Binding-incompetent adenovirus facilitates molecular conjugate-mediated gene transfer by the receptor-mediated endocytosis pathway

Molecular conjugate vectors may be constructed that accomplish high efficiency gene transfer by the receptor-mediated endocytosis pathway. In order to mediate escape from lysosomal degradation, we have incorporated adenoviruses into the functional design of the conjugate. In doing so, however, we have introduced an additional ligand, which can bind to receptors on the cell surface, undermining the potential for cell specific targeting. To overcome this, we have treated the adenovirus with a monoclonal anti-fiber antibody, which renders the virus incapable of binding to its receptor. The result is a multi-functional molecular conjugate vector, which has preserved its binding specificity while at the same time being capable of preventing lysosomal degradation of endosome-internalized conjugate-DNA complexes. This finding indicates that adenoviral binding is not a prerequisite for adenoviral-mediated endosome disruption

Using state space differential geometry for nonlinear blind source separation

Given a time series of multicomponent measurements of an evolving stimulus, nonlinear blind source separation (BSS) seeks to find a "source" time series, comprised of statistically independent combinations of the measured components. In this paper, we seek a source time series with local velocity cross correlations that vanish everywhere in stimulus state space. However, in an earlier paper the local velocity correlation matrix was shown to constitute a metric on state space. Therefore, nonlinear BSS maps onto a problem of differential geometry: given the metric observed in the measurement coordinate system, find another coordinate system in which the metric is diagonal everywhere. We show how to determine if the observed data are separable in this way, and, if they are, we show how to construct the required transformation to the source coordinate system, which is essentially unique except for an unknown rotation that can be found by applying the methods of linear BSS. Thus, the proposed technique solves nonlinear BSS in many situations or, at least, reduces it to linear BSS, without the use of probabilistic, parametric, or iterative procedures. This paper also describes a generalization of this methodology that performs nonlinear independent subspace separation. In every case, the resulting decomposition of the observed data is an intrinsic property of the stimulus' evolution in the sense that it does not depend on the way the observer chooses to view it (e.g., the choice of the observing machine's sensors). In other words, the decomposition is a property of the evolution of the "real" stimulus that is "out there" broadcasting energy to the observer. The technique is illustrated with analytic and numerical examples.Comment: Contains 14 pages and 3 figures. For related papers, see http://www.geocities.com/dlevin2001/ . New version is identical to original version except for URL in the bylin

Adaptation Algorithm and Theory Based on Generalized Discrepancy

We present a new algorithm for domain adaptation improving upon a discrepancy minimization algorithm previously shown to outperform a number of algorithms for this task. Unlike many previous algorithms for domain adaptation, our algorithm does not consist of a fixed reweighting of the losses over the training sample. We show that our algorithm benefits from a solid theoretical foundation and more favorable learning bounds than discrepancy minimization. We present a detailed description of our algorithm and give several efficient solutions for solving its optimization problem. We also report the results of several experiments showing that it outperforms discrepancy minimization

A Neuroanatomical Signature for Schizophrenia Across Different Ethnic Groups

Schizophrenia is a disabling clinical syndrome found across the world. While the incidence and clinical expression of this illness are strongly influenced by ethnic factors, it is unclear whether patients from different ethnicities show distinct brain deficits. In this multicentre study, we used structural Magnetic Resonance Imaging to investigate neuroanatomy in 126 patients with first episode schizophrenia who came from 4 ethnically distinct cohorts (White Caucasians, African-Caribbeans, Japanese, and Chinese). Each patient was individually matched with a healthy control of the same ethnicity, gender, and age (±1 year). We report a reduction in the gray matter volume of the right anterior insula in patients relative to controls (P < .05 corrected); this reduction was detected in all 4 ethnic groups despite differences in psychopathology, exposure to antipsychotic medication and image acquisition sequence. This finding provides evidence for a neuroanatomical signature of schizophrenia expressed above and beyond ethnic variations in incidence and clinical expression. In light of the existing literature, implicating the right anterior insula in bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety, we speculate that the neuroanatomical deficit reported here may represent a transdiagnostic feature of Axis I disorders

