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PubMed2026

Dichalcogenide Fidaxomicin Derivatives to Probe Thiol-Mediated Uptake into Bacteria.

The natural product fidaxomicin (Fdx) is a narrow-spectrum antibiotic clinically prescribed for the treatment of Clostrodioides difficile infections. However, limited cellular uptake reduces its therapeutic potential, particularly against Gram-negative bacteria and mycobacteria. In this study, we investigated Thiol-Mediated Uptake (TMU) to promote the delivery of Fdx into bacterial cells. We synthesized a library of Fdx derivatives bearing cyclic dichalcogenide moieties and evaluated their antimicrobial properties against C. difficile and Mycobacterium tuberculosis, respectively. Remarkably, the synthetic Fdx derivatives retained strong levels of antibacterial activity, and the disulfide-containing analogs outperformed their all-carbon control counterparts in many instances. We then developed a systematic study to investigate the mechanistic impact of the introduced disulfide functionalities by conducting experiments with TMU inhibitors and quantifying intracellular accumulation in Mycobacterium bovis BCG, a model organism for M. tuberculosis, via LC-MS/MS. While complete disentanglement of the factors influencing activity was not feasible, features such as compound stability and lipophilicity were identified as significant contributors. Overall, the superior performance of disulfide analogs suggests that differences in cellular entry or intracellular processing, potentially related to TMU, are involved. This work highlights that TMU remains a viable approach for modulating the uptake of therapeutic agents into bacterial cells.

Sulfhydryl Compounds↗

PubMed2004

Kinetically robust monomeric protein from a hyperthermophile.

Equilibrium and kinetic studies were carried out under denaturation conditions to clarify the energetic features of the high stability of a monomeric protein, ribonuclease HII, from a hyperthermophile, Thermococcus kodakaraensis (Tk-RNase HII). Guanidine hydrochloride (GdnHCl)-induced unfolding and refolding were measured with circular dichroism at 220 nm, and heat-induced denaturation was studied with differential scanning calorimetry. Both GdnHCl- and heat-induced denaturation are very reversible. It was difficult to obtain the equilibrated unfolding curve of Tk-RNase HII below 40 degrees C, because of the remarkably slow unfolding. The two-state unfolding and refolding reactions attained equilibrium at 50 degrees C after 2 weeks. The Gibbs energy change of GdnHCl-induced unfolding (DeltaG(H(2)O)) at 50 degrees C was 43.6 kJ mol(-1). The denaturation temperature in the DSC measurement shifted as a function of the scan rate; the denaturation temperature at a scan rate of 90 degrees C h(-1) was higher than at a scan rate of 5 degrees C h(-1). The unfolding and refolding kinetics of Tk-RNase HII were approximated as a first-order reaction. The ln k(u) and ln k(r) values depended linearly on the denaturant concentration between 10 and 50 degrees C. The DeltaG(H(2)O) value obtained from the rate constant in water using the two-state model at 50 degrees C, 44.5 kJ mol(-1), was coincident with that from the equilibrium study, 43.6 kJ mol(-1), suggesting the two-state folding of Tk-RNase HII. The values for the rate constant in water of the unfolding for Tk-RNase HII were much smaller than those of E. coli RNase HI and Thermus thermophilus RNase HI, which has a denaturation temperature similar to that of Tk-RNase HII. In contrast, little difference was observed in the refolding rates among these proteins. These results indicate that the stabilization mechanism of monomeric protein from a hyperthermophile, Tk-RNase HII, with reversible two-state folding is characterized by remarkably slow unfolding.

Archaeal Proteins↗

PubMedDate not supplied

Quantification of the influence of single-point mutations on haloalkane dehalogenase activity: a molecular quantum similarity study.

Controlled modifications in certain protein amino acid residues can lead to changes in their function and stability. Amino acid structural features and their relation to these changes were examined by using quantum molecular similarity techniques. The effect of deliberate mutations in position 172 of the haloalkane dehalogenase enzyme, yielding to variations on the dehalogenation of 1,2-dibromoethane, was studied qualitatively and quantitatively using molecular quantum similarity techniques. A valuable classification of the residues according to their effect on activity was obtained by representing the optimal two-dimensional classical scaling solution. In addition, satisfactory quantitative relationships were found, comparable to those attained by previous studies on this same data set using other techniques. Molecular quantum similarity analysis provides a consistent, unbiased, and homogeneous set of molecular descriptors and is a feasible alternative to the use of physicochemical properties.

