Evaluation of Vascular Control Mechanisms Utilizing Video Microscopy of Isolated Resistance Arteries of Rats

This protocol describes the use of in vitro television microscopy to evaluate vascular function in isolated cerebral resistance arteries (and other vessels), and describes techniques for evaluating tissue perfusion using Laser Doppler Flowmetry (LDF) and microvessel density utilizing fluorescently labeled Griffonia simplicifolia (GS1) lectin. Current methods for studying isolated resistance arteries at transmural pressures encountered in vivo and in the absence of parenchymal cell influences provide a critical link between in vivo studies and information gained from molecular reductionist approaches that provide limited insight into integrative responses at the whole animal level. LDF and techniques to selectively identify arterioles and capillaries with fluorescently-labeled GS1 lectin provide practical solutions to enable investigators to extend the knowledge gained from studies of isolated resistance arteries. This paper describes the application of these techniques to gain fundamental knowledge of vascular physiology and pathology in the rat as a general experimental model, and in a variety of specialized genetically engineered designer rat strains that can provide important insight into the influence of specific genes on important vascular phenotypes. Utilizing these valuable experimental approaches in rat strains developed by selective breeding strategies and new technologies for producing gene knockout models in the rat, will expand the rigor of scientific premises developed in knockout mouse models and extend that knowledge to a more relevant animal model, with a well understood physiological background and suitability for physiological studies because of its larger size

Type II Quasars from the Sloan Digital Sky Survey: V. Imaging host galaxies with the Hubble Space Telescope

Type II quasars are luminous Active Galactic Nuclei whose centers are obscured by large amounts of gas and dust. In this paper we present 3-band HST images of nine type II quasars with redshifts 0.2 < z < 0.4 selected from the Sloan Digital Sky Survey based on their emission line properties. The intrinsic luminosities of these AGN are estimated to be -24 > M_B > -26, but optical obscuration allows their host galaxies to be studied unencumbered by bright nuclei. Each object has been imaged in three continuum filters (`UV', `blue' and `yellow') placed between the strong emission lines. The spectacular, high quality images reveal a wealth of details about the structure of the host galaxies and their environments. Six of the nine galaxies in the sample are ellipticals with de Vaucouleurs light profiles, one object has a well-defined disk component and the remaining two have marginal disks. Stellar populations of type II quasar hosts are more luminous (by a median of 0.3-0.7 mag, depending on the wavelength) and bluer (by about 0.4 mag) than are M* galaxies at the same redshift. When smooth fits to stellar light are subtracted from the images, we find both positive and negative residuals that become more prominent toward shorter wavelengths. We argue that the negative residuals are due to kpc-scale dust obscuration, while most positive residuals are due to the light from the nucleus scattered off interstellar material in the host galaxy. Scattered light makes a significant contribution to the broad band continuum emission and can be the dominant component of the extended emission in the UV in extreme cases.Comment: 51 pages, including 12 grey scale figures, 4 color figures, 5 tables. In press in AJ. Version with higher-resolution images available at http://www.astro.princeton.edu/~nadia/qso2.html. (Minor changes in response to the referee report

Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer

SummaryChromosomal instability in human breast cancer is known to take place before mammary neoplasias display morphological signs of invasion. We describe here the unexpected finding of a tumor cell population with normal karyotypes isolated from bone marrow of breast cancer patients. By analyzing the same single cells for chromosomal aberrations, subchromosomal allelic losses, and gene amplifications, we confirmed their malignant origin and delineated the sequence of genomic events during breast cancer progression. On this trajectory of genomic progression, we identified a subpopulation of patients with very early HER2 amplification. Because early changes have the highest probability of being shared by genetically unstable tumor cells, the genetic characterization of disseminated tumor cells provides a novel rationale for selecting patients for targeted therapies

Radial Mixing in Galactic Disks: The Effects of Disk Structure and Satellite Bombardment

