Reporters for the analysis of N-glycosylation in \u3ci\u3eCandida albicans\u3c/i\u3e

A large proportion of Candida albicans cell surface proteins are decorated post-translationally by glycosylation. Indeed N-glycosylation is critical for cell wall biogenesis in this major fungal pathogen and for its interactions with host cells. A detailed understanding of N-glycosylation will yield deeper insights into host-pathogen interactions. However, the analysis of N-glycosylation is extremely challenging because of the complexity and heterogeneity of these structures. Therefore, in an attempt to reduce this complexity and facilitate the analysis of N-glycosylation, we have developed new synthetic C. albicans reporters that carry a single N-linked glycosylation site derived from Saccharomyces cerevisiae Suc2. These glycosylation reporters, which carry C. albicans Hex1 or Sap2 signal sequences plus carboxy-terminal FLAG3 and His6 tags, were expressed in C. albicans from the ACT1 promoter. The reporter proteins were successfully secreted and hyperglycosylated by C. albicans cells, and their outer chain glycosylation was dependent on Och1 and Pmr1, which are required for N-mannan synthesis, but not on Mnt1 and Mnt2 which are only required for O-mannosylation. These reporters are useful tools for the experimental dissection of N-glycosylation and other related processes in C. albicans, such as secretion

Reporters for the analysis of N-glycosylation in Candida albicans

Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.Peer reviewedPublisher PD

Cosmological parameters from SDSS and WMAP

We measure cosmological parameters using the three-dimensional power spectrum P(k) from over 200,000 galaxies in the Sloan Digital Sky Survey (SDSS) in combination with WMAP and other data. Our results are consistent with a ``vanilla'' flat adiabatic Lambda-CDM model without tilt (n=1), running tilt, tensor modes or massive neutrinos. Adding SDSS information more than halves the WMAP-only error bars on some parameters, tightening 1 sigma constraints on the Hubble parameter from h~0.74+0.18-0.07 to h~0.70+0.04-0.03, on the matter density from Omega_m~0.25+/-0.10 to Omega_m~0.30+/-0.04 (1 sigma) and on neutrino masses from <11 eV to <0.6 eV (95%). SDSS helps even more when dropping prior assumptions about curvature, neutrinos, tensor modes and the equation of state. Our results are in substantial agreement with the joint analysis of WMAP and the 2dF Galaxy Redshift Survey, which is an impressive consistency check with independent redshift survey data and analysis techniques. In this paper, we place particular emphasis on clarifying the physical origin of the constraints, i.e., what we do and do not know when using different data sets and prior assumptions. For instance, dropping the assumption that space is perfectly flat, the WMAP-only constraint on the measured age of the Universe tightens from t0~16.3+2.3-1.8 Gyr to t0~14.1+1.0-0.9 Gyr by adding SDSS and SN Ia data. Including tensors, running tilt, neutrino mass and equation of state in the list of free parameters, many constraints are still quite weak, but future cosmological measurements from SDSS and other sources should allow these to be substantially tightened.Comment: Minor revisions to match accepted PRD version. SDSS data and ppt figures available at http://www.hep.upenn.edu/~max/sdsspars.htm

Formation and Evolution of Supermassive Black Holes

The correlation between the mass of supermassive black holes in galaxy nuclei and the mass of the galaxy spheroids or bulges (or more precisely their central velocity dispersion), suggests a common formation scenario for galaxies and their central black holes. The growth of bulges and black holes can commonly proceed through external gas accretion or hierarchical mergers, and are both related to starbursts. Internal dynamical processes control and regulate the rate of mass accretion. Self-regulation and feedback are the key of the correlation. It is possible that the growth of one component, either BH or bulge, takes over, breaking the correlation, as in Narrow Line Seyfert 1 objects. The formation of supermassive black holes can begin early in the universe, from the collapse of Population III, and then through gas accretion. The active black holes can then play a significant role in the re-ionization of the universe. The nuclear activity is now frequently invoked as a feedback to star formation in galaxies, and even more spectacularly in cooling flows. The growth of SMBH is certainly there self-regulated. SMBHs perturb their local environment, and the mergers of binary SMBHs help to heat and destroy central stellar cusps. The interpretation of the X-ray background yields important constraints on the history of AGN activity and obscuration, and the census of AGN at low and at high redshifts reveals the downsizing effect, already observed for star formation. History appears quite different for bright QSO and low-luminosity AGN: the first grow rapidly at high z, and their number density decreases then sharply, while the density of low-luminosity objects peaks more recently, and then decreases smoothly.Comment: 31 pages, 13 figures, review paper for Astrophysics Update

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Cosmological constraints from galaxy clustering

In this manuscript I review the mathematics and physics that underpins recent work using the clustering of galaxies to derive cosmological model constraints. I start by describing the basic concepts, and gradually move on to some of the complexities involved in analysing galaxy redshift surveys, focusing on the 2dF Galaxy Redshift Survey (2dFGRS) and the Sloan Digital Sky survey (SDSS). Difficulties within such an analysis, particularly dealing with redshift space distortions and galaxy bias are highlighted. I then describe current observations of the CMB fluctuation power spectrum, and consider the importance of measurements of the clustering of galaxies in light of recent experiments. Finally, I provide an example joint analysis of the latest CMB and large-scale structure data, leading to a set of parameter constraints.Comment: 30 pages, 13 figures. Lecture given at Third Aegean Summer School, The invisible universe: Dark matter and Dark energ

Starting or Switching to an Integrase Inhibitor-Based Regimen Affects PTSD Symptoms in Women with HIV

As the use of Integrase inhibitor (INSTI)-class antiretroviral medications becomes more common to maintain long-term viral suppression, early reports suggest the potential for CNS side-effects when starting or switching to an INSTI-based regimen. In a population already at higher risk for developing mood and anxiety disorders, these drugs may have significant effects on PTSD scale symptom scores, particularly in women with HIV (WWH). A total of 551 participants were included after completing ≥ 1 WIHS study visits before and after starting/switching to an INSTI-based ART regimen. Of these, 14% were ART naïve, the remainder switched from primarily a protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. Using multivariable linear mixed effects models, we compared PTSD Civilian Checklist subscale scores before and after a “start/switch” to dolutegravir (DTG), raltegravir (RAL), or elvitegravir (EVG). Start/switch to EVG improved re-experiencing subscale symptoms (P’s 0.08). In WWH, an EVG-based ART regimen is associated with improved PTSD symptoms, in both treatment naïve patients and those switching from other ART. While a RAL-based regimen was associated with better PTSD symptoms than in treatment naïve patients, switching onto a RAL-based regimen was associated with worse PTSD symptoms. DTG-based regimens either did not affect, or worsened symptoms, in both naïve and switch patients. Further studies are needed to determine mechanisms underlying differential effects of EVG, RAL and DTG on stress symptoms in WWH

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy