Common trends in the critical behavior of the Ising and directed walk models

We consider layered two-dimensional Ising and directed walk models and show that the two problems are inherently related. The information about the zero-field thermodynamical properties of the Ising model is contained into the transfer matrix of the directed walk. For several hierarchical and aperiodic distributions of the couplings, critical exponents for the two problems are obtained exactly through renormalization.Comment: 4 pages, RevTeX file + 1 figure, epsf needed. To be published in PR

T-Branes and Monodromy

We introduce T-branes, or "triangular branes," which are novel non-abelian bound states of branes characterized by the condition that on some loci, their matrix of normal deformations, or Higgs field, is upper triangular. These configurations refine the notion of monodromic branes which have recently played a key role in F-theory phenomenology. We show how localized matter living on complex codimension one subspaces emerge, and explain how to compute their Yukawa couplings, which are localized in complex codimension two. Not only do T-branes clarify what is meant by brane monodromy, they also open up a vast array of new possibilities both for phenomenological constructions and for purely theoretical applications. We show that for a general T-brane, the eigenvalues of the Higgs field can fail to capture the spectrum of localized modes. In particular, this provides a method for evading some constraints on F-theory GUTs which have assumed that the spectral equation for the Higgs field completely determines a local model.Comment: 110 pages, 5 figure

Alcohol Production as an Adaptive Livelihood Strategy for Women Farmers in Tanzania and Its Potential for Unintended Consequences on Women's Reproductive Health.

Although women occupy a central position in agriculture in many developing countries, they face numerous constraints to achieving their full potential including unequal access to assets and limited decision-making authority. We explore the intersection of agricultural livelihoods, food and economic security, and women's sexual and reproductive health in Iringa Region, Tanzania. Our goal was to understand whether the benefits of supporting women in the agricultural sector might also extend to more distal outcomes, including sexual and reproductive health. Using the Sustainable Livelihoods Framework to guide data collection, we conducted 13 focus group discussions (FGD) with female (n = 11) and male farmers (n = 2) and 20 in-depth interviews with agricultural extension officers (n = 10) and village agro-dealers (n = 10). Despite providing the majority of agricultural labor, women have limited control over land and earned income and have little bargaining power. In response to these constraints, women adopt adaptive livelihood strategies, such as alcohol production, that allow them to retain control over income and support their households. However, women's central role in alcohol production, in concert with the ubiquitous nature of alcohol consumption, places them at risk by enhancing their vulnerability to unsafe or transactional sex. This represents a dangerous confluence of risk for female farmers, in which alcohol plays an important role in income generation and also facilitates high-risk sexual behavior. Alcohol production and consumption has the potential to both directly and indirectly place women at risk for undesirable sexual and reproductive health outcomes. Group formation, better access to finance, and engaging with agricultural extension officers were identified as potential interventions for supporting women farmers and challenging harmful gender norms. In addition, joint, multi-sectoral approaches from health and agriculture and alternative income-generating strategies for women might better address the complexities of achieving safe and sustainable livelihoods for women in this context

Inhibiting mycobacterial tryptophan synthase by targeting the inter-subunit interface

Drug discovery efforts against the pathogen Mycobacterium tuberculosis (Mtb) have been advanced through phenotypic screens of extensive compound libraries. Such a screen revealed sulfolane 1 and indoline-5-sulfonamides 2 and 3 as potent inhibitors of mycobacterial growth. Optimization in the sulfolane series led to compound 4, which has proven activity in an in vivo murine model of Mtb infection. Here we identify the target and mode of inhibition of these compounds based on whole genome sequencing of spontaneous resistant mutants, which identified mutations locating to the essential α- and β-subunits of tryptophan synthase. Over-expression studies confirmed tryptophan synthase as the biological target. Biochemical techniques probed the mechanism of inhibition, revealing the mutant enzyme complex incurs a fitness cost but does not prevent inhibitor binding. Mapping of the resistance conferring mutations onto a low-resolution crystal structure of Mtb tryptophan synthase showed they locate to the interface between the α- and β-subunits. The discovery of anti-tubercular agents inhibiting tryptophan synthase highlights the therapeutic potential of this enzyme and draws attention to the prospect of other amino acid biosynthetic pathways as future Mtb drug targets

Transverse-field Ising spin chain with inhomogeneous disorder

We consider the critical and off-critical properties at the boundary of the random transverse-field Ising spin chain when the distribution of the couplings and/or transverse fields, at a distance $l$ from the surface, deviates from its uniform bulk value by terms of order $l^{-\kappa}$ with an amplitude $A$. Exact results are obtained using a correspondence between the surface magnetization of the model and the surviving probability of a random walk with time-dependent absorbing boundary conditions. For slow enough decay, $\kappa<1/2$, the inhomogeneity is relevant: Either the surface stays ordered at the bulk critical point or the average surface magnetization displays an essential singularity, depending on the sign of $A$. In the marginal situation, $\kappa=1/2$, the average surface magnetization decays as a power law with a continuously varying, $A$-dependent, critical exponent which is obtained analytically. The behavior of the critical and off-critical autocorrelation functions as well as the scaling form of the probability distributions for the surface magnetization and the first gaps are determined through a phenomenological scaling theory. In the Griffiths phase, the properties of the Griffiths-McCoy singularities are not affected by the inhomogeneity. The various results are checked using numerical methods based on a mapping to free fermions.Comment: 11 pages (Revtex), 11 figure

