Structural Biology of Bacterial Multidrug Resistance Gene Regulators

Multidrug resistance (mdr)1 can be defined broadly as the ability of a cell to survive ordinarily lethal doses of more than one drug. Clearly, such resistance is a critical problem in the treatment of fungal and bacterial infections and cancer. Four general, but nonexclusive, mechanisms give rise to multidrug resistance: 1) detoxification by enzymatic modification or cleavage of drug; 2) genetic alteration of the intra- or extracellular targets; 3) decreased permeability of the cell membrane; and 4) active drug extrusion by multidrug transporters. Paramount to our understanding of mdr is the issue of recognition of structurally dissimilar substrates and how drug binding effects function. In bacteria many multidrug transporters are regulated directly (locally) by transcription factors, which also bind the substrates of these transporters, i.e. the drug can act as a transcriptional coactivator or inducer. Multiple mdr transporter genes are also regulated globally by activators such as MarA that do not necessarily bind drugs (1). The regulators are of keen interest because they are more amenable to structural studies than the membrane-bound transporters and thus offer a greater chance to obtain high resolution views of multidrug binding. Moreover, the local gene regulators are equally interesting as their DNA complexes directly reveal the mechanism of mdrtransporter gene regulation. This minireview will summarize the structures of known bacterial mdr regulators. Because our focus is more structural the reader is referred to one of several recent reviews that discuss the more biological aspects of global and local mdr regulation (2-5)

Crystal Structure of MtaN, a Global Multidrug Transporter Gene Activator

MtaN (Multidrug Transporter Activation, N terminus) is a constitutive, transcriptionally active 109-residue truncation mutant, which contains only the N-terminal DNA-binding and dimerization domains of MerR family member Mta. The 2.75 Å resolution crystal structure of apo-MtaN reveals a winged helix-turn-helix protein with a protruding 8-turn helix (α5) that is involved in dimerization by the formation of an antiparallel coiled-coil. The hydrophobic core and helices α1 through α4 are structurally homologous to MerR family member BmrR bound to DNA, whereas one wing (Wing 1) is shifted. Differences between the orientation of α5 with respect to the core and the revolution of the antiparallel coiled-coil lead to significantly altered conformations of MtaN and BmrR dimers. These shifts result in a conformation of MtaN that appears to be incompatible with the transcription activation mechanism of BmrR and suggest that additional DNA-induced structural changes are necessary

FIIs and Indian Stock Market: A Causality Investigation

While the volatility associated with portfolio capital flows is well known, there is also a concern that foreign institutional investors might introduce distortions in the host country markets due to the pressure on them to secure capital gains. In this context, present chapter attempts to find out the direction of causality between foreign institutional investors (FIIs) and performance of Indian stock market. To facilitate a better understanding of the causal linkage between FII flows and contemporaneous stock market returns (BSE National Index), a period of nineteen consecutive financial years ranging from January 1992 to December 2010 is selected. Granger Causality Test has been applied to test the direction of causality.Aczkolwiek brak stabilności związany z przepływami kapitału portfelowego jest dobrze znany, to istnieje również obawa, że zagraniczni inwestorzy instytucjonalni mogą wprowadzać zakłócenia na rynkach krajów przyjmujących z uwagi na wywieraną na nich presję, aby zapewniać zyski kapitałowe. W tym kontekście niniejszy rozdział próbuje poznać kierunek przyczynowości pomiędzy zagranicznymi inwestorami instytucjonalnymi (FIIs) i działaniem indyjskiej giełdy. Aby ułatwić lepsze zrozumienie związku przyczynowego między przepływami FII i mającymi miejsce w tym samym czasie wynikami giełdy papierów wartościowych (BSE National Index), wybrany został okres dziewiętnastu kolejnych lat począwszy od stycznia 1992 do grudnia 2010. Do zbadania kierunku przyczynowości zastosowano test przyczynowości Grangera

