Genetic Rodent Models of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective death of motor neurons in the motor cortex, brainstem, and spinal cord. A large number of rodent models are available that show motor neuron death and a progressive motor phenotype that is more or less reminiscent of what occurs in patients. These rodent models contain genes with spontaneous or induced mutations or (over) express different (mutant) genes. Some of these models have been of great value to delineate potential pathogenic mechanisms that cause and/or modulate selective motor neuron degeneration. In addition, these genetic rodent models play a crucial role in testing and selecting potential therapeutics that can be used to treat ALS and/or other motor neuron disorders. In this paper, we give a systematic overview of the most important genetic rodent models that show motor neuron degeneration and/or develop a motor phenotype. In addition, we discuss the value and limitations of the different models and conclude that it remains a challenge to find more and better rodent models based on mutations in new genes causing ALS

Intra-cavitary uterine pathology in women with abnormal uterine bleeding: a prospective study of 1220 women.

OBJECTIVES: Our primary aim was to assess how patients characteristics, bleeding pattern, sonographic endometrial thickness (ET) and additional features at unenhanced ultrasound examination (UTVS) and at fluid instillation sonography (FIS) contribute to the diagnosis of intracavitary uterine pathology in women presenting with abnormal uterine bleeding (AUB). We further aimed to report the prevalence of pathology in women presenting with AUB. METHODS: 1220 consecutive women presenting with AUB underwent UTVS, colour Doppler imaging (CDI) and FIS. Most women (n = 1042) had histological diagnosis. RESULTS: Mean age was 50 years and 37% were postmenopausal. Of 1220 women 54% were normal, polyps were diagnosed in 26%, intracavitary fibroids in 11%, hyperplasia without atypia in 4% and cancer in 3%. All cancers were diagnosed in postmenopausal (7%) or perimenopausal (1%) women. ET had a low predictive value in premenopausal women (LR+ and LR- of 1.34 and 0.74, respectively), while FIS had a LR+ and LR- of 6.20 and 0.24, respectively. After menopause, ET outperformed all patient characteristics for the prediction of endometrial pathology (LR+ and LR- of 3.13 and 0.24). The corresponding LR+ and LR- were 10.85 and 0.71 for CDI and 8.23 and 0.26 for FIS. CONCLUSION: About half of the women presenting to a bleeding clinic will have pathology. In premenopausal women, benign lesions are often the cause of AUB. For the prediction of intracavitary pathology ET is of little value in premenopausal women. CDI and FIS substantially improve the diagnostic accuracy

Evidence for a 3 x 10^8 solar mass black hole in NGC 7052 from HST observations of the nuclear gas disk

We present an HST study of the nuclear region of the E4 radio galaxy NGC 7052, which has a nuclear disk of dust and gas. The WFPC2 was used to obtain B, V and I broad-band images and an H_alpha+[NII] narrow-band image. The FOS was used to obtain H_alpha+[NII] spectra along the major axis, using a 0.26 arcsec diameter circular aperture. The observed rotation velocity of the ionized gas is V = 155 +/- 17 km/s at r = 0.2 arcsec from the nucleus. The Gaussian dispersion of the emission lines increases from sigma = 70 km/s at r=1 arcsec, to sigma = 400 km/s on the nucleus. To interpret the gas kinematics we construct axisymmetric models in which the gas and dust reside in a disk in the equatorial plane of the stellar body. It is assumed that the gas moves on circular orbits, with an intrinsic velocity dispersion due to turbulence. The circular velocity is calculated from the combined gravitational potential of the stars and a possible nuclear black hole (BH). Models without a BH predict a rotation curve that is shallower than observed (V_pred = 92 km/s at r = 0.2 arcsec), and are ruled out at > 99% confidence. Models with a BH of 3.3^{+2.3}_{-1.3} x 10^8 solar masses provide an acceptable fit. NGC 7052 can be added to the list of active galaxies for which HST spectra of a nuclear gas disk provide evidence for the presence of a central BH. The BH masses inferred for M87, M84, NGC 6251, NGC 4261 and NGC 7052 span a range of a factor 10, with NGC 7052 falling on the low end. By contrast, the luminosities of these galaxies are identical to within 25%. Any relation between BH mass and luminosity, as suggested by independent arguments, must therefore have a scatter of at least a factor 10.Comment: 39 pages, LaTeX, with 16 PostScript figures. Submitted to the Astronomical Journal. Postscript version with higher resolution figures available from http://sol.stsci.edu/~marel/abstracts/abs_R22.htm

Galaxy evolution in groups and clusters: satellite star formation histories and quenching timescales in a hierarchical Universe

Satellite galaxies in groups and clusters are more likely to have low star formation rates (SFR) and lie on the red-sequence than central (field) galaxies. Using galaxy group/cluster catalogs from SDSS DR7, together with a cosmological N-body simulation to track satellite orbits, we examine the star formation histories and quenching timescales of satellites of M_star > 5 x 10^9 M_sun at z=0. We first explore satellite infall histories: group preprocessing and ejected orbits are critical aspects of satellite evolution, and properly accounting for these, satellite infall typically occurred at z~0.5, or ~5 Gyr ago. To obtain accurate initial conditions for the SFRs of satellites at their time of first infall, we construct an empirical parametrization for the evolution of central galaxy SFRs and quiescent fractions. With this, we constrain the importance and efficiency of satellite quenching as a function of satellite and host halo mass, finding that satellite quenching is the dominant process for building up all quiescent galaxies at M_star < 10^10 M_sun. We then constrain satellite star formation histories, finding a 'delayed-then-rapid' quenching scenario: satellite SFRs evolve unaffected for 2-4 Gyr after infall, after which star formation quenches rapidly, with an e-folding time of < 0.8 Gyr. These quenching timescales are shorter for more massive satellites but do not depend on host halo mass: the observed increase in satellite quiescent fraction with halo mass arises simply because of satellites quenching in a lower mass group prior to infall (group preprocessing), which is responsible for up to half of quenched satellites in massive clusters. Because of the long time delay before quenching starts, satellites experience significant stellar mass growth after infall, nearly identical to central galaxies. This fact provides key physical insight into the subhalo abundance matching method.Comment: 25 pages, 13 figures. Accepted for publication in MNRAS, matches published versio

