1H NMR relaxometry in the TGBA* and TGBC* phases

Recent results obtained by 1H NMR relaxometry of liquid crystals having twist grain boundary (TGB) phases are here reviewed. In particular, three chiral rod-like lactate derivative mesogens were investigated. In the isotropic phase, three-exponential magnetization decay was observed in all cases and the three distinct spin-lattice relaxation times (T1) were assigned to three specific molecular groups of these molecules. In the TGBA* and TGBC* phases the magnetization decay is mono-exponential and the main features of the 1H NMR dispersion curves analyzed through a global target fitting procedure in terms of specific molecular and collective dynamics are discussed

Re-entrant ferroelectricity in liquid crystals

The ferroelectric (Sm C$^*$) -- antiferroelectric (Sm C$^*_A$) -- reentrant ferroelectric (re Sm C$^*$) phase temperature sequence was observed for system with competing synclinic - anticlinic interactions. The basic properties of this system are as follows (1) the Sm C$^*$ phase is metastable in temperature range of the Sm C$^*_A$ stability (2) the double inversions of the helix handedness at Sm C$^*$ -- Sm C$^*_A$ and Sm C$^*_A$% -- re-Sm C$^*$ phase transitions were found (3) the threshold electric field that is necessary to induce synclinic ordering in the Sm C$^*_A$ phase decreases near both Sm C$^*_A$ -- Sm C$^*$ and Sm C$^*_A$ -- re-Sm C$^*$ phase boundaries, and it has maximum in the middle of the Sm C$^*_A$ stability region. All these properties are properly described by simple Landau model that accounts for nearest neighboring layer steric interactions and quadrupolar ordering only.Comment: 10 pages, 5 figures, submitted to PR

Detection of Bronchial Neoplasia in Uranium Miners by Autofluorescence Endoscopy (SAFE-1000)

The increase in the detection rate for premalignant changes of bronchial epithelium was studied in 56 symptom-free volunteers from the risk group of Czech uranium miners (mean age 50.69 years, mean WLM 21.06 (1 Working Level Month is equal to the absorption of latent energy of 2.08 × 10–5 J/m3 in one month, i.e. 170 working hours)) by the additional employment of the System of Autofluorescence Endoscopy (SAFE-1000 Pentax) to conventional white-light bronchoscopy, comparing results with those of bronchial biopsy histopathology examination. Histopathology using hematoxylin and eosin staining confirmed intraepithelial neoplasias in 15 areas in 10 persons. White-light bronchoscopy sensitivity was 21.05%, and specificity 93.7% which an autofluorescence bronchoscopy sensitivity was 78.95% and specificity 81.89%

Developmentally regulated cleavage of tRNAs in the bacterium Streptomyces coelicolor

The ability to sense and respond to environmental and physiological signals is critical for the survival of the soil-dwelling Gram-positive bacterium Streptomyces coelicolor. Nutrient deprivation triggers the onset of a complex morphological differentiation process that involves the raising of aerial hyphae and formation of spore chains, and coincides with the production of a diverse array of clinically relevant antibiotics and other secondary metabolites. These processes are tightly regulated; however, the genes and signals involved have not been fully elucidated. Here, we report a novel tRNA cleavage event that follows the same temporal regulation as morphological and physiological differentiation, and is growth medium dependent. All tRNAs appear to be susceptible to cleavage; however, there appears to be a bias towards increased cleavage of those tRNAs that specify highly utilized codons. In contrast to what has been observed in eukaryotes, accumulation of tRNA halves in S. coelicolor is not significantly affected by amino acid starvation, and is also not affected by induction of the stringent response or inhibition of ribosome function. Mutants defective in aerial development and antibiotic production exhibit altered tRNA cleavage profiles relative to wild-type strains

Pregnane X Receptor and Yin Yang 1 Contribute to the Differential Tissue Expression and Induction of CYP3A5 and CYP3A4

The hepato-intestinal induction of the detoxifying enzymes CYP3A4 and CYP3A5 by the xenosensing pregnane X receptor (PXR) constitutes a key adaptive response to oral drugs and dietary xenobiotics. In contrast to CYP3A4, CYP3A5 is additionally expressed in several, mostly steroidogenic organs, which creates potential for induction-driven disturbances of the steroid homeostasis. Using cell lines and mice transgenic for a CYP3A5 promoter we demonstrate that the CYP3A5 expression in these organs is non-inducible and independent from PXR. Instead, it is enabled by the loss of a suppressing yin yang 1 (YY1)-binding site from the CYP3A5 promoter which occurred in haplorrhine primates. This YY1 site is conserved in CYP3A4, but its inhibitory effect can be offset by PXR acting on response elements such as XREM. Taken together, the loss of YY1 binding site from promoters of the CYP3A5 gene lineage during primate evolution may have enabled the utilization of CYP3A5 both in the adaptive hepato-intestinal response to xenobiotics and as a constitutively expressed gene in other organs. Our results thus constitute a first description of uncoupling induction from constitutive expression for a major detoxifying enzyme. They also suggest an explanation for the considerable tissue expression differences between CYP3A5 and CYP3A4

Tolerance to coxibs in patients with intolerance to non-steroidal anti-inflammatory drugs (NSAIDs): a systematic structured review of the literature

Adverse events triggered by non-steroidal anti-inflammatory drugs (NSAIDs) are among the most common drug-related intolerance reactions in medicine; they are possibly related to inhibition of cyclooxygenase-1. Coxibs, preferentially inhibiting cyclooxygenase-2, may therefore represent safe alternatives in patients with NSAID intolerance. We reviewed the literature in a systematic and structured manner to identify and evaluate studies on the tolerance of coxibs in patients with NSAID intolerance. We searched MEDLINE (1966–2006), the COCHRANE LIBRARY (4th Issue 2006) and EMBASE (1966–2006) up to December 9, 2006, and analysed all publications included using a predefined evaluation sheet. Symptoms and severity of adverse events to coxibs were analysed based on all articles comprising such information. Subsequently, the probability for adverse events triggered by coxibs was determined on analyses of double-blind prospective trials only. Among 3,304 patients with NSAID intolerance, 119 adverse events occurred under coxib medication. All adverse events, except two, have been allergic/urticarial in nature; none was lethal, but two were graded as life-threatening (grade 4). The two non-allergic adverse events were described as a grade 1 upper respiratory tract haemorrhage, and a grade 1 gastrointestinal symptom, respectively. In 13 double-blind prospective studies comprising a total of 591 patients with NSAID intolerance, only 13 adverse reactions to coxib provocations were observed. The triggering coxibs were rofecoxib (2/286), celecoxib (6/208), etoricoxib (4/56), and valdecoxib (1/41). This review documents the good tolerability of coxibs in patients with NSAID intolerance, for whom access to this class of drugs for short-term treatment of pain and inflammation is advantageous

Target protection as a key antibiotic resistance mechanism

Antibiotic resistance is mediated through several distinct mechanisms, most of which are relatively well understood and the clinical importance of which has long been recognized. Until very recently, neither of these statements was readily applicable to the class of resistance mechanism known as target protection, a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition. In this Review, we summarize recent progress in understanding the nature and importance of target protection. In particular, we describe the molecular basis of the known target protection systems, emphasizing that target protection does not involve a single, uniform mechanism but is instead brought about in several mechanistically distinct ways

Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens

he antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms