Heat activation of TRPM5 underlies thermal sensitivity of sweet taste

TRPM5, a cation channel of the TRP superfamily, is highly expressed in taste buds of the tongue, where it has a key role in the perception of sweet, umami and bitter tastes. Activation of TRPM5 occurs downstream of the activation of G-protein-coupled taste receptors and is proposed to generate a depolarizing potential in the taste receptor cells. Factors that modulate TRPM5 activity are therefore expected to influence taste. Here we show that TRPM5 is a highly temperature-sensitive, heat-activated channel: inward TRPM5 currents increase steeply at temperatures between 15 and 35 degrees C. TRPM4, a close homologue of TRPM5, shows similar temperature sensitivity. Heat activation is due to a temperature-dependent shift of the activation curve, in analogy to other thermosensitive TRP channels. Moreover, we show that increasing temperature between 15 and 35 degrees C markedly enhances the gustatory nerve response to sweet compounds in wild-type but not in Trpm5 knockout mice. The strong temperature sensitivity of TRPM5 may underlie known effects of temperature on perceived taste in humans, including enhanced sweetness perception at high temperatures and 'thermal taste', the phenomenon whereby heating or cooling of the tongue evoke sensations of taste in the absence of tastants.     

Observation of a pairing pseudogap in a two-dimensional Fermi gas

Pairing of fermions is ubiquitous in nature, underlying many phenomena. Examples include superconductivity, superfluidity of (3)He, the anomalous rotation of neutron stars, and the crossover between Bose-Einstein condensation of dimers and the BCS (Bardeen, Cooper and Schrieffer) regime in strongly interacting Fermi gases. When confined to two dimensions, interacting many-body systems show even more subtle effects, many of which are not understood at a fundamental level. Most striking is the (as yet unexplained) phenomenon of high-temperature superconductivity in copper oxides, which is intimately related to the two-dimensional geometry of the crystal structure. In particular, it is not understood how the many-body pairing is established at high temperature, and whether it precedes superconductivity. Here we report the observation of a many-body pairing gap above the superfluid transition temperature in a harmonically trapped, two-dimensional atomic Fermi gas in the regime of strong coupling. Our measurements of the spectral function of the gas are performed using momentum-resolved photoemission spectroscopy, analogous to angle-resolved photoemission spectroscopy in the solid state. Our observations mark a significant step in the emulation of layered two-dimensional strongly correlated superconductors using ultracold atomic gases.     

Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease

Machado-Joseph disease (MJD; also called spinocerebellar ataxia type 3) is a dominantly inherited late-onset neurodegenerative disorder caused by expansion of polyglutamine (polyQ)-encoding CAG repeats in the MJD1 gene (also known as ATXN3). Proteolytic liberation of highly aggregation-prone polyQ fragments from the protective sequence of the MJD1 gene product ataxin 3 (ATXN3) has been proposed to trigger the formation of ATXN3-containing aggregates, the neuropathological hallmark of MJD. ATXN3 fragments are detected in brain tissue of MJD patients and transgenic mice expressing mutant human ATXN3(Q71), and their amount increases with disease severity, supporting a relationship between ATXN3 processing and disease progression. The formation of early aggregation intermediates is thought to have a critical role in disease initiation, but the precise pathogenic mechanism operating in MJD has remained elusive. Here we show that L-glutamate-induced excitation of patient-specific induced pluripotent stem cell (iPSC)-derived neurons initiates Ca(2+)-dependent proteolysis of ATXN3 followed by the formation of SDS-insoluble aggregates. This phenotype could be abolished by calpain inhibition, confirming a key role of this protease in ATXN3 aggregation. Aggregate formation was further dependent on functional Na(+) and K(+) channels as well as ionotropic and voltage-gated Ca(2+) channels, and was not observed in iPSCs, fibroblasts or glia, thereby providing an explanation for the neuron-specific phenotype of this disease. Our data illustrate that iPSCs enable the study of aberrant protein processing associated with late-onset neurodegenerative disorders in patient-specific neurons.     

