Synthetic homeostatic materials with chemo-mechano-chemical self-regulation

Living organisms have unique homeostatic abilities, maintaining tight control of their local environment through interconversions of chemical and mechanical energy and self-regulating feedback loops organized hierarchically across many length scales. In contrast, most synthetic materials are incapable of continuous self-monitoring and self-regulating behaviour owing to their limited single-directional chemomechanical or mechanochemical modes. Applying the concept of homeostasis to the design of autonomous materials would have substantial impacts in areas ranging from medical implants that help stabilize bodily functions to 'smart' materials that regulate energy usage. Here we present a versatile strategy for creating self-regulating, self-powered, homeostatic materials capable of precisely tailored chemo-mechano-chemical feedback loops on the nano- or microscale. We design a bilayer system with hydrogel-supported, catalyst-bearing microstructures, which are separated from a reactant-containing 'nutrient' layer. Reconfiguration of the gel in response to a stimulus induces the reversible actuation of the microstructures into and out of the nutrient layer, and serves as a highly precise 'on/off' switch for chemical reactions. We apply this design to trigger organic, inorganic and biochemical reactions that undergo reversible, repeatable cycles synchronized with the motion of the microstructures and the driving external chemical stimulus. By exploiting a continuous feedback loop between various exothermic catalytic reactions in the nutrient layer and the mechanical action of the temperature-responsive gel, we then create exemplary autonomous, self-sustained homeostatic systems that maintain a user-defined parameter--temperature--in a narrow range. The experimental results are validated using computational modelling that qualitatively captures the essential features of the self-regulating behaviour and provides additional criteria for the optimization of the homeostatic function, subsequently confirmed experimentally. This design is highly customizable owing to the broad choice of chemistries, tunable mechanics and its physical simplicity, and may lead to a variety of applications in autonomous systems with chemo-mechano-chemical transduction at their core.     

RNA translocation and unwinding mechanism of HCV NS3 helicase and its coordination by ATP

Helicases are a ubiquitous class of enzymes involved in nearly all aspects of DNA and RNA metabolism. Despite recent progress in understanding their mechanism of action, limited resolution has left inaccessible the detailed mechanisms by which these enzymes couple the rearrangement of nucleic acid structures to the binding and hydrolysis of ATP. Observing individual mechanistic cycles of these motor proteins is central to understanding their cellular functions. Here we follow in real time, at a resolution of two base pairs and 20 ms, the RNA translocation and unwinding cycles of a hepatitis C virus helicase (NS3) monomer. NS3 is a representative superfamily-2 helicase essential for viral replication, and therefore a potentially important drug target. We show that the cyclic movement of NS3 is coordinated by ATP in discrete steps of 11 +/- 3 base pairs, and that actual unwinding occurs in rapid smaller substeps of 3.6 +/- 1.3 base pairs, also triggered by ATP binding, indicating that NS3 might move like an inchworm. This ATP-coupling mechanism is likely to be applicable to other non-hexameric helicases involved in many essential cellular functions. The assay developed here should be useful in investigating a broad range of nucleic acid translocation motors.     

Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes

The glomerular filtration barrier in the kidney is formed in part by a specialized intercellular junction known as the slit diaphragm, which connects adjacent actin-based foot processes of kidney epithelial cells (podocytes). Mutations affecting a number of slit diaphragm proteins, including nephrin (encoded by NPHS1), lead to renal disease owing to disruption of the filtration barrier and rearrangement of the actin cytoskeleton, although the molecular basis for this is unclear. Here we show that nephrin selectively binds the Src homology 2 (SH2)/SH3 domain-containing Nck adaptor proteins, which in turn control the podocyte cytoskeleton in vivo. The cytoplasmic tail of nephrin has multiple YDxV sites that form preferred binding motifs for the Nck SH2 domain once phosphorylated by Src-family kinases. We show that this Nck-nephrin interaction is required for nephrin-dependent actin reorganization. Selective deletion of Nck from podocytes of transgenic mice results in defects in the formation of foot processes and in congenital nephrotic syndrome. Together, these findings identify a physiological signalling pathway in which nephrin is linked through phosphotyrosine-based interactions to Nck adaptors, and thus to the underlying actin cytoskeleton in podocytes. Simple and widely expressed SH2/SH3 adaptor proteins can therefore direct the formation of a specialized cellular morphology in vivo.     

Magma-maintained rift segmentation at continental rupture in the 2005 Afar dyking episode

Seafloor spreading centres show a regular along-axis segmentation thought to be produced by a segmented magma supply in the passively upwelling mantle. On the other hand, continental rifts are segmented by large offset normal faults, and many lack magmatism. It is unclear how, when and where the ubiquitous segmented melt zones are emplaced during the continental rupture process. Between 14 September and 4 October 2005, 163 earthquakes (magnitudes greater than 3.9) and a volcanic eruption occurred within the approximately 60-km-long Dabbahu magmatic segment of the Afar rift, a nascent seafloor spreading centre in stretched continental lithosphere. Here we present a three-dimensional deformation field for the Dabbahu rifting episode derived from satellite radar data, which shows that the entire segment ruptured, making it the largest to have occurred on land in the era of satellite geodesy. Simple elastic modelling shows that the magmatic segment opened by up to 8 m, yet seismic rupture can account for only 8 per cent of the observed deformation. Magma was injected along a dyke between depths of 2 and 9 km, corresponding to a total intrusion volume of approximately 2.5 km3. Much of the magma appears to have originated from shallow chambers beneath Dabbahu and Gabho volcanoes at the northern end of the segment, where an explosive fissural eruption occurred on 26 September 2005. Although comparable in magnitude to the ten year (1975-84) Krafla events in Iceland, seismic data suggest that most of the Dabbahu dyke intrusion occurred in less than a week. Thus, magma intrusion via dyking, rather than segmented normal faulting, maintains and probably initiated the along-axis segmentation along this sector of the Nubia-Arabia plate boundary.     