Hydrolases↗

PubMed2005

X-ray absorption near-edge structure analysis of arsenic species for application to biological environmental samples.

Arsenic is an element that is ubiquitous in the environment and is known to form compounds with toxic, even carcinogenic properties. Arsenic toxicity is a function of its chemical form (species). Identification of arsenic species is necessary to accurately determine the transformation and fate of arsenicals as well as the actual risk posed by arsenic contamination. We report X-ray absorption near-edge structure (XANES) measurements of 16 biologically important arsenic compounds. Solid and aqueous standards were studied for differences in XANES spectral features, white line positions, stability during exposure to the beam, and stability between two beam exposures separated by 48 h. Samples containing As(III) (11870.0-11871.7+/-0.5 eV) and As(V) (11872.6-11875.3+/-0.5 eV) were easily distinguished by white line energies and could be further subdivided into a total of seven groups. Valuable examples include As(III)-sulfur compounds (11870.0+/-0.5 eV), arsenobetaine and arsenocholine (11872.6+/-0.5 eV), and a dimethyl arsinyl riboside (11873.3+/-0.5 eV). A growing number of environmental and biological studies use X-ray absorption spectroscopy (XAS) results to complement their more traditional analyses. Results provided here are intended to help make XAS more accessible to new users interested in the study of arsenic in the environment.

Arsenic↗

PubMed2003

Coordination properties of new bis(1,4,7-triazacyclononane) ligands: a highly active dizinc complex in phosphate diester hydrolysis.

The synthesis and characterization of three new bis([9]aneN(3)) ligands, containing respectively 2,2'-bipyridine (L(1)), 1,10-phenanthroline (L(2)), and quinoxaline (L(3)) moieties linking the two macrocyclic units, are reported. Proton binding and Cu(II), Zn(II), Cd(II), and Pb(II) coordination with L(1)-L(3) have been studied by potentiometric titrations and, for L(1) and L(2), by spectrophotometric UV-vis measurements in aqueous solutions. All ligands can give stable mono- and dinuclear complexes. In the case of L(1), trinuclear Cu(II) complexes are also formed. The stability constants and structural features of the formed complexes are strongly affected by the different architecture and binding properties of the spacers bridging the two [9]aneN(3) units. In the case of the L(1) and L(2) mononuclear complexes, the metal is coordinated by the three donors of one [9]aneN(3) moiety; in the [ML(2)](2+) complexes, however, the phenanthroline nitrogens are also involved in metal binding. Finally, in the [ML(3)](2+) complexes both macrocyclic units, at a short distance from each other, can be involved in metal coordination, giving rise to sandwich complexes. In the binuclear complexes each metal ion is generally coordinated by one [9]aneN(3) unit. In L(1), however, the dipyridine nitrogens can also act as a potential binding site for metals. The dinuclear complexes show a marked tendency to form mono-, di-, and, in some cases, trihydroxo species in aqueous solutions. The resulting M-OH functions may behave as nucleophiles in hydrolytic reactions. The hydrolysis rate of bis(p-nitrophenyl)phosphate (BNPP) was measured in aqueous solution at 308.1 K in the presence of the L(2) and L(3) dinuclear Zn(II) complexes. Both the L(2) complexes [Zn(2)L(2)(OH)(2)](2+) and [Zn(2)L(2)(OH)(3)](+) and the L(3) complex [Zn(2)L(3)(OH)(3)](+) promote BNPP hydrolysis. The [Zn(2)L(3)(OH)(3)](+) complex is ca. 2 orders of magnitude more active than the L(2) complexes, due both to the short distance between the metal centers in [Zn(2)L(3)(OH)(3)](+), which could allow a bridging interaction of the phosphate ester, and to the simultaneous presence of single-metal bound nucleophilic Zn-OH functions. These structural features are substantially corroborated by semiempirical PM3 calculations carried out on the mono-, di-, and trihydroxo species of the L(3) dizinc complex.

Journal Article↗

PubMed2004

Electron delocalization in a ruthenium(II) Bis(2,2':6',2' '-terpyridyl) complex.

