Deglacial landform assemblage records fast ice-flow and retreat, Inner Hebrides, Scotland

High-resolution bathymetric data have been central to recent advances in the understanding of past dynamics of the former British–Irish Ice Sheet (BIIS). As approximately two-thirds of the former BIIS was probably marine-based during the Last Glacial Maximum (LGM) (c. 29–23 ka), geomorphic observations of the seabed are required increasingly to understand the extent, pattern and timing of past glaciation. Until recently, glacial reconstructions for the Inner Hebrides, offshore of western Scotland, have been based primarily on terrestrial observations. Previous workers have proposed generalized reconstructions in which the Inner Hebrides are located within a significant former ice-sheet flow pathway that drained the western Scottish sector of the BIIS, feeding the Barra Fan during the LGM and earlier glaciations (Fig. 1). Results from numerical ice-sheet modelling suggest that former ice-flow velocities within the region were on the order of hundreds to thousands of metres per year, but yield further insight by demonstrating how dynamic binge/purge cycles may have affected ice-sheet mass balance over time (Hubbard et al. 2009). Following the LGM, ice-sheet retreat through the area is estimated to have been in the order of 20 m per year (Clark et al. 2012). Here we present swath-bathymetric data from the Inner Hebrides that provide in situ constraints on ice-sheet flow and subsequent retreat dynamics from within this important sector of the BIIS

Synthesis and Biological Evaluation (in Vitro and in Vivo) of Cyclic RGD Peptidomimetic - Paclitaxel Conjugates Targeting Integrin alphaVbeta3

A small library of integrin ligand - Paclitaxel conjugates 10-13 was synthesized with the aim of using the tumor-homing cyclo[DKP-RGD] peptidomimetics for site-directed delivery of the cytotoxic drug. All the Paclitaxel-RGD constructs 10-13 inhibited biotinylated vitronectin binding to the purified alphaVbeta3 integrin receptor at low nanomolar concentration and showed in vitro cytotoxic activity against a panel of human tumor cell lines similar to that of Paclitaxel. Among the cell lines, the cisplatin-resistant IGROV-1/Pt1 cells expressed high levels of integrin alphaVbeta3, making them attractive to be tested in in vivo models. Cyclo[DKP-f3-RGD]-PTX 11 displayed sufficient stability in physiological solution and in both human and murine plasma to be a good candidate for in vivo testing. In tumor-targeting experiments against the IGROV-1/Pt1 human ovarian carcinoma xenotransplanted in nude mice, compound 11 exhibited a superior activity than Paclitaxel, despite the lower (ca. half) molar dosage used

The census of nuclear activity of late-type galaxies in the Virgo cluster

The first spectroscopic census of AGNs associated to late-type galaxies in the Virgo cluster is carried on by observing 213 out of a complete set of 237 galaxies more massive than M_dyn>10^{8.5} solar masses. Among them, 77 are classified as AGNs (including 21 transition objects, 47 LINERs and 9 Seyferts), and comprize 32% of the late-type galaxies in Virgo. Due to spectroscopic incompleteness at most 21 AGNs are missed in the survey, so that the fraction would increase up to 41%. Using corollary Near-IR observations, that enable us to estimate galaxies dynamical masses, it is found that AGNs are hosted exclusively in massive galaxies, i.e. M_dyn\gsim 10^{10} solar masses. Their frequency increases steeply with the dynamical mass from zero at M_dyn\approx10^{9.5} solar masses to virtually 1 at M_dyn>10^{11.5} solar masses. These frequencies are consistent with the ones of low luminosity AGNs found in the general field by the SDSS. Massive galaxies that harbor AGNs commonly show conspicuous r-band star-like nuclear enhancements. Conversely they often, but not necessarily contain massive bulges. Few well known AGNs (e.g. M61, M100, NGC4535) are found in massive Sc galaxies with little or no bulge. The AGN fraction seems to be only marginally sensitive to galaxy environment. We infer the black hole masses using the known scaling relations of quiescent black holes. No black holes lighter than $\sim 10^6$ \msol are found active in our sample.Comment: The paper contains 13 figures and 5 tables; accepted for publication in MNRA

