Beyond amyloid: a diverse portfolio of novel drug discovery programs for Alzheimer's disease and related dementias

Although the molecular mechanisms underlying the pathogenesis of Alzheimer's disease and other related neurodegenerative diseases remain unclear, accumulation of misfolded proteins, neuroinflammation, mitochondrial dysfunction and perturbed calcium homeostasis have been identified as key events leading to neuronal loss during neurodegeneration. Evidence for 'druggable' targets for each of these key mechanisms was presented by the Alzheimer's Drug Discovery Foundation-funded investigators at the 12th International Conference on Alzheimer's Drug Discovery, Jersey City, NJ, 26-27 September 2011 http://www.worldeventsforum.com/addf/addrugdiscovery

Protein kinase C and rho activated coiled coil protein kinase 2 (ROCK2) modulate Alzheimer's APP metabolism and phosphorylation of the Vps10-domain protein, SorL1

<p>Abstract</p> <p>Background</p> <p>Generation of the amyloid β (Aβ) peptide of Alzheimer's disease (AD) is differentially regulated through the intracellular trafficking of the amyloid β precursor protein (APP) within the secretory and endocytic pathways. Protein kinase C (PKC) and rho-activated coiled-coil kinases (ROCKs) are two "third messenger" signaling molecules that control the relative utilization of these two pathways. Several members of the Vps family of receptors (Vps35, SorL1, SorCS1) play important roles in post-<it>trans</it>-Golgi network (<it>TGN</it>) sorting and generation of APP derivatives, including Aβ at the TGN, endosome and the plasma membrane. We now report that Vps10-domain proteins are candidate substrates for PKC and/or ROCK2 and act as phospho-state-sensitive physiological effectors for post-<it>TGN </it>sorting of APP and its derivatives.</p> <p>Results</p> <p>Analysis of the SorL1 cytoplasmic tail revealed multiple consensus sites for phosphorylation by protein kinases. SorL1 was subsequently identified as a phosphoprotein, based on sensitivity of its electrophoretic migration pattern to calf intestine alkaline phosphatase and on its reaction with anti-phospho-serine antibodies. Activation of PKC resulted in increased shedding of the ectodomains of both APP and SorL1, and this was paralleled by an apparent increase in the level of the phosphorylated form of SorL1. ROCK2, the neuronal isoform of another protein kinase, was found to form complexes with SorL1, and both ROCK2 inhibition and ROCK2 knockdown enhanced generation of both soluble APP and Aβ.</p> <p>Conclusion</p> <p>These results highlight the potential importance of SorL1 in elucidating phospho-state sensitive mechanisms in the regulation of metabolism of APP and Aβ by PKC and ROCK2.</p

Obscured star formation in intermediate-density environments:A Spitzer study of the Abell 901/902 supercluster

We explore the amount of obscured star formation as a function of environment in the Abell 901/902 (A901/902) supercluster at z = 0.165 in conjunction with a field sample drawn from the A901 and CDFS fields, imaged with the Hubble Space Telescope as part of the Space Telescope A901/902 Galaxy Evolution Survey and Galaxy Evolution from Morphology and Spectral Energy Distributions (SEDs) Survey. We combine the combo-17 near-UV/optical SED with Spitzer 24 mu m photometry to estimate both the unobscured and obscured star formation in galaxies with M-* > 10(10) M-circle dot. We find that the star formation activity in massive galaxies is suppressed in dense environments, in agreement with previous studies. Yet, nearly 40% of the star-forming (SF) galaxies have red optical colors at intermediate and high densities. These red systems are not starbursting; they have star formation rates (SFRs) per unit stellar mass similar to or lower than blue SF galaxies. More than half of the red SF galaxies have low infrared-to-ultraviolet (IR-to-UV) luminosity ratios, relatively high Sersicindices, and they are equally abundant at all densities. They might be gradually quenching their star formation, possibly but not necessarily under the influence of gas-removing environmental processes. The other greater than or similar to 40% of the red SF galaxies have high IR-to-UV luminosity ratios, indicative of high dust obscuration. They have relatively high specific SFRs and are more abundant at intermediate densities. Our results indicate that while there is an overall suppression in the SF galaxy fraction with density, the small amount of star formation surviving the cluster environment is to a large extent obscured, suggesting that environmental interactions trigger a phase of obscured star formation, before complete quenching

