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41.
Extracellular electron transfer via microbial nanowires 总被引:8,自引:0,他引:8
Microbes that can transfer electrons to extracellular electron acceptors, such as Fe(iii) oxides, are important in organic matter degradation and nutrient cycling in soils and sediments. Previous investigations on electron transfer to Fe(iii) have focused on the role of outer-membrane c-type cytochromes. However, some Fe(iii) reducers lack c-cytochromes. Geobacter species, which are the predominant Fe(iii) reducers in many environments, must directly contact Fe(iii) oxides to reduce them, and produce monolateral pili that were proposed, on the basis of the role of pili in other organisms, to aid in establishing contact with the Fe(iii) oxides. Here we report that a pilus-deficient mutant of Geobacter sulfurreducens could not reduce Fe(iii) oxides but could attach to them. Conducting-probe atomic force microscopy revealed that the pili were highly conductive. These results indicate that the pili of G. sulfurreducens might serve as biological nanowires, transferring electrons from the cell surface to the surface of Fe(iii) oxides. Electron transfer through pili indicates possibilities for other unique cell-surface and cell-cell interactions, and for bioengineering of novel conductive materials. 相似文献
42.
The large ribosomal subunit catalyses the reaction between the alpha-amino group of the aminoacyl-tRNA bound to the A site and the ester carbon of the peptidyl-tRNA bound to the P site, while preventing the nucleophilic attack of water on the ester, which would lead to unprogrammed deacylation of the peptidyl-tRNA. Here we describe three new structures of the large ribosomal subunit of Haloarcula marismortui (Hma) complexed with peptidyl transferase substrate analogues that reveal an induced-fit mechanism in which substrates and active-site residues reposition to allow the peptidyl transferase reaction. Proper binding of an aminoacyl-tRNA analogue to the A site induces specific movements of 23S rRNA nucleotides 2618-2620 (Escherichia coli numbering 2583-2585) and 2541(2506), thereby reorienting the ester group of the peptidyl-tRNA and making it accessible for attack. In the absence of the appropriate A-site substrate, the peptidyl transferase centre positions the ester link of the peptidyl-tRNA in a conformation that precludes the catalysed nucleophilic attack by water. Protein release factors may also function, in part, by inducing an active-site rearrangement similar to that produced by the A-site aminoacyl-tRNA, allowing the carbonyl group and water to be positioned for hydrolysis. 相似文献
43.
Classical studies show that for many proteins, the information required for specifying the tertiary structure is contained in the amino acid sequence. Here, we attempt to define the sequence rules for specifying a protein fold by computationally creating artificial protein sequences using only statistical information encoded in a multiple sequence alignment and no tertiary structure information. Experimental testing of libraries of artificial WW domain sequences shows that a simple statistical energy function capturing coevolution between amino acid residues is necessary and sufficient to specify sequences that fold into native structures. The artificial proteins show thermodynamic stabilities similar to natural WW domains, and structure determination of one artificial protein shows excellent agreement with the WW fold at atomic resolution. The relative simplicity of the information used for creating sequences suggests a marked reduction to the potential complexity of the protein-folding problem. 相似文献
44.
R Straussman T Morikawa K Shee M Barzily-Rokni ZR Qian J Du A Davis MM Mongare J Gould DT Frederick ZA Cooper PB Chapman DB Solit A Ribas RS Lo KT Flaherty S Ogino JA Wargo TR Golub 《Nature》2012,487(7408):500-504
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. 相似文献
45.
46.
Peroxiredoxins are conserved markers of circadian rhythms 总被引:1,自引:0,他引:1
47.