基于收益管理的班轮联盟舱位互换与分配优化

运用收益管理原理方法,研究了联盟条件下班轮公司舱位互换与分配问题,构建了综合考虑班轮联盟多条航线、不同种类和不同尺寸的集装箱等因素的舱位互换与分配随机优化共赢模型,运用机会约束方法加以求解,算例分析验证了模型和算法的适用性和有效性,结果表明舱位互换与分配优化可以明显地提高班轮联盟的总收益,联盟内舱位互换与分配数量及其总收益与合同客户需求量呈负相关、与现货市场需求量呈正相关,从而可为班轮公司制定舱位互换与分配策略提供科学的决策参考.     

Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2

TET2 is a close relative of TET1, an enzyme that converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) in DNA. The gene encoding TET2 resides at chromosome 4q24, in a region showing recurrent microdeletions and copy-neutral loss of heterozygosity (CN-LOH) in patients with diverse myeloid malignancies. Somatic TET2 mutations are frequently observed in myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), MDS/MPN overlap syndromes including chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemias (AML) and secondary AML (sAML). We show here that TET2 mutations associated with myeloid malignancies compromise catalytic activity. Bone marrow samples from patients with TET2 mutations displayed uniformly low levels of 5hmC in genomic DNA compared to bone marrow samples from healthy controls. Moreover, small hairpin RNA (shRNA)-mediated depletion of Tet2 in mouse haematopoietic precursors skewed their differentiation towards monocyte/macrophage lineages in culture. There was no significant difference in DNA methylation between bone marrow samples from patients with high 5hmC versus healthy controls, but samples from patients with low 5hmC showed hypomethylation relative to controls at the majority of differentially methylated CpG sites. Our results demonstrate that Tet2 is important for normal myelopoiesis, and suggest that disruption of TET2 enzymatic activity favours myeloid tumorigenesis. Measurement of 5hmC levels in myeloid malignancies may prove valuable as a diagnostic and prognostic tool, to tailor therapies and assess responses to anticancer drugs.     

Generalization of the linguistic aggregation operator and its application in decision making

A generalization of the linguistic aggregation functions (or operators) is presented by using generalized and quasiarithmetic means.Firstly,the linguistic weighted generalized mean (LWGM) and the linguistic generalized ordered weighted averaging (LGOWA) operator are introduced.These aggregation functions use linguistic information and generalized means in the weighted average (WA) and in the ordered weighted averaging (OWA) function.They are very useful for uncertain situations where the available information cannot be assessed with numerical values but it is possible to use linguistic assessments.These aggregation operators generalize a wide range of aggregation operators that use linguistic information such as the linguistic generalized mean (LGM),the linguistic OWA (LOWA) operator and the linguistic ordered weighted quadratic averaging (LOWQA) operator.We also introduce a further generalization by using quasi-arithmetic means instead of generalized means obtaining the quasi-LWA and the quasi-LOWA operator.Finally,we develop an application of the new approach where we analyze a decision making problem regarding the selection of strategies.     

Eukaryotic initiation factor 6 is rate-limiting in translation, growth and transformation

Cell growth and proliferation require coordinated ribosomal biogenesis and translation. Eukaryotic initiation factors (eIFs) control translation at the rate-limiting step of initiation. So far, only two eIFs connect extracellular stimuli to global translation rates: eIF4E acts in the eIF4F complex and regulates binding of capped messenger RNA to 40S subunits, downstream of growth factors, and eIF2 controls loading of the ternary complex on the 40S subunit and is inhibited on stress stimuli. No eIFs have been found to link extracellular stimuli to the activity of the large 60S ribosomal subunit. eIF6 binds 60S ribosomes precluding ribosome joining in vitro. However, studies in yeasts showed that eIF6 is required for ribosome biogenesis rather than translation. Here we show that mammalian eIF6 is required for efficient initiation of translation, in vivo. eIF6 null embryos are lethal at preimplantation. Heterozygous mice have 50% reduction of eIF6 levels in all tissues, and show reduced mass of hepatic and adipose tissues due to a lower number of cells and to impaired G1/S cell cycle progression. eIF6(+/-) cells retain sufficient nucleolar eIF6 and normal ribosome biogenesis. The liver of eIF6(+/-) mice displays an increase of 80S in polysomal profiles, indicating a defect in initiation of translation. Consistently, isolated hepatocytes have impaired insulin-stimulated translation. Heterozygous mouse embryonic fibroblasts recapitulate the organism phenotype and have normal ribosome biogenesis, reduced insulin-stimulated translation, and delayed G1/S phase progression. Furthermore, eIF6(+/-) cells are resistant to oncogene-induced transformation. Thus, eIF6 is the first eIF associated with the large 60S subunit that regulates translation in response to extracellular signals.