Inhibitors of beta-amyloid formation based on the beta-secretase cleavage site

A series of inhibitors of beta-amyloid formation have been developed based on the beta-secretase cleavage site (VNL-DA) of the Swedish mutant Amyloid Precursor Protein. A simple tripeptide aldehyde was found to be the most potent (IC50 = 700 nM) in the series displaying an inhibitory profile which is different from reported inhibitors of beta-amyloid formation. (C) 2000 Academic Press.

Effect of density on spatial distribution, pit formation and pit diameter of Myrmeleon acer Walker, (Neuroptera : Myrmeleontidae): patterns and processes

The effect of increasing population density on the formation of pits, their size and spatial distribution, and on levels of mortality was examined in the antlion Myrmeleon acer Walker. Antlions were kept at densities ranging from 0.4 to 12.8 individuals per 100 cm(2). The distribution of pits was regular or uniform across all densities, but antlions constructed proportionally fewer and smaller pits as density increased. Mortality through cannibalism was very low and only occurred at densities greater than five individuals per 100 cm(2). Antlions in artificially crowded situations frequently relocated their pits and when more space became available, individuals became more dispersed with time. Redistribution of this species results from active avoidance of other antlions and sand throwing associated with pit construction and maintenance, rather than any attempt to optimise prey capture per se.

Acyclic permutants of naturally occurring cyclic proteins - Characterization of cystine knot and beta-sheet formation in the macrocyclic polypeptide kalata B1

Kalata B1 is a prototypic member of the unique cyclotide family of macrocyclic polypeptides in which the major structural features are a circular peptide backbone, a triple stranded beta-sheet, and a cystine knot arrangement of three disulfide bonds. The cyclotides are the only naturally occurring family of circular proteins and have prompted us to explore the concept of acyclic permutation, i.e. opening the backbone of a cross-linked circular protein in topologically permuted ways. We have synthesized the complete suite of acyclic permutants of kalata B1 and examined the effect of acyclic permutation on structure and activity. Only two of six topologically distinct backbone loops are critical for folding into the native conformation, and these involve disruption of the embedded ring in the cystine knot. Surprisingly, it is possible to disrupt regions of the p-sheet and still allow folding into native-like structure, provided the cystine knot is intact. Kalata B1 has mild hemolytic activity, but despite the overall structure of the native peptide being retained in all but two cases, none of the acyclic permutants displayed hemolytic activity. This loss of activity is not localized to one particular region and suggests that cyclization is critical for hemolytic activity.

Aluminium alloys - their physical and mechanical properties: Grain formation in AlSi7Mg0.35 foundry alloy at low superheat

Hypoeutectic AI-Si alloys represent the most widely used alloy system for cast aluminium applications. This system has a unique behaviour with respect to grain formation where an increase in silicon content results in a transition to larger grain sizes after a minimum at an intermediate concentration. As a result of the already large solute content, grain refinement by solute additions is inefficient and nucleant particles from the common aluminium grain refiners are not as effective as in wrought alloys. However, casting conditions, such as a low pouring temperature, that promote the formation of wall crystals tie. crystals nucleated in the thermally undercooled layer at or next to mould walls) are very effective in yielding a small grain size. This paper presents results of an investigation of the effect of low superheat and mould preheat temperature on grain size. It was found that pouring temperature controls the effectiveness of the wall mechanism while mould preheat has little effect until high preheat temperatures at which a large increase in grain size occurs. The observed changes in grain size are explained in terms of the balance between nucleation rate and survival rate of crystal nuclei resulting from changes in superheat and mould temperature.

Circulating bone marrow cells can contribute to neointimal formation

To examine the source of smooth muscle-like cells during vascular healing, C57BL/6 (Ly 5.2) female mice underwent whole body irradiation followed by transfusion with 10(6) nucleated bone marrow cells from congenic (Ly 5.1) male donors. Successful repopulation (88.4 +/- 4.9%) by donor marrow was demonstrated in the female mice by flow cytometry with FITC-conjugated A20.1/Ly 5.1 monoclonal antibody after 4 weeks. The arteries of the female mice were then subjected to two types of insult: (1) The iliac artery was scratch-injured by 5 passes of a probe causing severe medial damage. After 4 weeks, the arterial lumen was obliterated by a cell-rich neointima, with cells containing a smooth muscle actin present around the residual lumen. Approximately half of these cells were of male donor origin, as evidenced by in situ hybridization with a Y-chromosome-specific probe. (2) In an organized arterial thrombus formed by inserting an 8-0 silk suture into the left common carotid artery, donor cells staining with alpha smooth muscle actin were found in those arteries sustaining serious damage but not in arteries with minimal damage, Our results suggest that bone marrow-derived cells are recruited in vascular healing as a complementary source of smooth muscle-like cells when the media is severely damaged and few resident smooth muscle cells are available to effect repair. Copyright (C) 2001 S. Karger AG, Basel.

