THE ROLE OF P53 IN OXIDATIVE STRESS AND POLYGLUTAMINE NEUROTOXICITY

Polyglutamine expansion disorders are progressive neurodegenerative diseasesthat are caused by the pathological expansion of polyglutamine repeats. Huntington\u27sdisease (HD) is a polyglutamine disorder caused by the expansion of an existingpolyglutamine tract in a novel protein, Huntingtin (Htt). Oxidative stress has beenimplicated in the neural dysfunction observed in multiple neurodegenerative conditionsincluding HD. The tumor suppressor p53 is a multifunctional protein that has roles inthe cell cycle, apoptosis and neurodevelopment. The role of p53 in HD-associatedneurodegeneration has been studied but not fully elucidated, nor has the role of p53 inoxidative stress toxicity been fully elucidated.Here I present work that demonstrates polyglutamine expansion inducedalterations to p53 stability, localization, and activity. The transcriptional activity of p53was found to have a role in oxidative stress mediated as well as polyglutaminemediated neurotoxicity in vitro. The expression of p53 was also altered in vivo in amouse model of HD as well as in HD brain.Taken together, these data demonstrate a role for p53 in polyglutamine and oxidativestress toxicity

A 10 kpc Scale Seyfert Galaxy Outflow: HST/COS Observations of IRAS F22456-5125

We present analysis of the UV-spectrum of the low-z AGN IRAS-F22456-5125 obtained with the Cosmic Origins Spectrograph on board the Hubble Space Telescope. The spectrum reveals six main kinematic components, spanning a range of velocities of up to 800 km s-1, which for the first time are observed in troughs associated with CII, CIV, NV, SiII, SiIII, SiIV and SIV. We also obtain data on the OVI troughs, which we compare to those available from an earlier FUSE epoch. Column densities measured from these ions allow us to derive a well-constrained photoionization solution for each outflow component. Two of these kinematic components show troughs associated with transitions from excited states of SiII\ and CII. The number density inferred from these troughs, in combination with the deduced ioinization parameter, allows us to determine the distance to these outflow components from the central source. We find these components to be at a distance of ~ 10 kpc. The distances and the number densities derived are consistent with the outflow being part of a galactic wind.Comment: 52 pages, 15 figures, accepted for publication in ApJ March 25, 201

Determining the Locations of Dust Sources in FeLoBAL Quasars

We conduct a spectroscopic search of quasars observed by the Sloan Digital Sky Survey (SDSS) with broad absorption line (BAL) troughs due to Mg II and troughs due to Fe II that simultaneously exhibit strong Balmer narrow emission lines (NELs). We find that in a redshift range of 0.4 less than or equal to z less than or equal to 0.9 approximately 23 of the 70 Mg II BALs and 4 of a subset of 15 Fe II BALs exhibit strong Balmer emission. We also find significant fractions of Mg II BALs (approximately 23%) and those Mg II BALs with Fe II troughs (approximately 27%) have strong continuum reddening, E(B - V) greater than or equal to 0.1. From measurements of the Balmer decrement in three objects, we find similarly significant reddening of the NEL region in three of the four objects; the NELs in the fourth object are not measurable. We also include one object in this study not taken from the SDSS sample that shows Fe II absorption and strong narrow emission, but due to measurement uncertainty and low continuum reddening the comparison is consistent but inconclusive. We find a trend in both the Mg II and Fe II BAL samples between the NEL reddening and continuum reddening. Because the narrow line reddening is consistent with the continuum reddening in every object in the two SDSS samples, it suggests that the reddening sources in these objects likely exist at larger radial distances than the narrow line regions from the central nucleus.Comment: 40 manuscript pages, accepted in ApJ (July

A Steadier Hand: The First Human Clinical Trial of a Single-Use Robotic-Assisted Surgical Device for Cochlear Implant Electrode Array Insertion

OBJECTIVE: To evaluate the safety and utility of an investigational robotic-assisted cochlear implant insertion system. STUDY DESIGN: Prospective, single-arm, open-label study under abbreviated Investigational Device Exemption requirements. SETTING: All procedures were performed, and all data were collected, at a single tertiary referral center. PATIENTS: Twenty-one postlingually deafened adult subjects that met Food and Drug Administration indication criteria for cochlear implantation. INTERVENTION: All patients underwent standard-of-care surgery for unilateral cochlear implantation with the addition of a single-use robotic-assisted insertion device during cochlear electrode insertion. MAIN OUTCOME MEASURES: Successful insertion of cochlear implant electrode array, electrode array insertion time, postoperative implant function. RESULTS: Successful robotic-assisted insertion of lateral wall cochlear implant electrode arrays was achieved in 20 (95.2%) of 21 patients. One insertion was unable to be achieved by either robotic-assisted or manual insertion methods, and the patient was retrospectively found to have a preexisting cochlear fracture. Mean intracochlear electrode array insertion time was 3 minutes 15 seconds. All implants with successful robotic-assisted electrode array insertion (n = 20) had normal impedance and neural response telemetry measures for up to 6 months after surgery. CONCLUSIONS: Here we report the first human trial of a single-use robotic-assisted surgical device for cochlear implant electrode array insertion. This device successfully and safely inserted lateral wall cochlear implant electrode arrays from the three device manufacturers with devices approved but he Food and Drug Administration

Performance of a fast, highly segmented electromagnetic calorimeter

We describe the energy, position, and angular resolutions of an electromagnetic calorimeter consisting of 56 layers of proportional wire and lead-filled tubes. The calorimeter was tested with two different electronic readout systems in a beam of electrons with energies ranging from 10 to 200 GeV.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29102/1/0000140.pd