Photophysical properties have been recorded for a ruthenium(II) bis(2,2':6',2' '-terpyridine) complex bearing a single ethynylene substituent. The target compound is weakly emissive in fluid solution at room temperature, but both the emission yield and lifetime increase dramatically as the temperature is lowered. As found for the unsubstituted parent complex, the full temperature dependence indicates that the lowest-energy triplet state couples to two higher-energy triplets and to the ground state. Luminescence occurs only from the lowest-energy triplet state, but the radiative and nonradiative decay rates indicate that electron delocalization occurs at the triplet level. Comparison of the target compound with the parent complex indicates that the ethynylene group reduces the size of the electron-vibrational coupling element for nonradiative decay of the lowest-energy triplet state. Although other factors are affected by substitution, this is by far the most important feature with regard to stabilization of the triplet state.

Journal Article↗

PubMed2001

Effects of metal ions on physicochemical properties and redox reactivity of phenolates and phenoxyl radicals: mechanistic insight into hydrogen atom abstraction by phenoxyl radical-metal complexes.

Phenolate and phenoxyl radical complexes of a series of alkaline earth metal ions as well as monovalent cations such as Na+ and K+ have been prepared by using 2,4-di-tert-butyl-6-(1,4,7,10-tetraoxa-13-aza-cyclopentadec-13-ylmethyl)phenol (L1H) and 2,4-di-tert-butyl-6-(1,4,7,10,13-pentaoxa-16-aza-cyclooctadec-16-ylmethyl)phenol (L2H) to examine the effects of the cations on the structure, physicochemical properties and redox reactivity of the phenolate and phenoxyl radical complexes. Crystal structures of the Mg2+- and Ca2+-complexes of L1- as well as the Ca2+- and Sr2+-complexes of L2- were determined by X-ray crystallographic analysis, showing that the crown ether rings in the Ca2+-complexes are significantly distorted from planarity, whereas those in the Mg2+- and Sr2+-complexes are fairly flat. The spectral features (UV-vis) as well as the redox potentials of the phenolate complexes are also influenced by the metal ions, depending on the Lewis acidity of the metal ions. The phenoxyl radical complexes are successfully generated in situ by the oxidation of the phenolate complexes with (NH4)(2)[Ce4+(NO3)6] (CAN). They exhibited strong absorption bands around 400 nm together with a broad one around 600-900 nm, the latter of which is also affected by the metal ions. The phenoxyl radical-metal complexes are characterized by resonance Raman, ESI-MS, and ESR spectra, and the metal ion effects on those spectroscopic features are also discussed. Stability and reactivity of the phenoxyl radical-metal complexes are significantly different, depending on the type of metal ions. The disproportionation of the phenoxyl radicals is significantly retarded by the electronic repulsion between the metal cation and a generated organic cation (Ln+), leading to stabilization of the radicals. On the other hand, divalent cations decelerate the rate of hydrogen atom abstraction from 10-methyl-9,10-dihydroacridine (AcrH2) and its 9-substituted derivatives (AcrHR) by the phenoxyl radicals. On the basis of primary kinetic deuterium isotope effects and energetic consideration of the electron-transfer step from AcrH2 to the phenoxyl radical-metal complexes, we propose that the hydrogen atom abstraction by the phenoxyl radical-alkaline earth metal complexes proceeds via electron transfer followed by proton transfer.

Free Radicals↗

PubMed2003

(Phosphino)(aryl)carbenes: effect of aryl substituents on their stabilization mode.

A broad range of (phosphino)(aryl)carbenes, 1b-d, 10a,b, and 14a,b, were prepared by photolysis of their diazo precursors. The influence of the steric and electronic properties of the aryl ring on the structure and stability of these carbenes was studied both experimentally and theoretically. Among the different stabilization modes investigated, those featuring an acceptor as well as a spectator aryl substituent result in stable or at least persistent carbenes that could be completely characterized by classical spectroscopic methods. In marked contrast, the new substitution pattern featuring a donor aryl ring results in a very fleeting carbene.

Journal Article↗

PubMed2005

Facile synthesis of silver nanoparticles useful for fabrication of high-conductivity elements for printed electronics.

