A Two-Study Comparison of Clinical and MRI Markers of Transition from Mild Cognitive Impairment to Alzheimer's Disease

A published predictor model in a single-site cohort study (questionable dementia, QD) that contained episodic verbal memory (SRT total recall), informant report of function (FAQ), and MRI measures was tested using logistic regression and ROC analyses with comparable measures in a second multisite cohort study (Alzheimer's Disease Neuroimaging Initiative, ADNI). There were 126 patients in QD and 282 patients in ADNI with MCI followed for 3 years. Within each sample, the differences in AUCs between the statistical models were very similar. Adding hippocampal and entorhinal cortex volumes to the model containing AVLT/SRT, FAQ, age and MMSE increased the area under the curve (AUC) in ADNI but not QD, with sensitivity increasing by 2% in ADNI and 2% in QD for a fixed specificity of 80%. Conversely, adding episodic verbal memory (SRT/AVLT) and FAQ to the model containing age, Mini Mental State Exam (MMSE), hippocampal and entorhinal cortex volumes increased the AUC in ADNI and QD, with sensitivity increasing by 17% in ADNI and 10% in QD for 80% specificity. The predictor models showed similar differences from each other in both studies, supporting independent validation. MRI hippocampal and entorhinal cortex volumes showed limited added predictive utility to memory and function measures

Enhancement of cellulosome-mediated deconstruction of cellulose by improving enzyme thermostability

Background: The concerted action of three complementary cellulases from Clostridium thermocellum, engineered to be stable at elevated temperatures, was examined on a cellulosic substrate and compared to that of the wild-type enzymes. Exoglucanase Cel48S and endoglucanase Cel8A, both key elements of the natural cellulosome from this bacterium, were engineered previously for increased thermostability, either by SCHEMA, a structure-guided, site-directed protein recombination method, or by consensus-guided mutagenesis combined with random mutagenesis using error-prone PCR, respectively. A thermostable β-glucosidase BglA mutant was also selected from a library generated by error-prone PCR that will assist the two cellulases in their methodic deconstruction of crystalline cellulose. The effects of a thermostable scaffoldin versus those of a largely mesophilic scaffoldin were also examined. By improving the stability of the enzyme subunits and the structural component, we aimed to improve cellulosome-mediated deconstruction of cellulosic substrates. Results: The results demonstrate that the combination of thermostable enzymes as free enzymes and a thermostable scaffoldin was more active on the cellulosic substrate than the wild-type enzymes. Significantly, “thermostable” designer cellulosomes exhibited a 1.7-fold enhancement in cellulose degradation compared to the action of conventional designer cellulosomes that contain the respective wild-type enzymes. For designer cellulosome formats, the use of the thermostabilized scaffoldin proved critical for enhanced enzymatic performance under conditions of high temperatures. Conclusions: Simple improvement in the activity of a given enzyme does not guarantee its suitability for use in an enzyme cocktail or as a designer cellulosome component. The true merit of improvement resides in its ultimate contribution to synergistic action, which can only be determined experimentally. The relevance of the mutated thermostable enzymes employed in this study as components in multienzyme systems has thus been confirmed using designer cellulosome technology. Enzyme integration via a thermostable scaffoldin is critical to the ultimate stability of the complex at higher temperatures. Engineering of thermostable cellulases and additional lignocellulosic enzymes may prove a determinant parameter for development of state-of-the-art designer cellulosomes for their employment in the conversion of cellulosic biomass to soluble sugars

Chandra Detection of a TypeII Quasar at z=3.288

We report on observations of a TypeII quasar at redshift z=3.288, identified as a hard X-ray source in a 185 ks observation with the Chandra X-ray Observatory and as a high-redshift photometric candidate from deep, multiband optical imaging. CXOJ084837.9+445352 (hereinafter CXO52) shows an unusually hard X-ray spectrum from which we infer an absorbing column density N(H) = (4.8+/-2.1)e23 / cm2 (90% confidence) and an implied unabsorbed 2-10 keV rest-frame luminosity of L(2-10) = 3.3e44 ergs/s, well within the quasar regime. Hubble Space Telescope imaging shows CXO52 to be elongated with slight morphological differences between the WFPC2 F814W and NICMOS F160W bands. Optical and near-infrared spectroscopy of CXO52 show high-ionization emission lines with velocity widths ~1000 km/s and flux ratios similar to a Seyfert2 galaxy or radio galaxy. The latter are the only class of high-redshift TypeII luminous AGN which have been extensively studied to date. Unlike radio galaxies, however, CXO52 is radio quiet, remaining undetected at radio wavelengths to fairly deep limits, f(4.8GHz) < 40 microJy. High-redshift TypeII quasars, expected from unification models of active galaxies and long-thought necessary to explain the X-ray background, are poorly constrained observationally with few such systems known. We discuss recent observations of similar TypeII quasars and detail search techniques for such systems: namely (1) X-ray selection, (2) radio selection, (3) multi-color imaging selection, and (4) narrow-band imaging selection. Such studies are likely to begin identifying luminous, high-redshift TypeII systems in large numbers. We discuss the prospects for these studies and their implications to our understanding of the X-ray background.Comment: 28 pages, 5 figures; to appear in The Astrophysical Journa