Flat Dielectric Grating Reflectors with High Focusing Power

Sub-wavelength dielectric gratings (SWG) have emerged recently as a promising alternative to distributed-Bragg-reflection (DBR) dielectric stacks for broadband, high-reflectivity filtering applications. A SWG structure composed of a single dielectric layer with the appropriate patterning can sometimes perform as well as thirty or forty dielectric DBR layers, while providing new functionalities such as polarization control and near-field amplification. In this paper, we introduce a remarkable property of grating mirrors that cannot be realized by their DBR counterpart: we show that a non-periodic patterning of the grating surface can give full control over the phase front of reflected light while maintaining a high reflectivity. This new feature of dielectric gratings could have a substantial impact on a number of applications that depend on low-cost, compact optical components, from laser cavities to CD/DVD read/write heads.Comment: submitted to Nature Photonic

Skeletal Characterization of Smurf2-Deficient Mice and In Vitro Analysis of Smurf2-Deficient Chondrocytes

Overexpression of Smad ubiquitin regulatory factor 2 (Smurf2) in chondrocytes was reported to cause spontaneous osteoarthritis (OA) in mice. However, it is unclear whether Smurf2 is involved in bone and cartilage homeostasis and if it is required for OA pathogenesis. Here we characterized age-related changes in the bone and articular cartilage of Smurf2-deficient (MT) mice by microCT and histology, and examined whether reduced Smurf2 expression affected the severity of OA upon surgical destabilization of the medial meniscus (DMM). Using immature articular chondrocytes (iMAC) from MT and wild-type (WT) mice, we also examined how Smurf2 deficiency affects chondrogenic and catabolic gene expressions and Smurf2 and Smurf1 proteins upon TGF-β3 or IL-1β treatment in culture. We found no differences in cortical, subchondral and trabecular bone between WT and MT in young (4 months) and old mice (16-24 months). The articular cartilage and age-related alterations between WT and MT were also similar. However, 2 months following DMM, young MT showed milder OA compared to WT (~70% vs ~30% normal or exhibiting only mild OA cartilage phenotype). The majority of the older WT and MT mice developed moderate/severe OA 2 months after DMM, but a higher subset of aged MT cartilage (27% vs. 9% WT) remained largely normal. Chondrogenic gene expression (Sox9, Col2, Acan) trended higher in MT iMACs than WT with/without TGF-β3 treatment. IL-1β treatment suppressed chondrgenic gene expression, but Sox9 expression in MT remained significantly higher than WT. Smurf2 protein in WT iMACs increased upon TGF-β3 treatment and decreased upon IL-1β treatment in a dose-dependent manner. Smurf1 protein elevated more in MT than WT upon TGF-β3 treatment, suggesting a potential, but very mild compensatory effect. Overall, our data support a role of Smurf2 in regulating OA development but suggest that inhibiting Smurf2 alone may not be sufficient to prevent or consistently mitigate post-traumatic OA across a broad age range

Corrections to and Discussion of "Implementation and Evaluation of Mixed-criticality Scheduling Approaches for Sporadic Tasks"

The AMC-IA mixed-criticality scheduling analysis was proposed as an improvement to the AMC-MAX adaptive mixed-criticality scheduling analysis. However, we have identified several necessary corrections to the AMC-IA analysis. In this letter we motivate and describe those corrections, and discuss and illustrate why the corrected AMC-IA analysis cannot be shown to outperform AMC-MAX

On the Evolution of the Velocity-Mass-Size Relations of Disk-Dominated Galaxies over the Past 10 Billion Years

We study the evolution of the scaling relations between maximum circular velocity, stellar mass and optical half-light radius of star-forming disk-dominated galaxies in the context of LCDM-based galaxy formation models. Using data from the literature combined with new data from the DEEP2 and AEGIS surveys we show that there is a consistent observational and theoretical picture for the evolution of these scaling relations from z\sim 2 to z=0. The evolution of the observed stellar scaling relations is weaker than that of the virial scaling relations of dark matter haloes, which can be reproduced, both qualitatively and quantitatively, with a simple, cosmologically-motivated model for disk evolution inside growing NFW dark matter haloes. In this model optical half-light radii are smaller, both at fixed stellar mass and maximum circular velocity, at higher redshifts. This model also predicts that the scaling relations between baryonic quantities evolve even more weakly than the corresponding stellar relations. We emphasize, though, that this weak evolution does not imply that individual galaxies evolve weakly. On the contrary, individual galaxies grow strongly in mass, size and velocity, but in such a way that they move largely along the scaling relations. Finally, recent observations have claimed surprisingly large sizes for a number of star-forming disk galaxies at z \sim 2, which has caused some authors to suggest that high redshift disk galaxies have abnormally high spin parameters. However, we argue that the disk scale lengths in question have been systematically overestimated by a factor \sim 2, and that there is an offset of a factor \sim 1.4 between H\alpha sizes and optical sizes. Taking these effects into account, there is no indication that star forming galaxies at high redshifts (z\sim 2) have abnormally high spin parameters.Comment: 19 pages, 10 figures, accepted to MNRAS, minor changes to previous versio

