The Effects of Huntingtin-Lowering: What Do We Know So Far?

Therapies targeting mutant huntingtin DNA, mRNA, and protein have a chance at becoming the first disease-modifying treatments for Huntington’s disease, a fatal inherited neurodegenerative disorder for which only symptom management treatments are available today. This review focuses on evidence addressing several key questions pertinent to huntingtin-lowering, ranging from the functions of wild-type huntingtin (wtHTT) that may be disrupted by huntingtin-lowering treatments through the various ways huntingtin can be lowered, the tolerability of wtHTT-lowering in mice and primates, what has been found in the Ionis Pharmaceutical safety trial of a huntingtin-lowering therapy, and to the question of how much mutant huntingtin may need to be lowered for a therapy to be clinically effective. We conclude that adverse consequences of lowering wtHTT in animals appear to be brain region-specific, and/or dependent upon the animal’s stage of development and the amount by which huntingtin is lowered. Therefore, safe approaches to huntingtin-lowering in patients may be to lower huntingtin only moderately, or lower huntingtin only in the most affected brain regions, or lower huntingtin allele-selectively, or all of the above. Many additional questions about huntingtin-lowering remain open, and will only be answered by upcoming clinical trials, such as whether the delivery approaches currently planned will be adequate to get the treatment to the necessary brain regions, and whether non-allele-selective huntingtin-lowering will be safe in the long run. Meantime, there is a role for preclinical research to address key knowledge gaps, including the effects of non-allele-selective huntingtin-lowering on protein trafficking and viability at the cellular level, the tolerability of wtHTT-lowering in the corticostriatal connections of the primate brain, and the effects of this lowering on the functioning of neurotransmitter systems and the transport of neurotrophic factors to the striatum

'Lad culture' in higher education: agency in the sexualisation debates

This paper reports on research funded by the National Union of Students, which explored women students’ experiences of ‘lad culture’ through focus groups and interviews. We found that although laddism is only one of various potential masculinities, for our participants it dominated social and sexual spheres of university life in problematic ways. However, their objections to laddish behaviours did not support contemporary models of ‘sexual panic’, even while oppugning the more simplistic celebrations of young women’s empowerment which have been observed in debates about sexualisation. We argue that in their ability to reject ‘lad culture’, our respondents expressed a form of agency which is often invisibilised in sexualisation discussions and which could be harnessed to tackle some of the issues we uncovered

Searching for the extra-tidal stars of globular clusters using high-dimensional analysis and a core particle spray code

Three-body interactions can eject stars from the core of a globular cluster, causing them to enter the Galactic halo as extra-tidal stars. While finding extra-tidal stars is imperative for understanding cluster evolution, connecting isolated extra-tidal field stars back to their birth cluster is extremely difficult. In this work, we present a new methodology consisting of high-dimensional data analysis and a particle spray code to identify extra-tidal stars of any Galactic globular cluster using M3 as a case study. Using the t-Stochastic Neighbour Embedding (t-SNE) and Uniform Manifold Approximation and Projection (UMAP) machine learning dimensionality reduction algorithms, we first identify a set of 103 extra-tidal candidates in the APOGEE DR17 data catalogue with chemical abundances similar to M3 stars. To confirm each candidate's extra-tidal nature, we introduce Corespray; a new Python-based three-body particle spray code that simulates extra-tidal stars for any Galactic globular cluster. Using Gaia EDR3 proper motions and APOGEE DR17 radial velocities, we apply multivariate Gaussian modelling and an extreme deconvolution to identify the extra-tidal candidates that are more likely to be associated with a distribution of Corespray-simulated M3 extra-tidal stars than the field. Through these methods, we identify 13 new high-probability extra-tidal stars of M3. Future applications of Corespray will yield better understandings of core dynamics, star formation histories and binary fractions in globular clusters.Comment: 15 pages, 8 figures, 2 tables. Submitted to Monthly Notices of the Royal Astronomical Societ

A catalogue of Galactic GEMS: Globular cluster Extra-tidal Mock Stars

This work presents the Globular cluster Extra-tidal Mock Star (GEMS) catalogue of extra-tidal stars and binaries created via three-body dynamical encounters in globular cluster cores. Using the particle-spray code Corespray, we sample N=50,000 extra-tidal stars and escaped recoil binaries for 159 Galactic globular clusters. Sky positions, kinematics, stellar properties and escape information are provided for all simulated stars. Stellar orbits are integrated in seven different static and time-varying Milky Way gravitational potential models where the structure of the disc, perturbations from the Large Magellanic Cloud and the mass and sphericity of the Milky Way's dark matter halo are all investigated. We find that the action coordinates of the mock extra-tidal stars are largely Galactic model independent, where minor offsets and broadening of the distributions between models are likely due to interactions with substructure. Importantly, we also report the first evidence for stellar stream contamination by globular cluster core stars and binaries for clusters with pericentre radii larger than five kiloparsecs. Finally, we provide a quantitative tool that uses action coordinates to match field stars to host clusters with probabilities. Ultimately, combining data from the GEMS catalogue with information of observed stars will allow for association of extra-tidal field stars with any Galactic globular cluster; a requisite tool for understanding population-level dynamics and evolution of clusters in the Milky Way.Comment: 23 pages, 12 figures, 1 table. Accepted for publication in Monthly Notices of the Royal Astronomical Society. For the associated GEMS catalogue, please visit https://zenodo.org/records/843670