A panchromatic study of BLAST counterparts: total star-formation rate, morphology, AGN fraction and stellar mass

We carry out a multi-wavelength study of individual galaxies detected by the Balloon-borne Large Aperture Submillimeter Telescope (BLAST) and identified at other wavelengths, using data spanning the radio to the ultraviolet (UV). We develop a Monte Carlo method to account for flux boosting, source blending, and correlations among bands, which we use to derive deboosted far-infrared (FIR) luminosities for our sample. We estimate total star-formation rates for BLAST counterparts with z < 0.9 by combining their FIR and UV luminosities. Star formation is heavily obscured at L_FIR > 10^11 L_sun, z > 0.5, but the contribution from unobscured starlight cannot be neglected at L_FIR < 10^11 L_sun, z < 0.25. We assess that about 20% of the galaxies in our sample show indication of a type-1 active galactic nucleus (AGN), but their submillimeter emission is mainly due to star formation in the host galaxy. We compute stellar masses for a subset of 92 BLAST counterparts; these are relatively massive objects, with a median mass of ~10^11 M_sun, which seem to link the 24um and SCUBA populations, in terms of both stellar mass and star-formation activity. The bulk of the BLAST counterparts at z<1 appear to be run-of-the-mill star-forming galaxies, typically spiral in shape, with intermediate stellar masses and practically constant specific star-formation rates. On the other hand, the high-z tail of the BLAST counterparts significantly overlaps with the SCUBA population, in terms of both star-formation rates and stellar masses, with observed trends of specific star-formation rate that support strong evolution and downsizing.Comment: Accepted for publication in the Astrophysical Journal. 44 pages, 11 figures. The SED template for the derivation of L_FIR has changed (added new figure) and the discussion on the stellar masses has been improved. The complete set of full-color postage-stamps can be found at http://blastexperiment.info/results_images/moncelsi

Enhancement of cellulosome-mediated deconstruction of cellulose by improving enzyme thermostability

Background: The concerted action of three complementary cellulases from Clostridium thermocellum, engineered to be stable at elevated temperatures, was examined on a cellulosic substrate and compared to that of the wild-type enzymes. Exoglucanase Cel48S and endoglucanase Cel8A, both key elements of the natural cellulosome from this bacterium, were engineered previously for increased thermostability, either by SCHEMA, a structure-guided, site-directed protein recombination method, or by consensus-guided mutagenesis combined with random mutagenesis using error-prone PCR, respectively. A thermostable β-glucosidase BglA mutant was also selected from a library generated by error-prone PCR that will assist the two cellulases in their methodic deconstruction of crystalline cellulose. The effects of a thermostable scaffoldin versus those of a largely mesophilic scaffoldin were also examined. By improving the stability of the enzyme subunits and the structural component, we aimed to improve cellulosome-mediated deconstruction of cellulosic substrates. Results: The results demonstrate that the combination of thermostable enzymes as free enzymes and a thermostable scaffoldin was more active on the cellulosic substrate than the wild-type enzymes. Significantly, “thermostable” designer cellulosomes exhibited a 1.7-fold enhancement in cellulose degradation compared to the action of conventional designer cellulosomes that contain the respective wild-type enzymes. For designer cellulosome formats, the use of the thermostabilized scaffoldin proved critical for enhanced enzymatic performance under conditions of high temperatures. Conclusions: Simple improvement in the activity of a given enzyme does not guarantee its suitability for use in an enzyme cocktail or as a designer cellulosome component. The true merit of improvement resides in its ultimate contribution to synergistic action, which can only be determined experimentally. The relevance of the mutated thermostable enzymes employed in this study as components in multienzyme systems has thus been confirmed using designer cellulosome technology. Enzyme integration via a thermostable scaffoldin is critical to the ultimate stability of the complex at higher temperatures. Engineering of thermostable cellulases and additional lignocellulosic enzymes may prove a determinant parameter for development of state-of-the-art designer cellulosomes for their employment in the conversion of cellulosic biomass to soluble sugars

