Sharpenings of Li's criterion for the Riemann Hypothesis

Exact and asymptotic formulae are displayed for the coefficients $\lambda_n$ used in Li's criterion for the Riemann Hypothesis. For $n \to \infty$ we obtain that if (and only if) the Hypothesis is true, $\lambda_n \sim n(A \log n +B)$ (with $A>0$ and $B$ explicitly given, also for the case of more general zeta or $L$-functions); whereas in the opposite case, $\lambda_n$ has a non-tempered oscillatory form.Comment: 10 pages, Math. Phys. Anal. Geom (2006, at press). V2: minor text corrections and updated reference

Coumarin-Annulated Ferrocenyl 1,3-Oxazine Derivatives Possessing In Vitro Antimalarial and Antitrypanosomal Potency

A tailored series of coumarin-based ferrocenyl 1,3-oxazine hybrid compounds was synthesized and investigated for potential antiparasitic activity, drawing inspiration from the established biological efficacy of the constituent chemical motifs. The structural identity of the synthesized compounds was confirmed by common spectroscopic techniques: NMR, HRMS and IR. Biological evaluation studies reveal that the compounds exhibit higher in vitro antiparasitic potency against the chemosensitive malarial strain (3D7 P. falciparum) over the investigated trypanosomiasis causal agent (T. b. brucei 427) with mostly single digit micromolar IC50 values. When read in tandem with the biological performance of previously reported structurally similar non-coumarin, phenyl derivatives (i.e., ferrocenyl 1,3-benzoxazines and α-aminocresols), structure-activity relationship analyses suggest that the presence of the coumarin nucleus is tolerated for biological activity though this may lead to reduced efficacy. Preliminary mechanistic studies with the most promising compound (11b) support hemozoin inhibition and DNA interaction as likely mechanistic modalities by which this class of compounds may act to produce plasmocidal and antitrypanosomal effects

Ultrahigh Bandwidth Spin Noise Spectroscopy: Detection of Large g-Factor Fluctuations in Highly n-Doped GaAs

We advance all optical spin noise spectroscopy (SNS) in semiconductors to detection bandwidths of several hundred gigahertz by employing an ingenious scheme of pulse trains from ultrafast laser oscillators as an optical probe. The ultrafast SNS technique avoids the need for optical pumping and enables nearly perturbation free measurements of extremely short spin dephasing times. We employ the technique to highly n-doped bulk GaAs where magnetic field dependent measurements show unexpected large g-factor fluctuations. Calculations suggest that such large g-factor fluctuations do not necessarily result from extrinsic sample variations but are intrinsically present in every doped semiconductor due to the stochastic nature of the dopant distribution.Comment: 5 pages, 3 figure

Structural and Evolutionary Analyses Show Unique Stabilization Strategies in the Type IV Pili of Clostridium difficile

Type IV pili are produced by many pathogenic Gram-negative bacteria and are important for processes as diverse as twitching motility, biofilm formation, cellular adhesion and horizontal gene transfer. However, many Gram-positive species, including C. difficile, also produce Type IV pili. Here, we identify the major subunit of the Type IV pili of C. difficile, PilA1, and describe multiple three-dimensional structures of PilA1, demonstrating the diversity found in three strains of C. difficile. We also model the incorporation of both PilA1 and a minor pilin, PilJ, into the pilus fiber. Although PilA1 contains no cysteine residues, and therefore cannot form the disulfide bonds found in all Gram-negative Type IV pilins, it adopts unique strategies to achieve a typical pilin fold. The structures of PilA1 and PilJ exhibit similarities with the Type IVb pilins from Gram-negative bacteria that suggest that the Type IV pili of C. difficile are involved in microcolony formation

Guiding structures with multiply connected cross-sections: evolution of propagation in external fields at complex Robin parameters

Properties of the two-dimensional ring and three-dimensional infinitely long straight hollow waveguide with unit width and inner radius $\rho_0$ in the superposition of the longitudinal uniform magnetic field $\bf B$ and Aharonov-Bohm flux are analyzed within the framework of the scalar Helmholtz equation under the assumption that the Robin boundary conditions at the inner and outer confining walls contain extrapolation lengths $\Lambda_{in}$ and $\Lambda_{out}$, respectively, with nonzero imaginary parts. It is shown that, compared to the disk geometry, the annulus opens up additional possibilities of varying magnetization and currents by tuning imaginary components of the Robin parameters on each confining circumference; in particular, the possibility of restoring a lossless longitudinal flux by zeroing imaginary part $E_i$ of the total transverse energy $E$ is discussed. The energy $E$ turns real under special correlation between the imaginary parts of $\Lambda_{in}$ and $\Lambda_{out}$ with the opposite signs what physically corresponds to the equal transverse fluxes through the inner and outer interfaces of the annulus. In the asymptotic case of the very large radius, simple expressions are derived and applied to the analysis of the dependence of the real energy $E$ on $\Lambda_{in}$ and $\Lambda_{out}$. New features also emerge in the magnetic field influence; for example, if, for the quantum disk, the imaginary energy $E_i$ is quenched by the strong intensities $B$, then for the annulus this takes place only when the inner Robin distance $\Lambda_{in}$ is real; otherwise, it almost quadratically depends on $B$ with the corresponding enhancement of the reactive scattering. Closely related problem of the hole in the otherwise uniform medium is also addressed for real and complex extrapolation lengths with the emphasis on the comparative analysis with its dot counterpart.Comment: 37 pages, 9 figure

