Mechanistic studies of amide bond scission during acidolytic deprotection of Pip containing peptide.

Unusual TFA catalyzed cleavage reaction is reported for peptide containing pipecolic acid residues. Although the use of TFA under standard cleavage conditions is sufficiently mild to prevent degradation of the desired products. the amide bond between consecutive pipecolic acid residues is unexpectedly hydrolyzed by standard TFA treatment. The hydrolysis is proposed to proceed via an oxazolinium ion intermediate, This mechanism is supported by H/D exchange as observed by ESI-MS and NMR experiments.

The impact of dose escalation and resistance modulation in older patients with acute myeloid leukaemia and high risk myelodysplastic syndrome: the results of the LRF AML14 trial.:the results of the LRF AML14 trial

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m(2) vs. 35 mg/m(2); (ii) Cytarabine 200 mg/m(2) vs. 400 mg/m(2) in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m(2) were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

Pulsating or not? A search for hidden pulsations below the red edge of the ZZ Ceti instability strip

The location of the red edge of the ZZ Ceti instability strip is defined observationally as being the lowest temperature for which a white dwarf with a H-rich atmosphere (DA) is known to exhibit periodic brightness variations. Whether this cut-off in flux variations is actually due to a cessation of pulsation or merely due to the attenuation of any variations by the convection zone, rendering them invisible, is not clear. The latter is a theoretical possibility because with decreasing effective temperature, the emergent flux variations become an ever smaller fraction of the amplitude of the flux variations in the interior. In contrast to the flux variations, the visibility of the velocity variations associated with the pulsations is not thought to be similarly affected. Thus, models imply that were it still pulsating, a white dwarf just below the observed red edge should show velocity variations. In order to test this possibility, we used time-resolved spectra of three DA white dwarfs that do not show photometric variability, but which have derived temperatures only slightly lower than the coolest ZZ Ceti variables. We find that none of our three targets show significant periodic velocity variations, and set 95% confidence limits on amplitudes of 3.0, 5.2, and 8.8 km s(-1). Thus, for two out of our three objects, we can rule out velocity variations as large as 5.4 km s(-1) observed for the strongest mode in the cool white dwarf pulsator ZZ Psc. In order to verify our procedures, we also examined similar data of a known ZZ Ceti, HL Tau 76. Applying external information from the light curve, we detect significant velocity variations for this object with amplitudes of up to 4 km s(-1). Our results suggest that substantial numbers of pulsators having large velocity amplitudes do not exist below the observed photometric red edge and that the latter probably reflects a real termination of pulsations.

Time-resolved optical spectroscopy of the pulsating DA white dwarf HS0507+0434B - New constraints on mode identification and pulsation properties

We present a detailed analysis of time-resolved optical spectra of the ZZ Ceti white dwarf, HS 0507+0434B. Using the wavelength dependence of observed mode amplitudes, we deduce the spherical degree, l, of the modes, most of which have l = 1. The presence of a large number of combination frequencies (linear sums or differences of the real modes) enabled us not only to test theoretical predictions but also to indirectly infer spherical and azimuthal degrees of real modes that had no observed splittings. In addition to the above, we measure line-of-sight velocities from our spectra. We find only marginal evidence for periodic modulation associated with the pulsation modes: at the frequency of the strongest mode in the lightcurve, we measure an amplitude of 2.6 +/- 1.0 kms(-1), which has a probability of 2% of being due to chance; for the other modes, we find lower values. Our velocity amplitudes and upper limits are smaller by a factor of two compared to the amplitudes found in ZZ Psc. We find that this is consistent with expectations based on the position of HS 0507+0434B in the instability strip. Combining all the available information from data such as ours is a first step towards constraining atmospheric properties in a convectionally unstable environment from an observational perspective.

Sequential expression of putative stem cell markers in gastric carcinogenesis

Gastric carcinogenesis has been well documented in the step-wise histopathological model, known as Correa pathway. Several biomarkers including CD44, Musashi-1 and CD133 have been reported as putative stem cell (PSC) markers.