Retrieval of the Alzheimer's amyloid precursor protein from the endosome to the TGN is S655 phosphorylation state-dependent and retromer-mediated

Background: Retrograde transport of several transmembrane proteins from endosomes to the trans-Golgi network (TGN) occurs via Rab 5-containing endosomes, mediated by clathrin and the recently characterized retromer complex. This complex and one of its putative sorting receptor components, SorLA, were reported to be associated to late onset Alzheimer's disease (AD). The pathogenesis of this neurodegenerative disorder is still elusive, although accumulation of amyloidogenic Abeta is a hallmark. This peptide is generated from the sucessive β- and γ- secretase proteolysis of the Alzheimer's amyloid precursor protein (APP), events which are associated with endocytic pathway compartments. Therefore, APP targeting and time of residence in endosomes would be predicted to modulate Abeta levels. However, the formation of an APP- and retromer-containing protein complex with potential functions in retrieval of APP from the endosome to the TGN had, to date, not been demonstrated directly. Further, the motif(s) in APP that regulate its sorting to the TGN have not been characterized. Results: Through the use of APP-GFP constructs, we show that APP containing endocytic vesicles targeted for the TGN, are also immunoreactive for clathrin-, Rab 5- and VPS35. Further, they frequently generate protruding tubules near the TGN, supporting an association with a retromer-mediated pathway. Importantly, we show for the first time, that mimicking APP phosphorylation at S655, within the APP 653YTSI656 basolateral motif, enhances APP retrieval via a retromer-mediated process. The phosphomimetic APP S655E displays decreased APP lysosomal targeting, enhanced mature half-life, and decreased tendency towards Abeta production. VPS35 downregulation impairs the phosphorylation dependent APP retrieval to the TGN, and decreases APP half-life. Conclusions: We reported for the first time the importance of APP phosphorylation on S655 in regulating its retromer-mediated sorting to the TGN or lysosomes. Significantly, the data are consistent with known interactions involving the retromer, SorLA and APP. Further, these findings add to our understanding of APP targeting and potentially contribute to our knowledge of sporadic AD pathogenesis representing putative new targets for AD therapeutic strategies

Technological capabilities to assess digital excellence in hospitals in high performing healthcare systems::an international eDelphi exercise

Background: Hospitals worldwide are developing ambitious digital transformation programs as part of broader efforts to create digitally advanced health care systems. However, there is as yet no consensus on how best to characterize and assess digital excellence in hospitals. Objective: Our aim was to develop an international agreement on a defined set of technological capabilities to assess digital excellence in hospitals. Methods: We conducted a two-stage international modified electronic Delphi (eDelphi) consensus-building exercise, which included a qualitative analysis of free-text responses. In total, 31 international health informatics experts participated, representing clinical, academic, public, and vendor organizations. Results: We identified 35 technological capabilities that indicate digital excellence in hospitals. These are divided into two categories: (a) capabilities within a hospital (n=20) and (b) capabilities enabling communication with other parts of the health and social care system, and with patients and carers (n=15). The analysis of free-text responses pointed to the importance of nontechnological aspects of digitally enabled change, including social and organizational factors. Examples included an institutional culture characterized by a willingness to transform established ways of working and openness to risk-taking. The availability of a range of skills within digitization teams, including technological, project management and business expertise, and availability of resources to support hospital staff, were also highlighted. Conclusions: We have identified a set of criteria for assessing digital excellence in hospitals. Our findings highlight the need to broaden the focus from technical functionalities to wider digital transformation capabilities