M Liu HY Hwang H Tao AC Strikwerda K Fan GR Keiser AJ Sternbach KG West S Kittiwatanakul J Lu SA Wolf FG Omenetto X Zhang KA Nelson RD Averitt 《Nature》2012,487(7407):345-348
Electron-electron interactions can render an otherwise conducting material insulating, with the insulator-metal phase transition in correlated-electron materials being the canonical macroscopic manifestation of the competition between charge-carrier itinerancy and localization. The transition can arise from underlying microscopic interactions among the charge, lattice, orbital and spin degrees of freedom, the complexity of which leads to multiple phase-transition pathways. For example, in many transition metal oxides, the insulator-metal transition has been achieved with external stimuli, including temperature, light, electric field, mechanical strain or magnetic field. Vanadium dioxide is particularly intriguing because both the lattice and on-site Coulomb repulsion contribute to the insulator-to-metal transition at 340?K (ref. 8). Thus, although the precise microscopic origin of the phase transition remains elusive, vanadium dioxide serves as a testbed for correlated-electron phase-transition dynamics. Here we report the observation of an insulator-metal transition in vanadium dioxide induced by a terahertz electric field. This is achieved using metamaterial-enhanced picosecond, high-field terahertz pulses to reduce the Coulomb-induced potential barrier for carrier transport. A nonlinear metamaterial response is observed through the phase transition, demonstrating that high-field terahertz pulses provide alternative pathways to induce collective electronic and structural rearrangements. The metamaterial resonators play a dual role, providing sub-wavelength field enhancement that locally drives the nonlinear response, and global sensitivity to the local changes, thereby enabling macroscopic observation of the dynamics. This methodology provides a powerful platform to investigate low-energy dynamics in condensed matter and, further, demonstrates that integration of metamaterials with complex matter is a viable pathway to realize functional nonlinear electromagnetic composites. 相似文献
48.
Smith CC Wang Q Chin CS Salerno S Damon LE Levis MJ Perl AE Travers KJ Wang S Hunt JP Zarrinkar PP Schadt EE Kasarskis A Kuriyan J Shah NP 《Nature》2012,485(7397):260-263
Effective targeted cancer therapeutic development depends upon distinguishing disease-associated 'driver' mutations, which have causative roles in malignancy pathogenesis, from 'passenger' mutations, which are dispensable for cancer initiation and maintenance. Translational studies of clinically active targeted therapeutics can definitively discriminate driver from passenger lesions and provide valuable insights into human cancer biology. Activating internal tandem duplication (ITD) mutations in FLT3 (FLT3-ITD) are detected in approximately 20% of acute myeloid leukaemia (AML) patients and are associated with a poor prognosis. Abundant scientific and clinical evidence, including the lack of convincing clinical activity of early FLT3 inhibitors, suggests that FLT3-ITD probably represents a passenger lesion. Here we report point mutations at three residues within the kinase domain of FLT3-ITD that confer substantial in vitro resistance to AC220 (quizartinib), an active investigational inhibitor of FLT3, KIT, PDGFRA, PDGFRB and RET; evolution of AC220-resistant substitutions at two of these amino acid positions was observed in eight of eight FLT3-ITD-positive AML patients with acquired resistance to AC220. Our findings demonstrate that FLT3-ITD can represent a driver lesion and valid therapeutic target in human AML. AC220-resistant FLT3 kinase domain mutants represent high-value targets for future FLT3 inhibitor development efforts. 相似文献
49.
Genetic recombination occurs during meiosis, the key developmental programme of gametogenesis. Recombination in mammals has been recently linked to the activity of a histone H3 methyltransferase, PR domain containing 9 (PRDM9), the product of the only known speciation-associated gene in mammals. PRDM9 is thought to determine the preferred recombination sites--recombination hotspots--through sequence-specific binding of its highly polymorphic multi-Zn-finger domain. Nevertheless, Prdm9 knockout mice are proficient at initiating recombination. Here we map and analyse the genome-wide distribution of recombination initiation sites in Prdm9 knockout mice and in two mouse strains with different Prdm9 alleles and their F(1) hybrid. We show that PRDM9 determines the positions of practically all hotspots in the mouse genome, with the exception of the pseudo-autosomal region (PAR)--the only area of the genome that undergoes recombination in 100% of cells. Surprisingly, hotspots are still observed in Prdm9 knockout mice, and as in wild type, these hotspots are found at H3 lysine 4 (H3K4) trimethylation marks. However, in the absence of PRDM9, most recombination is initiated at promoters and at other sites of PRDM9-independent H3K4 trimethylation. Such sites are rarely targeted in wild-type mice, indicating an unexpected role of the PRDM9 protein in sequestering the recombination machinery away from gene-promoter regions and other functional genomic elements. 相似文献
50.
Food intake, energy expenditure and body adiposity are homeostatically regulated. Central and peripheral signals communicate information about the current state of energy balance to key brain regions, including the hypothalamus and brainstem. Hunger and satiety represent coordinated responses to these signals, which include neural and hormonal messages from the gut. In recent years our understanding of how neural and hormonal brain-gut signalling regulates energy homeostasis has advanced considerably. Gut hormones have various physiological functions that include specifically targeting the brain to regulate appetite. New research suggests that gut hormones can be used to specifically regulate energy homeostasis in humans, and offer a target for anti-obesity drugs. 相似文献