A facile synthesis of stable silver nanoparticles having a particle size of <10 nm is described. The synthesis involved reduction of silver acetate with a substituted hydrazine, such as PhNHNH2, in the presence of a 1-alkylamine, such as C16H33NH2, in toluene at 25-60 degrees C. Spin-coated thin films or printed electronic features of alkylamine-stabilized silver nanoparticles could be easily converted at 120-160 degrees C into highly conductive films or elements with conductivity of 2-4 x 104 S cm-1. Organic thin-film transistors with printed silver source/drain electrodes of this nature exhibited field-effect transistor properties which are similar to those of the devices using vacuum-deposited silver electrodes.

Journal Article↗

PubMed2000

Structure-activity studies including a Psi(CH(2)-NH) scan of peptide YY (PYY) active site, PYY(22-36), for interaction with rat intestinal PYY receptors: development of analogues with potent in vivo activity in the intestine.

Peptide YY (PYY) is a gut hormone that inhibits secretion and promotes absorption and growth in the intestinal epithelium. We have performed structure-activity studies with the active site, N-alpha-Ac-PYY(22-36)-NH(2), for interaction with intestinal PYY receptors. Investigation of aromatic substitutions at position 27 resulted in analogues that exhibited potent in vitro antisecretory potencies with N-alpha-Ac-[Trp(27)]PYY(22-36)-NH(2) exhibiting even greater potency than intact PYY. In vivo studies in dogs revealed that this analogue also promoted intestinal absorption of water and electrolytes during continuous intravenous and intraluminal infusion. Investigations carried out to identify features that would enhance stability revealed that incorporation of Trp(30) increased affinity for PYY receptors. A "CH(2)-NH" scan revealed that incorporation of reduced bonds at position 28-29 or 35-36 imparted greater receptor affinity. In general, disubstituted analogues designed based on the results of single substitutions exhibited good receptor affinity with N-alpha-Ac-[Trp(27),CH(2)-NH(35-36)]PYY(22-36)-NH(2) having the greatest affinity (IC(50) = 0.28 nM). Conservative multiple substitutions with Nle-->Leu and Nva-->Val also imparted good affinity. An analogue designed to encompass most of the favored substitutions, N-alpha-Ac-[Nle(24,28),Trp(30),Nva(31), CH(2)-NH(35-36)]PYY(22-36)-NH(2), exhibited a proabsorptive effect in dogs comparable to, but longer lasting than, that of intact hormone. Selected analogues also exhibited good antisecretory potencies in rats with N-alpha-Ac-[Trp(30)]PYY(22-36)-NH(2) being even more potent than PYY. However, the potencies did not correlate well with the PYY receptor affinity or the proabsorptive potencies in dogs. These differences could be due to species effects and/or the involvement of multiple receptors and neuronal elements in controlling the in vivo activity of PYY compounds. PYY(22-36) analogues exhibited good affinity for neuronal Y2 receptors but poor affinity for Y1 receptors. Also, crucial analogues in this series hardly bound to Y4 and Y5 receptors. In summary, we have developed PYY(22-36) analogues which, via interacting with intestinal PYY receptors, promoted potent and long-lasting proabsorptive and antisecretory effects in in vivo models. These compounds or analogues based on them may have useful clinical application in treating malabsorptive disorders observed under a variety of conditions.

Animals↗

PubMed1999

Detection of circulating tumour DNA in the blood (plasma/serum) of cancer patients.

Small amounts of free DNA circulate in both healthy and diseased human plasma/serum, and increased concentrations of DNA are present in the plasma of cancer patients. Characteristics of tumour DNA have been found in genetic material extracted from the plasma of cancer patients. These features include decreased strand stability and the presence of specific oncogene, tumour suppressor gene and microsatellite alterations. Point mutations of the ras genes have been detected in the plasma DNA of patients suffering from haematopoetic malignancies, colorectal and pancreatic cancer, sometimes prior to clinical diagnosis. Rearranged immunoglobulin heavy chain DNA has been found in the plasma of patients with non-Hodgkins lymphoma and acute B cell leukaemia. Microsatellite instability, expressed either as a new allele or a loss of one allele (LOH) occurs in the plasma and serum DNA of patients suffering from head and neck, lung and renal cell cancer. The results obtained in many different cancers have opened a new research area indicating that plasma DNA might eventually be a suitable target for the development of non-invasive diagnostic, prognostic and follow-up tests for cancer.