Odor Identification Impairment and Change with Cholinesterase Inhibitor Treatment in Mild Cognitive Impairment

Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer’s disease (AD) pathology, and short-term change in odor identification impairment with cholinesterase inhibitor (CheI) treatment may predict longer term cognitive outcomes. Objective: In patients with mild cognitive impairment (MCI) treated prospectively with donepezil, a CheI, for 52 weeks, to determine if 1) acute decline in odor identification ability with anticholinergic challenge can predict cognitive improvement, and 2) change in odor identification over 8 weeks can predict cognitive improvement. Methods: MCI was diagnosed clinically without AD biomarkers. At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and this dose was maintained for 52 weeks. Main outcomes were ADAS-Cog total score and Selective Reminding Test (SRT) total immediate recall score measured at baseline, 26 and 52 weeks. Results: In 100 study participants, mean age 70.14 (SD 9.35) years, atropine-induced decrease in UPSIT score at baseline was not associated with change in ADAS-Cog or SRT scores over 52 weeks. Change in UPSIT score from 0 to 8 weeks did not show a significant association with change in the ADAS-Cog or SRT measures over 52 weeks. Conclusion: These negative findings in a relatively large sample of patients with MCI did not replicate results in much smaller samples. Change in odor identification with anticholinergic challenge, and over 8 weeks, may not be useful predictors of cognitive improvement with CheI in patients with MCI

The Size Evolution of High Redshift Galaxies

Hubble Space Telescope images of high-redshift galaxies selected via color and photometric redshifts are used to examine the size and axial-ratio distribution of galaxies as a function of redshift at lookback times t > 8 Gyr. These parameters are measured at rest-frame UV wavelengths (1200-2000 Angstroms) on images with a rest-frame resolution of less than 0.8 kpc. Galaxy radii are found to scale with redshift approximately as the inverse of the Hubble parameter H(z). This is in accord with the theoretical expectation that the typical sizes of the luminous parts of galaxies should track the expected evolution in the virial radius of dark-matter halos. The mean ratio of semi-major to semi-minor axis for a bright well-resolved sample of galaxies at z ~ 4 is b/a = 0.65, suggesting that these Lyman break galaxies are not drawn from a spheroidal population. However the median concentration index of this sample is C = 3.5, which is closer to the typical concentration indices, C ~ 4, of nearby elliptical galaxies than to the values, C<2 for local disk galaxies of type Sb and later.Comment: 5 pages, including 3 figures; uses emulateapj style; accepted by ApJL for publication in a special issue of early GOODS result

Clustering of the IR Background Light with Spitzer: Contribution from Resolved Sources

We describe the angular power spectrum of resolved sources at 3.6 microns (L-band) in Spitzer imaging data of the GOODS HDF-N, the GOODS CDF-S, and the NDWFS Bootes field in several source magnitude bins. We also measure angular power spectra of resolved sources in the Bootes field at K_S and J-bands using ground-based IR imaging data. In the three bands, J, K_S, and L, we detect the clustering of galaxies on top of the shot-noise power spectrum at multipoles between ell ~ 10^2 and 10^5. The angular power spectra range from the large, linear scales to small, non-linear scales of galaxy clustering, and in some magnitude ranges, show departure from a power-law clustering spectrum. We consider a halo model to describe clustering measurements and to establish the halo occup ation number parameters of IR bright galaxies at redshifts around one. We also extend our clustering results and completeness-corrected faint source number counts in GOODS fields to understand the underlying nature of unresolved sources responsible for IR background (IRB) anisotropies that were detected in deep Spitzer images. While these unresolved fluctuations were measured at sub-arcminute angular scales, if a high-redshift diffuse component associated with first galaxies exists in the IRB, then it's clustering properties are best studied with shallow, wide-field images that allow a measurement of the clustering spectrum from a few degrees to arcminute angular scales.Comment: 12 pages, 11 figures. Accepted version in press with ApJ. Revised version includes conditional luminosity function models for IR galaxy LFs, counts and clustering spectra. The faint, unresolved galaxy counts in these models can reproduce excess anisotropy fluctuations reported in astro-ph/0511105. Conditional luminosity function code is available at http://www.cooray.org/lumfunc.html V3: Includes all data from astro-ph/0511105 in revised Fig.8 and minor changes to tex