We use a suite of numerical simulations to investigate the mechanisms and effects of radial migration of stars in disk galaxies like the Milky Way (MW). An isolated, collisionless stellar disk with a MW-like scale-height shows only the radial "blurring" expected from epicyclic orbits. Reducing the disk thickness or adding gas to the disk substantially increases the level of radial migration, induced by interaction with transient spiral arms and/or a central bar. We also examine collisionless disks subjected to gravitational perturbations from a cosmologically motivated satellite accretion history. In the perturbed disk that best reproduces the observed properties of the MW, 20% of stars that end up in the solar annulus 7 kpc < R < 9 kpc started at R < 6 kpc, and 7% started at R > 10 kpc. This level of migration would add considerable dispersion to the age-metallicity relation of solar neighborhood stars. In the isolated disk models, the probability of migration traces the disk's radial mass profile, but in perturbed disks migration occurs preferentially at large radii, where the disk is more weakly bound. The orbital dynamics of migrating particles are also different in isolated and perturbed disks: satellite perturbations drive particles to lower angular momentum for a given change in radius. Thus, satellite perturbations appear to be a distinct mechanism for inducing radial migration, which can operate in concert with migration induced by bars and spiral structure. We investigate correlations between changes in radius and changes in orbital circularity or vertical energy, identifying signatures that might be used to test models and distinguish radial migration mechanisms in chemo-dynamical surveys of the MW disk.Comment: Full resolution paper available at http://www.astronomy.ohio-state.edu/~bird/bkw11_fullres.pdf . 13 pages, 12 figures; emulate MNRAS format. Accepted for publication in MNRA

Candidate Type II Quasars from the SDSS: III. Spectropolarimetry Reveals Hidden Type I Nuclei

We have conducted spectropolarimetry of 12 type II (obscured) quasar candidates selected from the spectroscopic database of the Sloan Digital Sky Survey based on their emission line properties. Polarization was detected in all objects, with nine being highly polarized (> 3%) and with polarization reaching as high as 17% in two objects. Broad lines were detected in the polarized spectra of five objects. These observations prove beyond a reasonable doubt that the objects in our sample are indeed type II quasars, in that they harbor luminous UV-excess AGNs in their centers and that the direct view to the AGN is highly obscured. For three of the objects in this paper, we have obtained HST images in three bands. The HST observations, combined with the spectropolarimetry data, imply that scattering off material outside the obscuration plane is the dominant polarization mechanism. In all three objects the sizes of scattering regions are a few kpc. For one object, the extent of the scattering region, coupled with the characteristics of the polarized spectrum, argue strongly that dust scattering rather than electron scattering dominates the polarized light. Our observations are well-described by the basic orientation-based unification model of toroidal obscuration and off-plane scattering, implying that the model can be extended to include at least some high-luminosity AGNs.Comment: 31 pages including 4 b/w pictures, 1 color HST image and 2 tables. Submitted to AJ on Sept 26, accepted for March 2005. Minor modifications to match the accepted versio

Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation

Hereditary transthyretin-mediated (hATTR) amyloidosis, or ATTRv amyloidosis, is a progressive disease, for which liver transplantation (LT) has been a long-standing treatment. However, disease progression continues post-LT. This Phase 3b, open-label trial evaluated efficacy and safety of patisiran in patients with ATTRv amyloidosis with polyneuropathy progression post-LT. Primary endpoint was median transthyretin (TTR) reduction from baseline. Twenty-three patients received patisiran for 12 months alongside immunosuppression regimens. Patisiran elicited a rapid, sustained TTR reduction (median reduction [Months 6 and 12 average], 91.0%; 95% CI: 86.1%-92.3%); improved neuropathy, quality of life, and autonomic symptoms from baseline to Month 12 (mean change [SEM], Neuropathy Impairment Score, -3.7 [2.7]; Norfolk Quality of Life-Diabetic Neuropathy questionnaire, -6.5 [4.9]; least-squares mean [SEM], Composite Autonomic Symptom Score-31, -5.0 [2.6]); and stabilized disability (Rasch-built Overall Disability Scale) and nutritional status (modified body mass index). Adverse events were mild or moderate; five patients experienced ≥1 serious adverse event. Most patients had normal liver function tests. One patient experienced transplant rejection consistent with inadequate immunosuppression, remained on patisiran, and completed the study. In conclusion, patisiran reduced serum TTR, was well tolerated, and improved or stabilized key disease impairment measures in patients with ATTRv amyloidosis with polyneuropathy progression post-LT (www.clinicaltrials.gov NCT03862807)