Dynamics and transport near quantum-critical points

The physics of non-zero temperature dynamics and transport near quantum-critical points is discussed by a detailed study of the O(N)-symmetric, relativistic, quantum field theory of a N-component scalar field in $d$ spatial dimensions. A great deal of insight is gained from a simple, exact solution of the long-time dynamics for the N=1 d=1 case: this model describes the critical point of the Ising chain in a transverse field, and the dynamics in all the distinct, limiting, physical regions of its finite temperature phase diagram is obtained. The N=3, d=1 model describes insulating, gapped, spin chain compounds: the exact, low temperature value of the spin diffusivity is computed, and compared with NMR experiments. The N=3, d=2,3 models describe Heisenberg antiferromagnets with collinear N\'{e}el correlations, and experimental realizations of quantum-critical behavior in these systems are discussed. Finally, the N=2, d=2 model describes the superfluid-insulator transition in lattice boson systems: the frequency and temperature dependence of the the conductivity at the quantum-critical coupling is described and implications for experiments in two-dimensional thin films and inversion layers are noted.Comment: Lectures presented at the NATO Advanced Study Institute on "Dynamical properties of unconventional magnetic systems", Geilo, Norway, April 2-12, 1997, edited by A. Skjeltorp and D. Sherrington, Kluwer Academic, to be published. 46 page

Insights into the regulation of DMSP synthesis in the diatom Thalassiosira pseudonana through APR activity, proteomics and gene expression analyses on cells acclimating to changes in salinity, light and nitrogen

Despite the importance of dimethylsulphoniopropionate (DMSP) in the global sulphur cycle and climate regulation, the biological pathways underpinning its synthesis in marine phytoplankton remain poorly understood. The intracellular concentration of DMSP increases with increased salinity, increased light intensity and nitrogen starvation in the diatom Thalassiosira pseudonana. We used these conditions to investigate DMSP synthesis at the cellular level via analysis of enzyme activity, gene expression and proteome comparison. The activity of the key sulphur assimilatory enzyme, adenosine 5′- phosphosulphate reductase was not coordinated with increasing intracellular DMSP concentration. Under all three treatments coordination in the expression of sulphur assimilation genes was limited to increases in sulphite reductase transcripts. Similarly, proteomic 2D gel analysis only revealed an increase in phosphoenolpyruvate carboxylase following increases in DMSP concentration. Our findings suggest that increased sulphur assimilation might not be required for increased DMSP synthesis, instead the availability of carbon and nitrogen substrates may be important in the regulation of this pathway. This contrasts with the regulation of sulphur metabolism in higher plants, which generally involves upregulation of several sulphur assimilatory enzymes. In T. pseudonana changes relating to sulphur metabolism were specific to the individual treatments and, given that little coordination was seen in transcript and protein responses across the three growth conditions, different patterns of regulation might be responsible for the increase in DMSP concentration seen under each treatment

Unique reporter-based sensor platforms to monitor signalling in cells

Introduction: In recent years much progress has been made in the development of tools for systems biology to study the levels of mRNA and protein, and their interactions within cells. However, few multiplexed methodologies are available to study cell signalling directly at the transcription factor level. &lt;p/&gt;Methods: Here we describe a sensitive, plasmid-based RNA reporter methodology to study transcription factor activation in mammalian cells, and apply this technology to profiling 60 transcription factors in parallel. The methodology uses two robust and easily accessible detection platforms; quantitative real-time PCR for quantitative analysis and DNA microarrays for parallel, higher throughput analysis. &lt;p/&gt;Findings: We test the specificity of the detection platforms with ten inducers and independently validate the transcription factor activation. &lt;p/&gt;Conclusions: We report a methodology for the multiplexed study of transcription factor activation in mammalian cells that is direct and not theoretically limited by the number of available reporters

Structural Basis for Substrate Specificity in Human Monomeric Carbonyl Reductases

Carbonyl reduction constitutes a phase I reaction for many xenobiotics and is carried out in mammals mainly by members of two protein families, namely aldo-keto reductases and short-chain dehydrogenases/reductases. In addition to their capacity to reduce xenobiotics, several of the enzymes act on endogenous compounds such as steroids or eicosanoids. One of the major carbonyl reducing enzymes found in humans is carbonyl reductase 1 (CBR1) with a very broad substrate spectrum. A paralog, carbonyl reductase 3 (CBR3) has about 70% sequence identity and has not been sufficiently characterized to date. Screening of a focused xenobiotic compound library revealed that CBR3 has narrower substrate specificity and acts on several orthoquinones, as well as isatin or the anticancer drug oracin. To further investigate structure-activity relationships between these enzymes we crystallized CBR3, performed substrate docking, site-directed mutagenesis and compared its kinetic features to CBR1. Despite high sequence similarities, the active sites differ in shape and surface properties. The data reveal that the differences in substrate specificity are largely due to a short segment of a substrate binding loop comprising critical residues Trp229/Pro230, Ala235/Asp236 as well as part of the active site formed by Met141/Gln142 in CBR1 and CBR3, respectively. The data suggest a minor role in xenobiotic metabolism for CBR3. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses