag Sand Land has experienced the most severe drought in the recent 40 years based on the 163-year drought reconstruction. Like summer precipitation in North China the reconstructed PDSI5-7 also displays a 20-year oscillation.     

A stomatin-domain protein essential for touch sensation in the mouse

Touch and mechanical pain are first detected at our largest sensory surface, the skin. The cell bodies of sensory neurons that detect such stimuli are located in the dorsal root ganglia, and subtypes of these neurons are specialized to detect specific modalities of mechanical stimuli. Molecules have been identified that are necessary for mechanosensation in invertebrates but so far not in mammals. In Caenorhabditis elegans, mec-2 is one of several genes identified in a screen for touch insensitivity and encodes an integral membrane protein with a stomatin homology domain. Here we show that about 35% of skin mechanoreceptors do not respond to mechanical stimuli in mice with a mutation in stomatin-like protein 3 (SLP3, also called Stoml3), a mammalian mec-2 homologue that is expressed in sensory neurons. In addition, mechanosensitive ion channels found in many sensory neurons do not function without SLP3. Tactile-driven behaviours are also impaired in SLP3 mutant mice, including touch-evoked pain caused by neuropathic injury. SLP3 is therefore indispensable for the function of a subset of cutaneous mechanoreceptors, and our data support the idea that this protein is an essential subunit of a mammalian mechanotransducer.     

Radioactive 26Al from massive stars in the Galaxy

Gamma-rays from radioactive 26Al (half-life approximately 7.2 x 10(5) years) provide a 'snapshot' view of continuing nucleosynthesis in the Galaxy. The Galaxy is relatively transparent to such gamma-rays, and emission has been found concentrated along its plane. This led to the conclusion that massive stars throughout the Galaxy dominate the production of 26Al. On the other hand, meteoritic data show evidence for locally produced 26Al, perhaps from spallation reactions in the protosolar disk. Furthermore, prominent gamma-ray emission from the Cygnus region suggests that a substantial fraction of Galactic 26Al could originate in localized star-forming regions. Here we report high spectral resolution measurements of 26Al emission at 1808.65 keV, which demonstrate that the 26Al source regions corotate with the Galaxy, supporting its Galaxy-wide origin. We determine a present-day equilibrium mass of 2.8 (+/- 0.8) solar masses of 26Al. We use this to determine that the frequency of core collapse (that is, type Ib/c and type II) supernovae is 1.9 (+/- 1.1) events per century.     

Control of four stereocentres in a triple cascade organocatalytic reaction

Efficient and elegant syntheses of complex organic molecules with multiple stereogenic centres continue to be important in both academic and industrial laboratories. In particular, catalytic asymmetric multi-component 'domino' reactions, used during total syntheses of natural products and synthetic building blocks, are highly desirable. These reactions avoid time-consuming and costly processes, including the purification of intermediates and steps involving the protection and deprotection of functional groups, and they are environmentally friendly and often proceed with excellent stereoselectivities. Therefore, the design of new catalytic and stereoselective cascade reactions is a continuing challenge at the forefront of synthetic chemistry. In addition, catalytic cascade reactions can be described as biomimetic, as they are reminiscent of tandem reactions that may occur during biosyntheses of complex natural products. Here we report the development of an asymmetric organocatalytic triple cascade reaction for the synthesis of tetra-substituted cyclohexene carbaldehydes. This three-component domino reaction proceeds by way of a catalysed Michael/Michael/aldol condensation sequence affording the products with good to moderate yields (25-58 per cent). During this sequence, four stereogenic centres are formed with high diastereoselectivity and complete enantioselectivity. In addition, variation of the starting materials can be used to obtain diverse polyfunctional cyclohexene derivatives, which can be used as building blocks in organic synthesis.