Terbinafine Resistance of Trichophyton Clinical Isolates Caused by Specific Point Mutations in the Squalene Epoxidase Gene.

Terbinafine is one of the allylamine antifungal agents whose target is squalene epoxidase (SQLE). This agent has been extensively used in the therapy of dermatophyte infections. The incidence of patients with tinea pedis or unguium tolerant to terbinafine treatment prompted us to screen the terbinafine resistance of all javax.xml.bind.JAXBElement@dc06fb4 clinical isolates from the laboratory of the Centre Hospitalier Universitaire Vaudois collected over a 3-year period and to identify their mechanism of resistance. Among 2,056 tested isolates, 17 (≈1%) showed reduced terbinafine susceptibility, and all of these were found to harbor javax.xml.bind.JAXBElement@374d721c gene alleles with different single point mutations, leading to single amino acid substitutions at one of four positions (Leu javax.xml.bind.JAXBElement@4655f570 , Phe javax.xml.bind.JAXBElement@112b804a , Phe javax.xml.bind.JAXBElement@1f18e014 , and His javax.xml.bind.JAXBElement@4319ac79 ) of the SQLE protein. Point mutations leading to the corresponding amino acid substitutions were introduced into the endogenous javax.xml.bind.JAXBElement@2a0e3f1f gene of a terbinafine-sensitive javax.xml.bind.JAXBElement@67eac3c4 (formerly javax.xml.bind.JAXBElement@3f2a876d ) strain. All of the generated javax.xml.bind.JAXBElement@315e9e95 transformants expressing mutated SQLE proteins exhibited obvious terbinafine-resistant phenotypes compared to the phenotypes of the parent strain and of transformants expressing wild-type SQLE proteins. Nearly identical phenotypes were also observed in javax.xml.bind.JAXBElement@6af3a966 transformants expressing mutant forms of javax.xml.bind.JAXBElement@5bb6b31f SQLE proteins. Considering that the genome size of dermatophytes is about 22 Mb, the frequency of terbinafine-resistant clinical isolates was strikingly high. Increased exposure to antifungal drugs could favor the generation of resistant strains

Production of Fusaric Acid by Fusarium spp. in Pure Culture and in Solid Medium Co-Cultures.

The ability of fungi isolated from nails of patients suffering from onychomycosis to induce de novo production of bioactive compounds in co-culture was examined. Comparison between the metabolite profiles produced by Sarocladium strictum, by Fusarium oxysporum, and by these two species in co-culture revealed de novo induction of fusaric acid based on HRMS. Structure confirmation of this toxin, using sensitive microflow NMR, required only three 9-cm Petri dishes of fungal culture. A targeted metabolomics study based on UHPLC-HRMS confirmed that the production of fusaric acid was strain-dependent. Furthermore, the detected toxin levels suggested that onychomycosis-associated fungal strains of the F. oxysporum and F. fujikuroi species complexes are much more frequently producing fusaric acid, and in higher amount, than strains of the F. solani species complex. Fusarium strains producing no significant amounts of this compound in pure culture, were shown to de novo produce that compound when grown in co-culture. The role of fusaric acid in fungal virulence and defense is discussed

Spectroscopy, Interactions and Level Splittings in Au Nanoparticles

We have measured the electronic energy spectra of nm-scale Au particles using a new tunneling spectroscopy configuration. The particle diameters ranged from 5nm to 9nm, and at low energies the spectrum is discrete, as expected by the electron-in-a-box model. The density of tunneling resonances increases rapidly with energy, and at higher energies the resonances overlap forming broad resonances. Near the Thouless energy, the broad resonances merge into a continuum. The tunneling resonances display Zeeman splitting in a magnetic field. Surprisingly, the g-factors (~0.3) of energy levels in Au nano-particles are much smaller than the g-factor (2.1) in bulk gold

A lattice in more than two Kac--Moody groups is arithmetic

Let $\Gamma$ be an irreducible lattice in a product of n infinite irreducible complete Kac-Moody groups of simply laced type over finite fields. We show that if n is at least 3, then each Kac-Moody groups is in fact a simple algebraic group over a local field and $\Gamma$ is an arithmetic lattice. This relies on the following alternative which is satisfied by any irreducible lattice provided n is at least 2: either $\Gamma$ is an S-arithmetic (hence linear) group, or it is not residually finite. In that case, it is even virtually simple when the ground field is large enough. More general CAT(0) groups are also considered throughout.Comment: Subsection 2.B was modified and an example was added ther

Superconducting gap node spectroscopy using nonlinear electrodynamics

We present a method to determine the nodal structure of the energy gap of unconventional superconductors such as high $T_c$ materials. We show how nonlinear electrodynamics phenomena in the Meissner regime, arising from the presence of lines on the Fermi surface where the superconducting energy gap is very small or zero, can be used to perform ``node spectroscopy'', that is, as a sensitive bulk probe to locate the angular position of those lines. In calculating the nonlinear supercurrent response, we include the effects of orthorhombic distortion and $a-b$ plane anisotropy. Analytic results presented demonstrate a systematic way to experimentally distinguish order parameters of different symmetries, including cases with mixed symmetry (for example, $d+s$ and $s+id$). We consider, as suggested by various experiments, order parameters with predominantly $d$-wave character, and describe how to determine the possible presence of other symmetries. The nonlinear magnetic moment displays a distinct behavior if nodes in the gap are absent but regions with small, finite, values of the energy gap exist.Comment: 18 pages, Revtex, 9 postscript figures. Submitted to Phys. Rev