Use of ionic liquid in leaching process of brass wastes for copper and zinc recovery

Brass ash from the industrial brass manufacturer in Turkey was leached using the solutions of ionic liquid (IL) 1-butyl-3-methyl-imidazolium hydrogen sulfate ([bmim]HSO₄) at ambient pressure in the presence of hydrogen peroxide (H₂O₂) and potassium peroxymonosulfate (oxone) as the oxidants. Parameters affecting leaching efficiency, such as dissolution time, IL concentration, and oxidizing agent addition, were investigated. The results show that [bmim]HSO₄ is an efficient IL for the brass ash leaching, providing the dissolution efficiencies of 99% for Zn and 24.82% for Cu at a concentration of 50vol% [bmim]HSO₄ in the aqueous solution without any oxidant. However, more than 99% of zinc and 82% of copper are leached by the addition of 50vol% H₂O₂ to the [bmim]HSO₄ solution. Nevertheless, the oxone does not show the promising oxidant behavior in leaching using [bmim]HSO₄.     

Structure and nucleic-acid binding of the Drosophila Argonaute 2 PAZ domain

RNA interference is a conserved mechanism that regulates gene expression in response to the presence of double-stranded (ds)RNAs. The RNase III-like enzyme Dicer first cleaves dsRNA into 21-23-nucleotide small interfering RNAs (siRNAs). In the effector step, the multimeric RNA-induced silencing complex (RISC) identifies messenger RNAs homologous to the siRNAs and promotes their degradation. The Argonaute 2 protein (Ago2) is a critical component of RISC. Both Argonaute and Dicer family proteins contain a common PAZ domain whose function is unknown. Here we present the three-dimensional nuclear magnetic resonance structure of the Drosophila melanogaster Ago2 PAZ domain. This domain adopts a nucleic-acid-binding fold that is stabilized by conserved hydrophobic residues. The nucleic-acid-binding patch is located in a cleft between the surface of a central beta-barrel and a conserved module comprising strands beta3, beta4 and helix alpha3. Because critical structural residues and the binding surface are conserved, we suggest that PAZ domains in all members of the Argonaute and Dicer families adopt a similar fold with nucleic-acid binding function, and that this plays an important part in gene silencing.     

Sinian-Cambrian stratigraphic framework for shallow- to deep-water environments of the Yangtze Platform: an integrated approach

The Sinian (Terminal Proterozoic) and Early Cambrian shallow- to deep-water sequences of the Yangtze Platform were investigated. Based on integrated lithostratigraphic, biostratigraphic, and other approaches, the shallow-water sequence from the base of the Sinian (base of the Doushantuo Formation) to the top of the Qiongzhusian (top of the Yu'anshan Formation) was subdivided into 12 stratigraphic intervals. These 12 intervals were applied in turn to the subdivision and correlation of the sequences present in various facies of the Yangtze Platform. The high-resolution stratigraphic framework here developed can serve as a time frame for ongoing multidisciplinary analyses of the "Cambrian explosion".     

Protective role of phospholipid oxidation products in endotoxin-induced tissue damage

Lipopolysaccharide (LPS), an outer-membrane component of Gram-negative bacteria, interacts with LPS-binding protein and CD14, which present LPS to toll-like receptor 4 (refs 1, 2), which activates inflammatory gene expression through nuclear factor kappa B (NF kappa B) and mitogen-activated protein-kinase signalling. Antibacterial defence involves activation of neutrophils that generate reactive oxygen species capable of killing bacteria; therefore host lipid peroxidation occurs, initiated by enzymes such as NADPH oxidase and myeloperoxidase. Oxidized phospholipids are pro-inflammatory agonists promoting chronic inflammation in atherosclerosis; however, recent data suggest that they can inhibit expression of inflammatory adhesion molecules. Here we show that oxidized phospholipids inhibit LPS-induced but not tumour-necrosis factor-alpha-induced or interleukin-1 beta-induced NF kappa B-mediated upregulation of inflammatory genes, by blocking the interaction of LPS with LPS-binding protein and CD14. Moreover, in LPS-injected mice, oxidized phospholipids inhibited inflammation and protected mice from lethal endotoxin shock. Thus, in severe Gram-negative bacterial infection, endogenously formed oxidized phospholipids may function as a negative feedback to blunt innate immune responses. Furthermore, identified chemical structures capable of inhibiting the effects of endotoxins such as LPS could be used for the development of new drugs for treatment of sepsis.