AEGIS: Enhancement of Dust-enshrouded Star Formation in Close Galaxy Pairs and Merging Galaxies up to z ~ 1

Using data from the DEEP2 Galaxy Redshift Survey and HST/ACS imaging in the Extended Groth Strip, we select nearly 100 interacting galaxy systems including kinematic close pairs and morphologically identified merging galaxies. Spitzer MIPS 24 micron fluxes of these systems reflect the current dusty star formation activity, and at a fixed stellar mass (M_{*}) the median infrared luminosity (L_{IR}) among merging galaxies and close pairs of blue galaxies is twice (1.9 +/- 0.4) that of control pairs drawn from isolated blue galaxies. Enhancement declines with galaxy separation, being strongest in close pairs and mergers and weaker in wide pairs compared to the control sample. At z ~ 0.9, 7.1% +/- 4.3% of massive interacting galaxies (M_{*} > 2*10^{10} M_{solar}) are found to be ULIRGs, compared to 2.6% +/- 0.7% in the control sample. The large spread of IR luminosity to stellar mass ratio among interacting galaxies suggests that this enhancement may depend on the merger stage as well as other as yet unidentified factors (e.g., galaxy structure, mass ratio, orbital characteristics, presence of AGN or bar). The contribution of interacting systems to the total IR luminosity density is moderate (<= 36 %).Comment: 12 pages, 2 figures, 1 table, minor changes to match the proof version, accepted for publication in the ApJL AEGIS Special Issu

Individual prognosis at diagnosis in nonmetastatic prostate cancer: Development and external validation of the PREDICT Prostate multivariable model.

BACKGROUND: Prognostic stratification is the cornerstone of management in nonmetastatic prostate cancer (PCa). However, existing prognostic models are inadequate-often using treatment outcomes rather than survival, stratifying by broad heterogeneous groups and using heavily treated cohorts. To address this unmet need, we developed an individualised prognostic model that contextualises PCa-specific mortality (PCSM) against other cause mortality, and estimates the impact of treatment on survival. METHODS AND FINDINGS: Using records from the United Kingdom National Cancer Registration and Analysis Service (NCRAS), data were collated for 10,089 men diagnosed with nonmetastatic PCa between 2000 and 2010 in Eastern England. Median follow-up was 9.8 years with 3,829 deaths (1,202 PCa specific). Totals of 19.8%, 14.1%, 34.6%, and 31.5% of men underwent conservative management, prostatectomy, radiotherapy (RT), and androgen deprivation monotherapy, respectively. A total of 2,546 men diagnosed in Singapore over a similar time period represented an external validation cohort. Data were randomly split 70:30 into model development and validation cohorts. Fifteen-year PCSM and non-PCa mortality (NPCM) were explored using separate multivariable Cox models within a competing risks framework. Fractional polynomials (FPs) were utilised to fit continuous variables and baseline hazards. Model accuracy was assessed by discrimination and calibration using the Harrell C-index and chi-squared goodness of fit, respectively, within both validation cohorts. A multivariable model estimating individualised 10- and 15-year survival outcomes was constructed combining age, prostate-specific antigen (PSA), histological grade, biopsy core involvement, stage, and primary treatment, which were each independent prognostic factors for PCSM, and age and comorbidity, which were prognostic for NPCM. The model demonstrated good discrimination, with a C-index of 0.84 (95% CI: 0.82-0.86) and 0.84 (95% CI: 0.80-0.87) for 15-year PCSM in the UK and Singapore validation cohorts, respectively, comparing favourably to international risk-stratification criteria. Discrimination was maintained for overall mortality, with C-index 0.77 (95% CI: 0.75-0.78) and 0.76 (95% CI: 0.73-0.78). The model was well calibrated with no significant difference between predicted and observed PCa-specific (p = 0.19) or overall deaths (p = 0.43) in the UK cohort. Key study limitations were a relatively small external validation cohort, an inability to account for delayed changes to treatment beyond 12 months, and an absence of tumour-stage subclassifications. CONCLUSIONS: 'PREDICT Prostate' is an individualised multivariable PCa prognostic model built from baseline diagnostic information and the first to our knowledge that models potential treatment benefits on overall survival. Prognostic power is high despite using only routinely collected clinicopathological information.The Urology Foundatio