Cyclic RGD peptidomimetics containing bifunctional diketopiperazine scaffolds as new potent integrin ligands

The synthesis of eight bifunctional diketopiperazine (DKP) scaffolds is described; these were formally derived from 2,3-diaminopropionic acid and aspartic acid (DKP-1-DKP-7) or glutamic acid (DKP-8) and feature an amine and a carboxylic acid functional group. The scaffolds differ in the configuration at the two stereocenters and the substitution at the diketopiperazinic nitrogen atoms. The bifunctional diketopiperazines were introduced into eight cyclic peptidomimetics containing the Arg-Gly-Asp (RGD) sequence. The resulting RGD peptidomimetics were screened for their ability to inhibit biotinylated vitronectin binding to the purified integrins \u3b1 v\u3b2 3 and \u3b1 v\u3b2 5, which are involved in tumor angiogenesis. Nanomolar IC 50 values were obtained for the RGD peptidomimetics derived from trans DKP scaffolds (DKP-2-DKP-8). Conformational studies of the cyclic RGD peptidomimetics by 1H NMR spectroscopy experiments (VT-NMR and NOESY spectroscopy) in aqueous solution and Monte Carlo/Stochastic Dynamics (MC/SD) simulations revealed that the highest affinity ligands display well-defined preferred conformations featuring intramolecular hydrogen-bonded turn motifs and an extended arrangement of the RGD sequence [C\u3b2(Arg)-C\u3b2(Asp) average distance 658.8 \uc5]. Docking studies were performed, starting from the representative conformations obtained from the MC/SD simulations and taking as a reference model the crystal structure of the extracellular segment of integrin \u3b1 v\u3b2 3 complexed with the cyclic pentapeptide, Cilengitide. The highest affinity ligands produced top-ranked poses conserving all the important interactions of the X-ray complex. Copyright \ua9 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease

Ferritins: furnishing proteins with iron

Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe2+ oxidation and O2 reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores and examine in detail how three selected ferritins oxidise Fe2+ in order to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins

Trichphyton violaceum and T. soudanese: re-emerging pathogens in Italy, 2005-2013

Dermatomycoses due to Trichophyton violaceum are described in Mediterranean Countries, North Africa and in the Horn of Africa where T. soudanense is present too, but it was rare until few years ago in Italy. Aim of the present study was to evaluate an Italian multicenter 9 year (2005-2013) experience concerning these re-emerging pathogens. Fifty three fungal strains were sent from clinical laboratories to the Medical Mycology Committee (CoSM) - Italian Association of Clinical Microbiology (AMCLI) for mycological confirmation. Strains were identified as T. violaceum (23) and T. soudanense (30) by phenotypic and genotypic methods. These dermatophytes present epidemiological (high rate of inter-human transmission, high risk among adopted children coming from countries of either the Horn of Africa or Sub-Saharan Africa also in outbreaks of tinea capitis) and clinical peculiarities (reduced alopecia, presence of exudative lesions) confirming the originality of these \u201cimported\u201d dermatophyte infection

Bacterial toxin inhibitors based on multivalent scaffolds.

Protein toxins released by certain intestinal bacteria are the cause of many diarrhoeal diseases including cholera and travellers' diarrhoea. The toxins enter their target cells by first binding to specific glycolipids in the cell membrane. Inhibition of these protein-carbohydrate interactions has the potential to prevent the toxins from reaching their site of action, and thus avoid the ensuing diarrhoea. Simple oligosaccharides typically have low affinities for the protein toxins, therefore inhibitor design has focussed on exploiting the principles of multivalency: multiple weak interactions acting in concert can enhance the overall binding interaction. The major classes of multivalent inhibitors investigated to date will be discussed; these include glycopolymers, glycodendrimers, tailored glycoclusters and inhibitors exploiting templated assembly

Four domains for concurrency

AbstractWe give four domains for concurrency in a uniform way by means of domain equations. The domains are intended for modelling the four possible combinations of linear time versus branching time, and of interleaving versus noninterleaving concurrency. We use the linear time, noninterleaved domain to give operational and denotational semantics for a simple concurrent language with recursion, and prove that O = D