Interacting Galaxies in the A901/902 Supercluster with STAGES

We present a study of galaxy mergers and the influence of environment in the Abell 901/902 supercluster at z~0.165. We use HST ACS F606W data from the STAGES survey, COMBO-17, Spitzer 24um, and XMM-Newton X-ray data. Our analysis utilizes both a visual classification system, and quantitative CAS parameters to identify systems which show evidence of a recent or ongoing merger of mass ratio >1/10. Our results are: (1) After visual classification and minimizing the contamination from false projection pairs, we find that the merger fraction f_merge is 0.023+/-0.007. The estimated fractions of likely major mergers, likely minor mergers, and ambiguous cases are 0.01+/-0.004, 0.006+/-0.003, and 0.007+/-0.003, respectively. (2) The mergers lie outside the cluster core of radius R < 0.25 Mpc: the lack of mergers in the core is likely due to the large galaxy velocity dispersion in the core. Mergers populate the region (0.25 Mpc < R <= 2 Mpc) between the core and outskirt. In this region, the estimated frequency of mergers is similar to those seen at typical group overdensities. This suggests ongoing growth of the clusters via accretion of group and field galaxies. (3) We compare our observed merger fraction with those reported in other clusters and groups out to z~0.4. Existing data points on the merger fraction for L<= L* galaxies in clusters allow for a range of evolutionary scenarios. (4) The fraction of mergers, which lie on the blue cloud is 80%+/-18% versus 34%+/-7% for non-interacting galaxies, implying that interacting galaxies are preferentially blue. (5) The average SFR, based on UV or UV+IR data, is enhanced by a factor of ~1.5 to 2 in mergers compared to non-interacting galaxies. However, mergers in the clusters contribute only a small fraction (between 10% and 15%) of the total SFR density.(Abridged)Comment: Accepted for publication in ApJ. 34 pages, 16 figures. Version with full resolution figures available at: http://www.as.utexas.edu/~alh/apj/int/ ; updated abridged abstrac

Barred Galaxies in the Abell 901/2 Supercluster with STAGES

We present a study of bar and host disk evolution in a dense cluster environment, based on a sample of ~800 bright (MV <= -18) galaxies in the Abell 901/2 supercluster at z~0.165. We use HST ACS F606W imaging from the STAGES survey, and data from Spitzer, XMM-Newton, and COMBO-17. We identify and characterize bars through ellipse-fitting, and other morphological features through visual classification. (1) We explore three commonly used methods for selecting disk galaxies. We find 625, 485, and 353 disk galaxies, respectively, via visual classification, a single component S'ersic cut (n <= 2.5), and a blue-cloud cut. In cluster environments, the latter two methods miss 31% and 51%, respectively, of visually-identified disks. (2) For moderately inclined disks, the three methods of disk selection yield a similar global optical bar fraction (f_bar-opt) of 34% +10%/-3%, 31% +10%/-3%, and 30% +10%/-3%, respectively. (3) f_bar-opt rises in brighter galaxies and those which appear to have no significant bulge component. Within a given absolute magnitude bin, f_bar-opt is higher in visually-selected disk galaxies that have no bulge as opposed to those with bulges. For a given morphological class, f_bar-opt rises at higher luminosities. (4) For bright early-types, as well as faint late-type systems with no evident bulge, the optical bar fraction in the Abell 901/2 clusters is comparable within a factor of 1.1 to 1.4 to that of field galaxies at lower redshifts (5) Between the core and the virial radius of the cluster at intermediate environmental densities, the optical bar fraction does not appear to depend strongly on the local environment density and varies at most by a factor of ~1.3. We discuss the implications of our results for the evolution of bars and disks in dense environments.Comment: accepted for publication in ApJ, abstract abridged, for high resolution figures see http://www.as.utexas.edu/~marinova/STAGES/STAGES_bars.pd

Less than 10 percent of star formation in z=0.6 massive galaxies is triggered by major interactions

