Replication of a cis-syn thymine dimer at atomic resolution

Ultraviolet light damages DNA by catalysing covalent bond formation between adjacent pyrimidines, generating cis-syn cyclobutane pyrimidine dimers (CPDs) as the most common lesion. CPDs block DNA replication by high-fidelity DNA polymerases, but they can be efficiently bypassed by the Y-family DNA polymerase pol eta. Mutations in POLH encoding pol eta are implicated in nearly 20% of xeroderma pigmentosum, a human disease characterized by extreme sensitivity to sunlight and predisposition to skin cancer. Here we have determined two crystal structures of Dpo4, an archaeal pol eta homologue, complexed with CPD-containing DNA, where the 3' and 5' thymine of the CPD separately serves as a templating base. The 3' thymine of the CPD forms a Watson-Crick base pair with the incoming dideoxyATP, but the 5' thymine forms a Hoogsteen base pair with the dideoxyATP in syn conformation. Dpo4 retains a similar tertiary structure, but each unusual DNA structure is individually fitted into the active site for catalysis. A model of the pol eta-CPD complex built from the crystal structures of Saccharomyces cerevisiae apo-pol eta and the Dpo4-CPD complex suggests unique features that allow pol eta to efficiently bypass CPDs.     

Microscopic electronic inhomogeneity in the high-Tc superconductor Bi2Sr2CaCu2O8+x

The parent compounds of the copper oxide high-transition-temperature (high-Tc) superconductors are unusual insulators (so-called Mott insulators). Superconductivity arises when they are 'doped' away from stoichiometry. For the compound Bi2Sr2CaCu2O8+x, doping is achieved by adding extra oxygen atoms, which introduce positive charge carriers ('holes') into the CuO2 planes where the superconductivity is believed to originate. Aside from providing the charge carriers, the role of the oxygen dopants is not well understood, nor is it clear how the charge carriers are distributed on the planes. Many models of high-Tc superconductivity accordingly assume that the introduced carriers are distributed uniformly, leading to an electronically homogeneous system as in ordinary metals. Here we report the presence of an electronic inhomogeneity in Bi2Sr2CaCu2O8+x, on the basis of observations using scanning tunnelling microscopy and spectroscopy. The inhomogeneity is manifested as spatial variations in both the local density of states spectrum and the superconducting energy gap. These variations are correlated spatially and vary on the surprisingly short length scale of approximately 14 A. Our analysis suggests that this inhomogeneity is a consequence of proximity to a Mott insulator resulting in poor screening of the charge potentials associated with the oxygen ions left in the BiO plane after doping, and is indicative of the local nature of the superconducting state.     

Ethanol preference in rats with a prior history of acetaldehyde self-administration

Peripherally self-injected acetaldehyde in interaction with environmental and nutritional variables significantly enhances alcohol drinking in rats and suggests an involvement of acetaldehyde in voluntary alcohol intake.     

激光光散射及荧光光谱法研究金属离子对牛磺胆酸钠胶团性质的影响

采用激光光散射的方法，研究了Ｃａ￣（２＋）、Ｌａ￣（３＋）、Ｅｕ￣（３＋）存在下，ＮａＴＣ胶团及其与胆固醇、卵磷脂形成的混合胶团平均流体力学半径变化，发现金属离子能使胶团长大，并对胶团的结构及对胆固醇的增溶性有影响。以芘为荧光探针，研究了Ｃａ￣（２＋）、Ｌａ￣（３＋）离子对胶团内部微极性的影响，及通过Ｅｕ￣（３＋）的荧光光谱表征其配位场特征，证明金属离子与胆盐胶团间相互作用发生在胶团的表面。     

Variance intervention

Variance intervention is a simple state-space approach to handling sharp discontinuities of level or slope in the states or parameters of models for non-stationary time-series. It derives from earlier procedures used in the 1960s for the design of self-adaptive, state variable feedback control systems. In the alternative state-space forecasting context considered in the present paper, it is particularly useful when applied to structural time series models. The paper compares the variance intervention procedure with the related ‘subjective intervention’ approach proposed by West and Harrison in a recent issue of the Journal of Forecasting, and demonstrates it efficacy by application to various time-series data, including those used by West and Harrison.     

Pluralism, Economic Rhetoric, and Common Property

This paper presents a preliminary discussion of different ideological traditions of economic thought. The philosophical foundations and methodological implications of neoclassical, institutional, and neo-Marxist political economy are discussed by building upon the "system of systems methodologies" as a starting "modelling space". Drawing upon postmodern discourses, this typology is used as a rhetorical tool to assist with clear exposition. Two general applications are discussed, firstly a conceptual application to some contemporary perspectives of common property, and secondly a practical application to questions of investment in stormwater and wastewater. It is concluded that previously unrecognised common ground can emerge from attempts to communicate across traditional organisational and ideological divides.     

Energy-dependent regulation of cell structure by AMP-activated protein kinase

AMP-activated protein kinase (AMPK, also known as SNF1A) has been primarily studied as a metabolic regulator that is activated in response to energy deprivation. Although there is relatively ample information on the biochemical characteristics of AMPK, not enough data exist on the in vivo function of the kinase. Here, using the Drosophila model system, we generated the first animal model with no AMPK activity and discovered physiological functions of the kinase. Surprisingly, AMPK-null mutants were lethal with severe abnormalities in cell polarity and mitosis, similar to those of lkb1-null mutants. Constitutive activation of AMPK restored many of the phenotypes of lkb1-null mutants, suggesting that AMPK mediates the polarity- and mitosis-controlling functions of the LKB1 serine/threonine kinase. Interestingly, the regulatory site of non-muscle myosin regulatory light chain (MRLC; also known as MLC2) was directly phosphorylated by AMPK. Moreover, the phosphomimetic mutant of MRLC rescued the AMPK-null defects in cell polarity and mitosis, suggesting MRLC is a critical downstream target of AMPK. Furthermore, the activation of AMPK by energy deprivation was sufficient to cause dramatic changes in cell shape, inducing complete polarization and brush border formation in the human LS174T cell line, through the phosphorylation of MRLC. Taken together, our results demonstrate that AMPK has highly conserved roles across metazoan species not only in the control of metabolism, but also in the regulation of cellular structures.