Galaxy threshing and the formation of ultracompact dwarf galaxies

Recent spectroscopic and morphological observational studies of galaxies around NGC 1399 in the Fornax Cluster have discovered several ultracompact dwarf galaxies with intrinsic sizes of similar to 100 pc and absolute B-band magnitudes ranging from -13 to -11 mag. In order to elucidate the origin of these enigmatic objects, we perform numerical simulations on the dynamical evolution of nucleated dwarf galaxies orbiting NGC 1399 and suffering from its strong tidal gravitational field. Adopting a plausible scaling relation for dwarf galaxies, we find that the outer stellar components of a nucleated dwarf are totally removed. This is due to them being tidally stripped over the course of several passages past the central region of NGC 1399. The nucleus, however, manages to survive. We also find that the size and luminosity of the remnant are similar to those observed for ultracompact dwarf galaxies, if the simulated precursor nucleated dwarf has a mass of similar to 10(8) M.. These results suggest that ultracompact dwarf galaxies could have previously been more luminous dwarf spheroidal or elliptical galaxies with rather compact nuclei.

A new formation model for M32: a threshed early-type spiral galaxy?

The origin of M32, the closest compact elliptical galaxy (cE), is a long-standing puzzle of galaxy fort-nation in the Local Group. Our N-body/smoothed particle hydrodynamics simulations suggest a new scenario in which the strong tidal field of M31 can transform a spiral galaxy into a compact elliptical galaxy. As a low-luminosity spiral galaxy plunges into the central region of M31, most of the outer stellar and gaseous components of its disk are dramatically stripped as a result of M31's tidal field. The central bulge component, on the other hand, is just weakly influenced by the tidal field, owing to its compact configuration, and retains its morphology. M31's strong tidal field also induces rapid gas transfer to the central region, triggers a nuclear starburst, and consequently forms the central high-density and more metal-rich stellar populations with relatively young ages. Thus, in this scenario, M32 was previously the bulge of a spiral galaxy tidally interacting with M31 several gigayears ago. Furthermore, we suggest that cE's like M32 are rare, the result of both the rather narrow parameter space for tidal interactions that morphologically transform spiral galaxies into cE's and the very short timescale (less than a few times 10(9) yr) for cE's to be swallowed by their giant host galaxies (via dynamical friction) after their formation.

The evolution and star formation of dwarf galaxies in the Fornax Cluster

We present the results of a spectroscopic survey of 675 bright (16.5 < b(J) < 18) galaxies in a 6 degrees field centred on the Fornax cluster with the FLAIR-II spectrograph on the UK Schmidt Telescope. Three galaxy samples were observed: compact galaxies to search for new blue compact dwarfs, candidate M 32-like compact dwarf ellipticals, and a subset of the brightest known cluster members in order to study the cluster dynamics. We measured redshifts for 516 galaxies, of which 108 were members of the Fornax Cluster. Defining dwarf galaxies to be those with b(J) greater than or equal to 15 (M-B greater than or equal to - 16.5), there are a total of 62 dwarf cluster galaxies in our sample. Nine of these are new cluster members previously misidentified as background galaxies. The cluster dynamics show that the dwarf galaxies are still falling into the cluster whereas the giants are virialized. We classified the observed galaxies as late-type if we detected H alpha emission at an equivalent width greater than 1 Angstrom. The spectra were obtained through fixed apertures, so they reflect activity in the galaxy cores, but this does not significantly bias the classifications of the compact dwarfs in our sample. The new classifications reveal a higher rate of star formation among the dwarf galaxies than suggested by morphological classification: 35 per cent have significant H alpha emission indicative of star formations but only 19 per cent were morphologically classified as late-types. The star-forming dwarf galaxies span the full range of physical sizes and we find no evidence in our data for a distinct class of star-forming blue compact dwarf (BCD) galaxy. The distribution of scale sizes is consistent with evolutionary processes which transform late-type dwarfs to early-type dwarfs. The fraction of dwarfs with active star formation drops rapidly towards the cluster centre: this is the usual density-morphology relation confirmed here for dwarf galaxies. The star-forming dwarfs are concentrated in the outer regions of the cluster, the most extreme in an infalling subcluster. We estimate gas depletion time-scales for five dwarfs with detected Hi emission: these are long (of order 10(10) yr), indicating that an active gas removal process must be involved if they are transformed into gas-poor dwarfs as they fall further into the cluster. Finally, in agreement with our previous results, we find no compact dwarf elliptical (M 32-like) galaxies in the Fornax Cluster.