Strongly coupled quantum criticality with a Fermi surface in two dimensions: fractionalization of spin and charge collective modes

We describe two dimensional models with a metallic Fermi surface which display quantum phase transitions controlled by strongly interacting critical field theories below their upper critical dimension. The primary examples involve transitions with a topological order parameter associated with dislocations in collinear spin density wave ("stripe") correlations: the gapping of the order parameter fluctuations leads to a fractionalization of spin and charge collective modes, and this transition has been proposed as a candidate for the cuprates near optimal doping. The coupling between the order parameter and long-wavelength volume and shape deformations of the Fermi surface is analyzed by the renormalization group, and a runaway flow to a non-perturbative regime is found in most cases. A phenomenological scaling analysis of simple observable properties of possible second order quantum critical points is presented, with results quite similar to those near quantum spin glass transitions and to phenomenological forms proposed by Schroeder et al. (cond-mat/0011002).Comment: 16 pages, 4 figures; (v2) additional clarifying remark

Midgap edge states and pairing symmetry of quasi-one-dimensional organic superconductors

The singlet s-, d- and triplet p-wave pairing symmetries in quasi-one-dimensional organic superconductors can be experimentally discriminated by probing the Andreev bound states at the sample edges. These states have the energy in the middle of the superconducting gap and manifest themselves as a zero-bias peak in tunneling conductance into the corresponding edge. Their existence is related to the sign change of the pairing potential around the Fermi surface. We present an exact self-consistent solution of the edge problem showing the presence of the midgap states for p_x-wave superconductivity. The spins of the edge state respond paramagnetically to a magnetic field parallel to the vector d that characterizes triplet pairing.Comment: 6 pages, 4 figures. V.2: New section on spin response is added and references are updated. V.3: Final version accepted to PRB. Typos are corrected and important note is added in proof

Formation of regulatory modules by local sequence duplication

Turnover of regulatory sequence and function is an important part of molecular evolution. But what are the modes of sequence evolution leading to rapid formation and loss of regulatory sites? Here, we show that a large fraction of neighboring transcription factor binding sites in the fly genome have formed from a common sequence origin by local duplications. This mode of evolution is found to produce regulatory information: duplications can seed new sites in the neighborhood of existing sites. Duplicate seeds evolve subsequently by point mutations, often towards binding a different factor than their ancestral neighbor sites. These results are based on a statistical analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome, and a comparison set of intergenic regulatory sequence in Saccharomyces cerevisiae. In fly regulatory modules, pairs of binding sites show significantly enhanced sequence similarity up to distances of about 50 bp. We analyze these data in terms of an evolutionary model with two distinct modes of site formation: (i) evolution from independent sequence origin and (ii) divergent evolution following duplication of a common ancestor sequence. Our results suggest that pervasive formation of binding sites by local sequence duplications distinguishes the complex regulatory architecture of higher eukaryotes from the simpler architecture of unicellular organisms

Genomic Transition to Pathogenicity in Chytrid Fungi

Understanding the molecular mechanisms of pathogen emergence is central to mitigating the impacts of novel infectious disease agents. The chytrid fungus Batrachochytrium dendrobatidis (Bd) is an emerging pathogen of amphibians that has been implicated in amphibian declines worldwide. Bd is the only member of its clade known to attack vertebrates. However, little is known about the molecular determinants of - or evolutionary transition to - pathogenicity in Bd. Here we sequence the genome of Bd's closest known relative - a non-pathogenic chytrid Homolaphlyctis polyrhiza (Hp). We first describe the genome of Hp, which is comparable to other chytrid genomes in size and number of predicted proteins. We then compare the genomes of Hp, Bd, and 19 additional fungal genomes to identify unique or recent evolutionary elements in the Bd genome. We identified 1,974 Bd-specific genes, a gene set that is enriched for protease, lipase, and microbial effector Gene Ontology terms. We describe significant lineage-specific expansions in three Bd protease families (metallo-, serine-type, and aspartyl proteases). We show that these protease gene family expansions occurred after the divergence of Bd and Hp from their common ancestor and thus are localized to the Bd branch. Finally, we demonstrate that the timing of the protease gene family expansions predates the emergence of Bd as a globally important amphibian pathogen

Phenomenological description of the microwave surface impedance and complex conductivity of high-TcT_c single crystals

Measurements of the microwave surface impedance $Z_s(T)=R_s(T)+iX_s(T)$ and of the complex conductivity $\sigma_s(T)$ of high-quality, high-$T_c$ single crystals of YBCO, BSCCO, TBCCO, and TBCO are analyzed. Experimental data of $Z_s(T)$ and $\sigma_s(T)$ are compared with calculations based on a modified two-fluid model which includes temperature-dependent quasiparticle scattering and a unique temperature variation of the density of superconducting carriers. We elucidate agreement as well as disagreement of our analysis with the salient features of the experimental data. Existing microscopic models are reviewed which are based on unconventional symmetry types of the order parameter and on novel mechanisms of quasiparticle relaxation.Comment: 15 pages, 17 figures, 1 tabl