Understanding experiences of potential harm among MSM (cis and trans) using HIV self-testing in the SELPHI randomised controlled trial in England and Wales: a mixed-methods study

Background: The potential of HIV self-testing (HIVST) to cause harm is a concern hindering widespread implementation. The aim of this paper is to understand the relationship between HIVST and harm in SELPHI (An HIV Self-testing Public Health Intervention), the largest randomised trial of HIVST in a high-income country to date. Methods: 10 111 cis and trans men who have sex with men (MSM) recruited online (geolocation social/sexual networking apps, social media), aged 16+, reporting previous anal intercourse and resident in England or Wales were first randomised 60/40 to baseline HIVST (baseline testing, BT) or not (no baseline testing, nBT) (randomisation A). BT participants reporting negative baseline test, sexual risk at 3 months and interest in further HIVST were randomised to three-monthly HIVST (repeat testing, RT) or not (no repeat testing, nRT) (randomisation B). All received an exit survey collecting data on harms (to relationships, well-being, false results or being pressured/persuaded to test). Nine participants reporting harm were interviewed in-depth about their experiences in an exploratory substudy; qualitative data were analysed narratively. Results Baseline: predominantly cis MSM, 90% white, 88% gay, 47% university educated and 7% current/former pre-exposure prophylaxis (PrEP) users. Final survey response rate was: nBT=26% (1056/4062), BT=45% (1674/3741), nRT=41% (471/1147), RT=50% (581/1161). Harms were rare and reported by 4% (n=138/3691) in exit surveys, with an additional two false positive results captured in other study surveys. 1% reported harm to relationships and to well-being in BT, nRT and RT combined. In all arms combined, being pressured or persuaded to test was reported by 1% (n=54/3678) and false positive results in 0.7% (n=34/4665). Qualitative analysis revealed harms arose from the kit itself (technological harms), the intervention (intervention harms) or from the social context of the participant (socially emergent harms). Intervention and socially emergent harms did not reduce HIVST acceptability, whereas technological harms did. Discussion: HIVST harms were rare but strategies to link individuals experiencing harms with psychosocial support should be considered for HIVST scale-up

Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response

BACKGROUND: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. METHODS: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. RESULTS: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. CONCLUSIONS: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura

Mode equivalence and acceptability of tablet computer-, interactive voice response system-, and paper-based administration of the U.S. National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)

Background PRO-CTCAE is a library of items that measure cancer treatment-related symptomatic adverse events (NCI Contracts: HHSN261201000043C and HHSN 261201000063C). The objective of this study is to examine the equivalence and acceptability of the three data collection modes (Web-enabled touchscreen tablet computer, Interactive voice response system [IVRS], and paper) available within the US National Cancer Institute (NCI) Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) measurement system. Methods Participants (n = 112; median age 56.5; 24 % high school or less) receiving treatment for cancer at seven US sites completed 28 PRO-CTCAE items (scoring range 0–4) by three modes (order randomized) at a single study visit. Subjects completed one page (approx. 15 items) of the EORTC QLQ-C30 between each mode as a distractor. Item scores by mode were compared using intraclass correlation coefficients (ICC); differences in scores within the 3-mode crossover design were evaluated with mixed-effects models. Difficulties with each mode experienced by participants were also assessed. Results 103 (92 %) completed questionnaires by all three modes. The median ICC comparing tablet vs IVRS was 0.78 (range 0.55–0.90); tablet vs paper: 0.81 (0.62–0.96); IVRS vs paper: 0.78 (0.60–0.91); 89 % of ICCs were ≥0.70. Item-level mean differences by mode were small (medians [ranges] for tablet vs. IVRS = −0.04 [−0.16–0.22]; tablet vs paper = −0.02 [−0.11–0.14]; IVRS vs paper = 0.02 [−0.07–0.19]), and 57/81 (70 %) items had bootstrapped 95 % CI around the effect sizes within +/−0.20. The median time to complete the questionnaire by tablet was 3.4 min; IVRS: 5.8; paper: 4.0. The proportion of participants by mode who reported “no problems” responding to the questionnaire was 86 % tablet, 72 % IVRS, and 98 % paper. Conclusions Mode equivalence of items was moderate to high, and comparable to test-retest reliability (median ICC = 0.80). Each mode was acceptable to a majority of respondents. Although the study was powered to detect moderate or larger discrepancies between modes, the observed ICCs and very small mean differences between modes provide evidence to support study designs that are responsive to patient or investigator preference for mode of administration, and justify comparison of results and pooled analyses across studies that employ different PRO-CTCAE modes of administration. Trial registration NCT Clinicaltrials.gov identifier: NCT0215863

Self-Censorship for Democrats

On the face of it, self-censorship is profoundly subversive of democracy, particularly in its talk-centric forms, and undermines the culture of openness and publicity on which it relies. This paper has two purposes. The first is to develop a conception of self-censorship that allows us to capture what is distinctive about the concept from a political perspective and which allows us to understand the democratic anxiety about self-censorship: if it is not obvious that biting our tongues is always wrong, we need a fuller account of the moral sensibility that finds it so troubling and this is elaborated here. The second is to develop an argument to the effect that this sensibility should not have the last, or only, word, but instead that self-censorship should be viewed as an ‘ordinary vice’ of democratic societies. The grounds for tolerating it rest on the democratic values that critics believe it threatens