Both observations and simulations show that major tidal interactions or mergers between gas-rich galaxies can lead to intense bursts of starformation. Yet, the average enhancement in star formation rate (SFR) in major mergers and the contribution of such events to the cosmic SFR are not well estimated. Here we use photometric redshifts, stellar masses and UV SFRs from COMBO-17, 24 micron SFRs from Spitzer and morphologies from two deep HST cosmological survey fields (ECDFS/GEMS and A901/STAGES) to study the enhancement in SFR as a function of projected galaxy separation. We apply two-point projected correlation function techniques, which we augment with morphologically-selected very close pairs (separation <2 arcsec) and merger remnants from the HST imaging. Our analysis confirms that the most intensely star-forming systems are indeed interacting or merging. Yet, for massive (M* > 10^10 Msun) star-forming galaxies at 0.4<z<0.8, we find that the SFRs of galaxies undergoing a major interaction (mass ratios <1:4 and separations < 40 kpc) are only 1.80 +/- 0.30 times higher than the SFRs of non-interacting galaxies when averaged over all interactions and all stages of the interaction, in good agreement with other observational works. We demonstrate that these results imply that <10% of star formation at 0.4 < z < 0.8 is triggered directly by major mergers and interactions; these events are not important factors in the build-up of stellar mass since z=1.Comment: Submitted to ApJ. 41 pages, 11 figure

STAGES: the Space Telescope A901/2 Galaxy Evolution Survey

We present an overview of the Space Telescope A901/2 Galaxy Evolution Survey (STAGES). STAGES is a multiwavelength project designed to probe physical drivers of galaxy evolution across a wide range of environments and luminosity. A complex multi-cluster system at z~0.165 has been the subject of an 80-orbit F606W HST/ACS mosaic covering the full 0.5x0.5 (~5x5 Mpc^2) span of the supercluster. Extensive multiwavelength observations with XMM-Newton, GALEX, Spitzer, 2dF, GMRT, and the 17-band COMBO-17 photometric redshift survey complement the HST imaging. Our survey goals include simultaneously linking galaxy morphology with other observables such as age, star-formation rate, nuclear activity, and stellar mass. In addition, with the multiwavelength dataset and new high resolution mass maps from gravitational lensing, we are able to disentangle the large-scale structure of the system. By examining all aspects of environment we will be able to evaluate the relative importance of the dark matter halos, the local galaxy density, and the hot X-ray gas in driving galaxy transformation. This paper describes the HST imaging, data reduction, and creation of a master catalogue. We perform Sersic fitting on the HST images and conduct associated simulations to quantify completeness. In addition, we present the COMBO-17 photometric redshift catalogue and estimates of stellar masses and star-formation rates for this field. We define galaxy and cluster sample selection criteria which will be the basis for forthcoming science analyses, and present a compilation of notable objects in the field. Finally, we describe the further multiwavelength observations and announce public access to the data and catalogues.Comment: 29 pages, 22 figures; accepted to MNRAS. Full data release available at http://www.nottingham.ac.uk/astronomy/stage

STAGES: the Space Telescope A901/2 Galaxy Evolution Survey

We present an overview of the Space Telescope A901/2 Galaxy Evolution Survey (STAGES). STAGES is a multiwavelength project designed to probe physical drivers of galaxy evolution across a wide range of environments and luminosity. A complex multicluster system at z∼ 0.165 has been the subject of an 80-orbit F606W Hubble Space Telescope (HST)/Advanced Camera for Surveys (ACS) mosaic covering the full span of the supercluster. Extensive multiwavelength observations with XMM-Newton, GALEX, Spitzer, 2dF, Giant Metrewave Radio Telescope and the 17-band COMBO-17 photometric redshift survey complement the HST imaging. Our survey goals include simultaneously linking galaxy morphology with other observables such as age, star formation rate, nuclear activity and stellar mass. In addition, with the multiwavelength data set and new high-resolution mass maps from gravitational lensing, we are able to disentangle the large-scale structure of the system. By examining all aspects of an environment we will be able to evaluate the relative importance of the dark matter haloes, the local galaxy density and the hot X-ray gas in driving galaxy transformation. This paper describes the HST imaging, data reduction and creation of a master catalogue. We perform the Sérsic fitting on the HST images and conduct associated simulations to quantify completeness. In addition, we present the COMBO-17 photometric redshift catalogue and estimates of stellar masses and star formation rates for this field. We define galaxy and cluster sample selection criteria, which will be the basis for forthcoming science analyses, and present a compilation of notable objects in the field. Finally, we describe the further multiwavelength observations and announce public access to the data and catalogue