Postural activity of the diaphragm is reduced in humans when respiratory demand increases

1. Respiratory activity of the diaphragm and other respiratory muscles is normally co-ordinated with their other functions, such as for postural control of the trunk when the limbs move. The integration may occur by summation of two inputs at the respiratory motoneurons. The present study investigated whether postural activity of the diaphragm changed when respiratory drive increased with hypercapnoea. 2. Electromyographic (EMG) recordings of the diaphragm and other trunk muscles were made with intramuscular electrodes in 13 healthy volunteers. Under control conditions and while breathing through increased dead-space,subjects made rapid repetitive arm movements to disturb the stability of the spine for four periods each lasting 10 s, separated by 50 s. 3. End-tidal CO2, and ventilation increased for the first 60-120 s of the trial then reached a plateau. During rapid arm movement at the start of dead-space breathing, diaphragm EMG became tonic with superimposed modulation at the frequencies of respiration and arm movement. However, when the arm was moved after 60 s of hypercapnoea, the tonic diaphragm EMG during expiration and the phasic activity with arm movement were reduced or absent. Similar changes occurred for the expiratory muscle transversus abdominis, but not for the erector spinae. The mean amplitude of intra-abdominal pressure and the phasic changes with arm movement were reduced after 60 s of hypercapnoea. 4. The present data suggest that increased central respiratory drive may attenuate the postural commands reaching motoneurons. This attenuation can affect the key inspiratory and expiratory muscles and is likely to be co-ordinated at a pre-motoneuronal site.

Neointimal formation by circulating bone marrow cells

The origin of smooth muscle cells involved in vascular healing was examined. Eighteen C57BL/6 (Ly 5.2) female mice underwent whole body irradiation followed by transfusion with 10(6) bone nucleated marrow cells from congenic (Ly 5.1) male donors. Successful repopulation by donor marrow was demonstrated after 4 weeks by flow cytometry with FITC-conjugated A20.1/Ly 5.1 monoclonal antibody. The iliac artery of six of the chimeric mice was scratch-injured by five passes of a probe, causing severe medial damage. After 4 weeks the arterial lumen was obliterated by a cell-rich neointima, with alpha-smooth muscle actin-containing cells present around the residual lumen. Approximately half of these cells were of male donor origin, as evidenced by in situ hybridization with a Y chromosome-specific probe. An organized arterial thrombus was formed in the remaining 12 chimeric mice by inserting an 8.0 silk suture into the left common carotid artery. Donor cells staining with alpha-smooth muscle actin were found in those arteries sustaining serious damage but not in arteries with minimal damage. Our results suggest that bone marrow-derived cells are recruited in vascular healing as a complementary source of smooth muscle-like cells when the media is severely damaged and few resident smooth muscle cells are available to effect repair.

Halo formation in directional solidification

A new model of halo formation in directional solidification is presented. The model describes halo formation in terms of competitive growth between the halo phase and coupled eutectic in liquid with a nominal composition that follows the primary phase liquidus extension with decreasing temperature. The model distinguishes between the effects of constitutional, capillarity and (where applicable) kinetic undercooling and avoids a number of theoretical inconsistencies associated with previous models. The critical growth rate for halo formation in directionally solidified hypereutectic Al-Si alloys is calculated using the model in conjunction with models of primary phase and coupled eutectic growth from the literature. The calculated result agrees reasonably well with the experimental result of Yilmaz and Elliott (Met. Sci. 18 (1984) 362), given the use of a relatively simple isolated dendrite tip model to calculate the growth undercooling of the halo tip. (C) 2002 Acta Materialia Inc. Published by Elsevier Science Ltd. All rights reserved.