Ornithokinin (avian bradykinin) from the skin of the Chinese bamboo odorous frog, Odorrana versabilis

One of the most widespread and abundant families of pharmacologically active peptides in amphibian defensive skin secretions is the bradykinins and related peptides. Despite retaining certain primary structural attributes that assign them to this peptide family, bradykinins and related peptides are unique among amphibian skin peptides in that they exhibit a wide range of primary structural variations, post-translational modifications and/or N-terminal or C-terminal extensions. Initially it was believed that their high degree of primary structural heterogeneity was reflective of random gene mutations within species, but latterly, there is an increasing body of evidence that the spectrum of structural modifications found within this peptide family is reflective of the vertebrate predator spectrum of individual species. Here we report the discovery of ornithokinin (avian bradykinin – Thr6, Leu8-bradykinin) in the skin secretion of the Chinese bamboo odorous frog, Odorrana versabilis. Molecular cloning of its biosynthetic precursor-encoding cDNA from a skin secretion-derived cDNA library revealed a deduced open-reading frame of 86 amino acid residues, encoding a single copy of ornithokinin towards its C-terminus. The domain architecture of this ornithokinin precursor protein was consistent with that of a typical amphibian skin peptide and quite different to that of the ornithokininogen from chicken plasma. Ornithokinin was reported to induce hypotension in the chicken and to contract the chicken oviduct but to have no obvious effect on the rat uterus. However, in this study, synthetic ornithokinin was found to contract the rat ileum (EC50 = 539 nM) and to increase contraction frequency in the rat uterus (EC50 = 1.87 μM).

Prescriptive Durability Specification

A specification that defines required results, criteria by which performance will be judged, and methods of evaluation, without requirements for how the results are to be obtained

Test methods for concrete durability indicators

Durability of concrete structures is primarily dependent on the environmental influences, i.e. the penetration of aggressive substances in the structural element from the environment. Penetrability is an important durability indicator of concrete and by specifying different classes of penetrability of concrete it should be possible to design a structure with the required resistance to environmental loads. This chapter covers descriptions of the available and commonly applied in situ and laboratory, non-invasive and semi-invasive test methods for evaluating concrete penetrability properties.

Principles of the performance-based approach for concrete durability

In general, design approaches for durability can be divided into prescriptive design concepts and performance-based design concepts.

Application examples of performance-based specification and quality control

This chapter presents an overview on several performance-based approaches for concrete durability specification and conformity assessment of the as-built structure.

Anti-biofilm activity of ultrashort cinnamic acid peptide derivatives against medical device-related pathogens

The threat of antimicrobial resistance has placed increasing emphasis on the development of innovative approaches to eradicate multidrug-resistant pathogens. Biofilm-forming microorganisms, for example, Staphylococcus epidermidis and Staphylococcus aureus, are responsible for increased incidence of biomaterial infection, extended hospital stays and patient morbidity and mortality. This paper highlights the potential of ultrashort tetra-peptide conjugated to hydrophobic cinnamic acid derivatives. These peptidomimetic molecules demonstrate selective and highly potent activity against resistant biofilm forms of Gram-positive medical device-related pathogens. 3-(4-Hydroxyphenyl)propionic)-Orn-Orn-Trp-Trp-NH2 displays particular promise with minimum biofilm eradication concentration (MBEC) values of 125 µg/ml against methicillin sensitive (ATCC 29213) and resistant (ATCC 43300) S. aureus and activity shown against biofilm forms of Escherichia coli (MBEC: 1000 µg/ml). Kill kinetics confirms complete eradication of established 24-h biofilms at MBEC with 6-h exposure. Reduced cell cytotoxicity, relative to Gram-positive pathogens, was proven via tissue culture (HaCaT) and haemolysis assays (equine erythrocytes).

Existing in nature as part of the immune response, antimicrobial peptides display great promise for exploitation by the pharmaceutical industry in order to increase the library of available therapeutic molecules. Ultrashort variants are particularly promising for translation as clinical therapeutics as they are more cost-effective, easier to synthesise and can be tailored to specific functional requirements based on the primary sequence allowing factors such as spectrum of activity to be varied.