Self-interest And Public Interest: The Motivations Of Political Actors

Self-Interest and Public Interest in Western Politics showed that the public, politicians, and bureaucrats are often public spirited. But this does not invalidate public-choice theory. Public-choice theory is an ideal type, not a claim that self-interest explains all political behavior. Instead, public-choice theory is useful in creating rules and institutions that guard against the worst case, which would be universal self-interestedness in politics. In contrast, the public-interest hypothesis is neither a comprehensive explanation of political behavior nor a sound basis for institutional design

Tetra­kis(1,2-dimethoxy­ethane-κ2 O,O′)ytterbium(II) bis­(μ2-phenyl­selenolato-κ2 Se:Se)bis­[bis­(phenyl­selenolato-κSe)mercurate(II)]

The title salt, [Yb(C4H10O2)4][Hg2(C6H5Se)6], consists of eight-coordinate homoleptic [Yb(DME)4]2+ dications (DME is 1,2-dimethoxy­ethane) countered with [Hg2(SePh)6]2− di­anions. The cations and anions have twofold rotation and inversion symmetry, respectively. The Yb centre displays a square-anti­prismatic coordination geometry and the Hg centre has a distorted tetra­hedral coordination environment. One phenyl­selenolate anion and one methyl group of a DME ligand are disordered over two positions with equal occupancies. This structure is unique in that it represents a less common mol­ecular lanthanide species in which the lanthanide ion is not directly bonded to an anionic ligand. There are no occurrences of the [Hg2(SePh)6]2− dianion in the Cambridge Structural Database (Version of November 2007), but there are similar oligomeric and polymeric Hgx(SePh)y species. The crystal structure is characterized by alternating layers of cations and anions stacked along the c axis

Memory and comprehension for health information among older adults: distinguishing the effects of domain-general and domain-specific knowledge

While there is evidence that knowledge influences understanding of health information, less is known about the processing mechanisms underlying this effect and its impact on memory. We used the moving window paradigm to examine how older adults varying in domain-general crystallised ability (verbal ability) and health knowledge allocate attention to understand health and domain-general texts. Participants (n = 107, age: 60-88 years) read and recalled single sentences about hypertension and about non-health topics. Mixed-effects modelling of word-by-word reading times suggested that domain-general crystallised ability increased conceptual integration regardless of text domain, while health knowledge selectively increased resource allocation to conceptual integration at clause boundaries in health texts. These patterns of attentional allocation were related to subsequent recall performance. Although older adults with lower levels of crystallised ability were less likely to engage in integrative processing, when they did, this strategy had a compensatory effect in improving recall. These findings suggest that semantic integration during reading is an important comprehension process that supports the construction of the memory representation and is engendered by knowledge. Implications of the findings for theories of text processing and memory as well as for designing patient education materials are discussed

The social, cosmopolitanism and beyond

First, this article will outline the metaphysics of ‘the social’ that implicitly and explicitly connects the work of lassical and contemporary cosmopolitan sociologists as different as Durkheim, Weber, Beck and Luhmann. In a second step, I will show that the cosmopolitan outlook of classical sociology is driven by exclusive differences. In understanding human affairs, both classical sociology and contemporary cosmopolitan sociology reflect a very modernist outlook of epistemological, conceptual, methodological and disciplinary rigour that separates the cultural sphere from the natural objects of concern. I will suggest that classical sociology – in order to be cosmopolitan – is forced (1) to exclude non-social and non-human objects as part of its conceptual and methodological rigour, and (2) consequently and methodologically to rule out the non-social and the non-human. Cosmopolitan sociology imagines ‘the social’ as a global, universal explanatory device to conceive and describe the non-social and non-human. In a third and final step the article draws upon the work of the French sociologist Gabriel Tarde and offers a possible alternative to the modernist social and cultural other-logics of social sciences. It argues for a inclusive conception of ‘the social’ that gives the non-social and non-human a cosmopolitan voice as well