Broad expertise retrieval in sparse data environments

Expertise retrieval has been largely unexplored on data other than the W3C collection. At the same time, many intranets of universities and other knowledge-intensive organisations offer examples of relatively small but clean multilingual expertise data, covering broad ranges of expertise areas. We first present two main expertise retrieval tasks, along with a set of baseline approaches based on generative language modeling, aimed at finding expertise relations between topics and people. For our experimental evaluation, we introduce (and release) a new test set based on a crawl of a university site. Using this test set, we conduct two series of experiments. The first is aimed at determining the effectiveness of baseline expertise retrieval methods applied to the new test set. The second is aimed at assessing refined models that exploit characteristic features of the new test set, such as the organizational structure of the university, and the hierarchical structure of the topics in the test set. Expertise retrieval models are shown to be robust with respect to environments smaller than the W3C collection, and current techniques appear to be generalizable to other settings

Speech register influences listeners’ word expectations

We utilized the N400 effect to investigate the influence of speech register on predictive language processing. Participants listened to long stretches (4 – 15 min) of naturalistic speech from different registers (dialogues, news broadcasts, and read-aloud books), totalling approximately 50,000 words, while the EEG signal was recorded. We estimated the surprisal of words in the speech materials with the aid of a statistical language model in such a manner that it reflected different predictive processing strategies; generic, register-specific, or recency-based. The N400 amplitude was best predicted with register-specific word surprisal, indicating that the statistics of the wider context (i.e., register) influences predictive language processing. Furthermore, adaptation to speech register cannot merely be explained by recency effects; instead, listeners adapt their word anticipations to the presented speech register

A Stellar Dynamical Mass Measurement of the Black Hole in NGC 3998 from Keck Adaptive Optics Observations

We present a new stellar dynamical mass measurement of the black hole in the nearby, S0 galaxy NGC 3998. By combining laser guide star adaptive optics observations obtained with the OH-Suppressing Infrared Imaging Spectrograph on the Keck II telescope with long-slit spectroscopy from the Hubble Space Telescope and the Keck I telescope, we map out the stellar kinematics on both small spatial scales, well within the black hole sphere of influence, and on large scales. We find that the galaxy is rapidly rotating and exhibits a sharp central peak in the velocity dispersion. Using the kinematics and the stellar luminosity density derived from imaging observations, we construct three-integral, orbit-based, triaxial stellar dynamical models. We find the black hole has a mass of M_BH = (8.1_{-1.9}^{+2.0}) x 10^8 M_sun, with an I-band stellar mass-to-light ratio of M/L = 5.0_{-0.4}^{+0.3} M_sun/L_sun (3-sigma uncertainties), and that the intrinsic shape of the galaxy is very round, but oblate. With the work presented here, NGC 3998 is now one of a very small number of galaxies for which both stellar and gas dynamical modeling have been used to measure the mass of the black hole. The stellar dynamical mass is nearly a factor of four larger than the previous gas dynamical black hole mass measurement. Given that this cross-check has so far only been attempted on a few galaxies with mixed results, carrying out similar studies in other objects is essential for quantifying the magnitude and distribution of the cosmic scatter in the black hole mass - host galaxy relations.Comment: 19 pages, 15 figures, accepted for publication in Ap

Randomized controlled trial of adalimumab in patients with nonpsoriatic peripheral spondyloarthritis

Objective. To evaluate the efficacy and safety of adalimumab in patients with active nonpsoriatic peripheral spondyloarthritis (SpA). Methods. ABILITY-2 is an ongoing phase III, multicenter study of adalimumab treatment. Eligible patients age 18 years fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for peripheral SpA, did not have a prior diagnosis of psoriasis, psoriatic arthritis (PsA), or ankylosing spondylitis (AS), and had an inadequate response or intolerance to nonsteroidal antiinflammatory drugs (NSAIDs). Patients were randomized 1:1 to receive adalimumab 40 mg every other week or matching placebo for 12 weeks, followed by a 144-week open-label period. The primary end point was the proportion of patients achieving 40% improvement in disease activity according to the Peripheral SpA Response Criteria (PSpARC40) at week 12. This was defined as 40% improvement from baseline (20-mm absolute improvement on a visual analog scale) in patient's global assessments of disease activity and pain, and 40% improvement in at least one of the following features: swollen joint and tender joint counts, total enthesitis count, or dactylitis count. Adverse events were recorded throughout the study. Results. In total, 165 patients were randomized to a treatment group, of whom 81 were randomized to receive placebo and 84 to receive adalimumab. Baseline demographics and disease characteristics were generally similar between the 2 groups. At week 12, a greater proportion of patients receiving adalimumab achieved a PSpARC40 response compared to patients receiving placebo (39% versus 20%; P = 0.006). Overall, improvement in other outcomes was greater in the adalimumab group compared to the placebo group. The rates of adverse events were similar in both treatment groups. Conclusion. Treatment with adalimumab ameliorated the signs and symptoms of disease and improved physical function in patients with active nonpsoriatic peripheral SpA who exhibited an inadequate response or intolerance to NSAIDs, with a safety profile consistent with that observed in patients with AS, PsA, or other immune-mediated diseases