Blockade of vascular smooth muscle cell proliferation and intimal thickening after balloon injury by the sulfated oligosaccharide PI-88: Phosphomannopentaose sulfate directly binds FGF-2, blocks cellular signaling, and inhibits proliferation

Percutaneous transluminal coronary angioplasty is a frequently used interventional technique to reopen arteries that have narrowed because of atherosclerosis. Restenosis, or renarrowing of the artery shortly after angioplasty, is a major limitation to the success of the procedure and is due mainly to smooth muscle cell accumulation in the artery wall at the site of balloon injury. In the present study, we demonstrate that the antiangiogenic sulfated oligosaccharide, PI-88, inhibits primary vascular smooth muscle cell proliferation and reduces intimal thickening 14 days after balloon angioplasty of rat and rabbit arteries. PI-88 reduced heparan sulfate content in the injured artery wall and prevented change in smooth muscle phenotype. However, the mechanism of PI-88 inhibition was not merely confined to the antiheparanase activity of this compound. PI-88 blocked extracellular signal-regulated kinase-1/2 (ERK1/2) activity within minutes of smooth muscle cell injury. It facilitated FGF-2 release from uninjured smooth muscle cells in vitro, and super-released FGF-2 after injury while inhibiting ERK1/2 activation. PI-88 inhibited the decrease in levels of FGF-2 protein in the rat artery wall within 8 minutes of injury. PI-88 also blocked injury-inducible ERK phosphorylation, without altering the clotting time in these animals. Optical biosensor studies revealed that PI-88 potently inhibited (K-i 10.3 nmol/L) the interaction of FGF-2 with heparan sulfate. These findings show for the first time the capacity of this sulfated oligosaccharide to directly bind FGF-2, block cellular signaling and proliferation in vitro, and inhibit injury-induced smooth muscle cell hyperplasia in two animal models. As such, this study demonstrates a new role for PI-88 as an inhibitor of intimal thickening after balloon angioplasty. The full text of this article is available online at http://www.circresaha.org.

Micromorphological study of slumping in a hardsetting seedbed under various wetting conditions

Slumping of hardsetting seedbeds upon wetting has not been extensively studied despite the likelihood that it determines the physical properties after drying. Slumping results from processes similar to those involved in crusting except that overburden pressure can dominate rather than rainfall kinetic energy. Only a few studies have dealt with the morphological description of slumping. To simulate different climatic and management conditions, repacked seedbeds of a hardsetting sandy-loam soil were subjected to a range of wetting conditions, e.g. capillary rise, immersion, and rainfall simulation. Slumping processes were characterized using qualitative and quantitative micromorphological observations of polished blocks and thin sections from resin-impregnated samples. A morphogenetical framework was proposed to help description of the complex associations of processes which can lead to structural collapse (crusting and slumping) on wetting. Three main stages were considered, i.e. aggregate disruption or abrasion, relocation of the released material, and compaction. In the hardsetting material studied here, structural collapse under slow wetting occurred at the bottom of cores due to aggregate coalescence under overburden pressure. Coalescence required aggregate cohesion being reduced by microcracking; therefore, it differed from the coalescence previously described in unstable silty loam soils where microcracking was not necessary for aggregates to coalesce. Macroporosity decreased most strongly under fast wetting due to physical dispersion and aggregate breakdown. Under simulated rainfall, compaction by raindrops could not be distinguish from aggregate breakdown. The role of overburden pressure and of rainfall kinetic energy remains to be stated; new data are required including measurement of total porosity in the initial, wet, and dry states. (C) 2003 Elsevier B.V. All rights reserved.

Potential triggers for akinete differentiation in an Australian strain of the cyanobacterium Cylindrospermopsis raciborskii (AWT 205/1)

Understanding the triggers for some cyanobacteria of the Nostocales and Stigonematales orders to produce specialised reproductive cells termed akinetes, is very important to gain further insights into their ecology. By improving our understanding of their life cycle, appropriate management options may be devised to control the formation of these cells, and therefore the potential bloom inoculum which they are thought to provide, may be reduced. This study investigated the effect of chemical (phosphorus limitation), and environmental variables (temperature shock) on akinete differentiation in the freshwater cyanobacterium Cylindrospermopsis raciborskii (AWT 205/1). From the preliminary results, it is suggested that the availability of phosphorus and changes in temperature were a necessary requirement for the formation of akinetes in this particular strain of C. raciborskii. In the four phosphorus treatments investigated (0, 3, 38 and 75 mug l(-1) P), only the two higher treatments produced akinetes (approximately 220 ml(-1)). When the first akinetes were observed in the 38 and 75 mug l(-1) P treatments, filterable reactive phosphorus (FRP) concentrations in the medium were approximately 22 and 52 mug l(-1) P, respectively, indicating that there was no phosphorus limitation. In the temperature shock experiment, akinetes were observed in the 15 and 20degreesC treatments. However, akinetes were degraded (pale yellow colour, limited swelling and shrivelled edges) and in much lower concentrations, which was thought to be a result of the daily temperature shock. We suggest that the formation of akinetes in C. raciborskii (AWT 205/1) can be triggered by an initial temperature shock and that phosphorus is a necessary requirement to allow further growth and full development of akinetes.