Identification of a novel zinc metalloprotease through a global analysis of clostridium difficile extracellular proteins

Clostridium difficile is a major cause of infectious diarrhea worldwide. Although the cell surface proteins are recognized to be important in clostridial pathogenesis, biological functions of only a few are known. Also, apart from the toxins, proteins exported by C. difficile into the extracellular milieu have been poorly studied. In order to identify novel extracellular factors of C. difficile, we analyzed bacterial culture supernatants prepared from clinical isolates, 630 and R20291, using liquid chromatography-tandem mass spectrometry. The majority of the proteins identified were non-canonical extracellular proteins. These could be largely classified into proteins associated to the cell wall (including CWPs and extracellular hydrolases), transporters and flagellar proteins. Seven unknown hypothetical proteins were also identified. One of these proteins, CD630_28300, shared sequence similarity with the anthrax lethal factor, a known zinc metallopeptidase. We demonstrated that CD630_28300 (named Zmp1) binds zinc and is able to cleave fibronectin and fibrinogen in vitro in a zinc-dependent manner. Using site-directed mutagenesis, we identified residues important in zinc binding and enzymatic activity. Furthermore, we demonstrated that Zmp1 destabilizes the fibronectin network produced by human fibroblasts. Thus, by analyzing the exoproteome of C. difficile, we identified a novel extracellular metalloprotease that may be important in key steps of clostridial pathogenesis

Increased sporulation underpins adaptation of Clostridium difficile strain 630 to a biologically–relevant faecal environment, with implications for pathogenicity

Abstract Clostridium difficile virulence is driven primarily by the processes of toxinogenesis and sporulation, however many in vitro experimental systems for studying C. difficile physiology have arguably limited relevance to the human colonic environment. We therefore created a more physiologically–relevant model of the colonic milieu to study gut pathogen biology, incorporating human faecal water (FW) into growth media and assessing the physiological effects of this on C. difficile strain 630. We identified a novel set of C. difficile–derived metabolites in culture supernatants, including hexanoyl– and pentanoyl–amino acid derivatives by LC-MSn. Growth of C. difficile strain 630 in FW media resulted in increased cell length without altering growth rate and RNA sequencing identified 889 transcripts as differentially expressed (p < 0.001). Significantly, up to 300–fold increases in the expression of sporulation–associated genes were observed in FW media–grown cells, along with reductions in motility and toxin genes’ expression. Moreover, the expression of classical stress–response genes did not change, showing that C. difficile is well–adapted to this faecal milieu. Using our novel approach we have shown that interaction with FW causes fundamental changes in C. difficile biology that will lead to increased disease transmissibility

Biogenesis and functions of bacterial S-layers.

The outer surface of many archaea and bacteria is coated with a proteinaceous surface layer (known as an S-layer), which is formed by the self-assembly of monomeric proteins into a regularly spaced, two-dimensional array. Bacteria possess dedicated pathways for the secretion and anchoring of the S-layer to the cell wall, and some Gram-positive species have large S-layer-associated gene families. S-layers have important roles in growth and survival, and their many functions include the maintenance of cell integrity, enzyme display and, in pathogens and commensals, interaction with the host and its immune system. In this Review, we discuss our current knowledge of S-layer and related proteins, including their structures, mechanisms of secretion and anchoring and their diverse functions

2D versus 3D human induced pluripotent stem cell-derived cultures for neurodegenerative disease modelling

Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS), affect millions of people every year and so far, there are no therapeutic cures available. Even though animal and histological models have been of great aid in understanding disease mechanisms and identifying possible therapeutic strategies, in order to find disease-modifying solutions there is still a critical need for systems that can provide more predictive and physiologically relevant results. One possible avenue is the development of patient-derived models, e.g. by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), which can then be differentiated into any cell type for modelling. These systems contain key genetic information from the donors, and therefore have enormous potential as tools in the investigation of pathological mechanisms underlying disease phenotype, and progression, as well as in drug testing platforms. hiPSCs have been widely cultured in 2D systems, but in order to mimic human brain complexity, 3D models have been proposed as a more advanced alternative. This review will focus on the use of patient-derived hiPSCs to model AD, PD, HD and ALS. In brief, we will cover the available stem cells, types of 2D and 3D culture systems, existing models for neurodegenerative diseases, obstacles to model these diseases in vitro, and current perspectives in the field

Comparing Notes: Recording and Criticism

This chapter charts the ways in which recording has changed the nature of music criticism. It both provides an overview of the history of recording and music criticism, from the advent of Edison’s Phonograph to the present day, and examines the issues arising from this new technology and the consequent transformation of critical thought and practice