Animals↗

PubMed1988

Telomeric repeat from T. thermophila cross hybridizes with human telomeres.

The ends (telomeres) of eukaryotic chromosomes must have special features to ensure their stability and complete replication. Studies in yeast, protozoa, slime moulds and flagellates show that telomeres are tandem repeats of simple sequences that have a G-rich and a C-rich strand. Mammalian telomeres have yet to be isolated and characterized, although a DNA fragment within 20 kilobases of the telomeres of the short arms of the human sex chromosomes has been isolated. Recently we showed that a chromosome from the fission yeast Schizosaccharomyces pombe could, in some cases, replicate as an autonomous mini-chromosome in mouse cells. By extrapolation from other systems, we reasoned that mouse telomeres could be added to the S. pombe chromosome ends in the mouse cells. On setting out to test this hypothesis we found to our surprise that the telomeric probe used (containing both the S. pombe and Tetrahymena thermophila repeats) hybridized to a series of discrete fragments in normal mouse DNA and DNA from a wide range of eukaryotes. We show here that the sequences hybridizing to this probe are located at the telomeres of most, if not all, human chromosomes and are similar to the Tetrahymena telomeric-repeat component of the probe.

Animals↗

PubMed2005

Knockin of SV40 Tag oncogene in a mouse adenocarcinoma of the prostate model demonstrates advantageous features over the transgenic model.

Prostate cancer (CaP) is the most common cancer in adult men in North America. Since there is no naturally occurring prostate cancer in the mouse, preclinical studies stipulate for the establishment of a genetically manipulated mouse CaP model with features close to the human situation. In view of the limitations of transgenic technique-derived CaP models, herein we report the first application of knockin technology to establish a new mouse adenocarcinoma prostate model (PSP-KIMAP) by targeting of SV40 Tag to a prostate tissue-specific gene, PSP94 (prostate secretory protein of 94 amino acids). In order to demonstrate its novelty, we compared KIMAP to a PSP94 gene-directed transgenic mouse adenocarcinoma of the prostate (PSP-TGMAP) model. The CaP development of the PSP-KIMAP mice started almost immediately after puberty at 10 weeks of age from mouse prostatic intraepithelial neoplasia (mPIN) with microinvasion to well-differentiated CaP, and demonstrated a close-to-human kinetics of prolonged tumor growth and a predominance of well and moderately differentiated tumors. The invasive nature of KIMAP model was demonstrated by multitissue metastases (lymph node, lung and liver etc) and also by immunohistochemical study of multiple invasive prostate tumor markers. PSP-KIMAP model is responsive to androgen deprivation (castration). The knockin technology in our KIMAP model demonstrates highly predictive CaP development procedures and many advantageous features, which the traditional transgenic technique-derived CaP models could not reach for both basic and clinical studies. These features include the high stability of both phenotype and genotype, highly synchronous prostate cancer development, high and precise prostate tissue targeting and with no founder line variation. The differences between the two CaP models were attributed to the introduction of a single endogenous knockin mutation, resulting in a CaP model self-regulated and controlled by a prostate gene promoter/enhancer of PSP94.

Adenocarcinoma↗

PubMed2003

Development of an orally infectious Sindbis virus transducing system that efficiently disseminates and expresses green fluorescent protein in Aedes aegypti.

We have constructed an orally infectious Sindbis virus, ME2/5'2J/GFP, that expresses green fluorescent protein (GFP) in the midgut of Aedes aegypti and in other tissues as the virus disseminates. This virus has two unique features that are improvements over the SIN-based expression systems currently used in mosquitoes. First, a subgenomic RNA promoter and GFP coding sequence is located 5'- to the second subgenomic promoter and structural genes of the virus. Second, the E2 glycoprotein gene of TE/5'2J/GFP is replaced with the E2 gene of MRE16 SIN virus. The first feature enhances virus genome stability during virus dissemination from the midgut to other tissues and the second allows efficient virus entry into the midgut epithelial cells and then spread of the virus throughout the mosquito.

Aedes↗

PubMed1999

Folding stability of the kinetoplastid membrane protein-11 (KMP-11) from Leishmania infantum.