Teaching Mathematics with Technology: TPACK and Effective Teaching Practices

This paper examines how 17 secondary mathematics teacher candidates (TCs) in four university teacher preparation programs implemented technology in their classrooms to teach for conceptual understanding in online, hybrid, and face to face classes during COVID-19. Using the Professional Development: Research, Implementation, and Evaluation (PrimeD) framework, TCs, classroom mentor teachers, field experience supervisors, and university faculty formed a Networked Improvement Community (NIC) to discuss a commonly agreed upon problem of practice and a change idea to implement in the classroom. Through Plan-Do-Study-Act cycles, participants documented their improvement efforts and refinements to the change idea and then reported back to the NIC at the subsequent monthly meeting. The Technology Pedagogical Content Knowledge framework (TPACK) and the TPACK levels rubric were used to examine how teacher candidates implemented technology for Mathematics conceptual understanding. The Mathematics Classroom Observation Protocol for Practices (MCOP2) was used to further examine how effective mathematics teaching practices (e.g., student engagement) were implemented by TCs. MCOP2 results indicated that TCs increased their use of effective mathematics teaching practices. However, growth in TPACK was not significant. A relationship between TPACK and MCOP2 was not evident, indicating a potential need for explicit focus on using technology for mathematics conceptual understanding

Frequency and evolution of sleep-wake disturbances after ischemic stroke: A 2-year prospective study of 437 patients.

OBJECTIVE In the absence of systematic and longitudinal data, this study prospectively assessed both frequency and evolution of sleep-wake disturbances (SWD) after stroke. METHODS In 437 consecutively recruited patients with ischemic stroke or transient ischemic attack (TIA), stroke characteristics and outcome were assessed within the 1st week and 3.2 ± 0.3 years (M±SD) after the acute event. SWD were assessed by interview and questionnaires at 1 and 3 months as well as 1 and 2 years after the acute event. Sleep disordered breathing (SDB) was assessed by respirography in the acute phase and repeated in one fifth of the participants 3 months and 1 year later. RESULTS Patients (63.8% male, 87% ischemic stroke and mean age 65.1 ± 13.0 years) presented with mean NIHSS-score of 3.5 ± 4.5 at admission. In the acute phase, respiratory event index was >15/h in 34% and >30/h in 15% of patients. Over the entire observation period, the frequencies of excessive daytime sleepiness (EDS), fatigue and insomnia varied between 10-14%, 22-28% and 20-28%, respectively. Mean insomnia and EDS scores decreased from acute to chronic stroke, whereas restless legs syndrome (RLS) percentages (6-9%) and mean fatigue scores remained similar. Mean self-reported sleep duration was enhanced at acute stroke (month 1: 07:54 ± 01:27h) and decreased at chronic stage (year 2: 07:43 ± 01:20h). CONCLUSIONS This study documents a high frequency of SDB, insomnia, fatigue and a prolonged sleep duration after stroke/TIA, which can persist for years. Considering the negative effects of SWD on physical, brain and mental health these data suggest the need for a systematic assessment and management of post-stroke SWD

A Maternal High-Fat, High-Sucrose Diet Has Sex-Specific Effects on Fetal Glucocorticoids with Little Consequence for Offspring Metabolism and Voluntary Locomotor Activity in Mice

Maternal overnutrition and obesity during pregnancy can have long-term effects on offspring physiology and behaviour. These developmental programming effects may be mediated by fetal exposure to glucocorticoids, which is regulated in part by placental 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and 2. We tested whether a maternal high-fat, high-sucrose diet would alter expression of placental 11β-HSD1 and 2, thereby increasing fetal exposure to maternal glucocorticoids, with downstream effects on offspring physiology and behaviour. C57BL/6J mice were fed a high-fat, high-sucrose (HFHS) diet or a nutrient-matched low-fat, no-sucrose control diet prior to and during pregnancy and lactation. At day 17 of gestation, HFHS dams had ~20% lower circulating corticosterone levels than controls. Furthermore, there was a significant interaction between maternal diet and fetal sex for circulating corticosterone levels in the fetuses, whereby HFHS males tended to have higher corticosterone than control males, with no effect in female fetuses. However, placental 11β-HSD1 or 11β-HSD2 expression did not differ between diets or show an interaction between diet and sex. To assess potential long-term consequences of this sex-specific effect on fetal corticosterone, we studied locomotor activity and metabolic traits in adult offspring. Despite a sex-specific effect of maternal diet on fetal glucocorticoids, there was little evidence of sex-specific effects on offspring physiology or behaviour, although HFHS offspring of both sexes had higher circulating corticosterone at 9 weeks of age. Our results suggest the existence of as yet unknown mechanisms that mitigate the effects of altered glucocorticoid exposure early in development, making offspring resilient to the potentially negative effects of a HFHS maternal diet