Kinetoplastid membrane protein-11 (KMP-11) is a major component of the cell surface of kinetoplastids, and acts as a potent B- and T-cell immunogen during Leishmania infection. Here we report that the Leishmania infantum KMP-11 secondary structure adopts mainly an alpha-helical conformation at pH 7.5 and that its urea- and thermally-induced unfolding constitute a fully reversible two-step process. This allows estimation of a half-denaturation temperature of approximately 65 degrees C, a delta GDH2O at 20 degrees C of approximately 14.63 kJ.mol-1, and an increment of the reaction heat of approximately 183.92 kJ.mol-1 and an entropy of approximately 543.4 J.mol-1.deg-1, respectively, for the native-denatured equilibrium of the KMP-11 in solution. We also report that the KPM-11 protein is induced to adopt a molten globule state at a pH range between pH 4 and pH 6. As a whole, the stability and the specific features of the denaturing effect induced by changes in pH are similar in KMP-11 to various other lipoproteins.

Amino Acid Sequence↗

PubMed1991

Integration of form across saccadic eye movements.

To perceive a stable world, one must somehow be able to relate visual information from successive fixations. Little is known, however, about the nature of the integrative process. By using a task which requires the integration of spatial position information from different fixations, it is demonstrated that visual information from previous fixations is preserved in a world-centered representation which is precise enough to support judgements of geometric shape. It is also shown that successive views are aligned with respect to common visual features, indicating that visual stability may be normally accomplished by a visual matching strategy in combination with cancellation by an eye-position signal.

Attention↗

PubMed1996

Ribosomal association of poly(A)-binding protein in poly(A)-deficient Saccharomyces cerevisiae.

Poly(A)-binding protein, the most abundant eukaryotic mRNP protein, is known primarily for its association with polyadenylate tails of mRNA. In the yeast, Saccharomyces cerevisiae, this protein (Pabp) was found to be essential for viability and has been implicated in models featuring roles in mRNA stability and as an enhancer of translation initiation. Although the mechanism of action is unknown, it is thought to require an activity to bind poly(A) tails and an additional capacity for an interaction with 60 S ribosomal subunits, perhaps via ribosomal protein L46 (Rpl46). We have found that a significant amount of Pabp in wild-type cells is not associated with polyribosome complexes. The remaining majority, which is found in these complexes, maintains its association even in yeast cells deficient in polyadenylated mRNA and/or Rpl46. These observations suggest that Pabp may not require interaction with poly(A) tails during translation. Further treatment of polyribosome lysates with agents known to differentially disrupt components of polyribosomes indicated that Pabp may require contact with some RNA component of the polyribosome, which could be either non-poly(A)-rich sequences of the translated mRNA or possibly a component of the ribosome. These findings suggest that Pabp may possess the ability to bind to ribosomes independently of its interaction with poly(A). We discuss these conclusions with respect to current models suggesting a multifunctional binding capacity of Pabp.

Poly A↗

PubMed2000

Dizziness in discus throwers is related to motion sickness generated while spinning.

While both discus and hammer throwing involve rotating movements resulting in the throw of an object, discus throwers sometimes report dizziness, a condition never experienced by hammer throwers. We investigated whether this susceptibility was related to the sensitivity of the thrower or to the type of throwing achieved. For the latter, we compared the determining features of gesture, gaze stabilization and projectile trajectory in both sports. A total of 22 high-level sportsmen in these 2 disciplines, half of them practising both sports, were interviewed. Slow motion video recordings of discus and hammer throwing were examined to determine the visual referential, head movements and plantar surface support area involved at each stage of the motions. Discomfort was reported by 59% of the sportsmen while throwing discus, but by none while throwing hammer. Because several individuals practised both sports, these results exclude the hypothesis of individual susceptibility to dizziness. Video analysis evidenced that during hammer throwing, visual bearings can be used more easily than during discus throwing. Moreover, there is a loss of plantar afferents and generation of head movements liable to induce motion sickness, such as Coriolis acceleration. In conclusion, although hammer and discus-throwing present numerous similarities, we demonstrate here that crucial differences in the specific execution of each sport are responsible for the dizziness experienced by discus throwers.

Adult↗