Reducing dose for digital cranial radiography : The increased source to the image-receptor distance approach

This investigation proposes that an increased source to the image-receptor distance (SID) technique can be used to optimize occipital frontal and lateral cranial radiographs acquired with direct digital radiography. Although cranial radiography is not performed on a routine basis, it should nonetheless be optimized to keep the dose to the patient as low as reasonably achievable, particularly because it can form part of the facial bone and sinus series. Dose measurements were acquired at various SIDs, and image quality was assessed using visual grading analysis. Statistically significant reductions in the effective dose between 19.2% and 23.9% were obtained when the SID was increased from the standard 100 to 150 cm (P ≤.05), and visual grading analysis scores indicate that image quality remained diagnostically acceptable for both projections. This investigation concludes that increasing the SID effectively optimizes occipital frontal and lateral skull radiographs. Radiology departments must be advised of the benefits of this technique with the goal of introducing an updated reference SID of 150 cm into clinical practice.Peer reviewe

How a University Hospital improves its prevention performance: results of two biennial studies 2004-2006

Introduction. Prevention is a legal obligation for French hos- pitals and should be systematically assessed. Aim. To measure how a French University Hospital improved its prevention performance between two biennial prevention studies after incentives measures were applied. Methods. 45 medical, obstetrical or surgical units were included. A doctor-nurse pair was free to select inpatients at random. 14 preventive procedures were evaluated: blood pressure check, measures of weight, height and body mass index, screenings for diabetes, cervix and breast cancers, tetanus and influenza immunizations, serologies of viruses, research for a prostatic and cognitive disorder and evaluation of alcohol and tobacco consumptions and addictions. Incentives measures for prevention were enacted during the same time. Results. In 2004 and in 2006, respectively 253 inpatients and 243 inpatients were respectively included. Tetanus immunization was checked in less than one tenth of cases in both the studies. Seven acts were performed more in 2006 and only body mass index was measured less. Discussion. The results were encouraging but insufficient espe- cially for tetanus immunization. Weight was measured more than body mass index, probably meaning that?s weight and more precisely its variations are a better clinical sign. Bad results for tetanus immunization meant that incentive strategies only displayed within the hospital were ineffective. Lastly, two propositions were done to improve the questionnaire and the prevention performance: to add five preventive services and a medical file first page, common to all units, summing up all preventive procedures evaluated. Conclusion. The ability of this University Hospital to improve its prevention performance answering to local incentive measures was weak. Another solutions need to be found

The dominant mechanism(s) for populating the outskirts of star clusters with neutron star binaries

It has been argued that heavy binaries composed of neutron stars (NSs) and millisecond pulsars (MSPs) can end up in the outskirts of star clusters via an interaction with a massive black hole (BH) binary expelling them from the core. We argue here, however, that this mechanism will rarely account for such observed objects. Only for primary masses $\lesssim$ 100 M$_{\odot}$ and a narrow range of orbital separations should a BH-BH binary be both dynamically hard and produce a sufficiently low recoil velocity to retain the NS binary in the cluster. Hence, BH binaries are in general likely to eject NSs from clusters. We explore several alternative mechanisms that would cause NS/MSP binaries to be observed in the outskirts of their host clusters after a Hubble time. The most likely mechanism is a three-body interaction involving the NS/MSP binary and a normal star. We compare to Monte Carlo simulations of cluster evolution for the globular clusters NGC 6752 and 47 Tuc, and show that the models not only confirm that normal three-body interactions involving all stellar-mass objects are the dominant mechanism for putting NS/MSP binaries into the cluster outskirts, they also reproduce the observed NS/MSP binary radial distributions without needing to invoke the presence of a massive BH binary. Higher central densities and an episode of core-collapse can broaden the radial distributions of NSs/MSPs and NS/MSP binaries due to three-body interactions, making these clusters more likely to host NSs in the cluster outskirts.Comment: 13 pages, 7 figures, 2 tables, submitted to MNRA

Relationship between nerve fiber layer hemorrhages and outcomes in central retinal vein occlusion

Copyright 2020 The Authors PURPOSE. To evaluate the depth and pattern of retinal hemorrhage in acute central retinal vein occlusion (CRVO) and to correlate these with visual and anatomic outcomes. METHODS. Retinal hemorrhages were evaluated with color fundus photography and fluorescein angiography at baseline and follow-up. Snellen visual acuity (VA), central foveal thickness (CFT), extent of retinal ischemia, and development of neovascularization were analyzed. RESULTS. 108 eyes from 108 patients were evaluated. Mean age was 63.6 ± 16.1 years with a predilection for the right eye (73.1%). Average follow-up was 17.2 ± 19.2 months. Mean VA at baseline was 20/126 and 20/80 at final follow-up. Baseline (P = 0.005) and final VA (P = 0.02) in eyes with perivascular nerve fiber layer (NFL) hemorrhages were significantly worse than in eyes with deep hemorrhages alone. Baseline CFT was greater in the group with perivascular hemorrhages (826 ± 394 μm) compared to the group with deep hemorrhages alone (455 ± 273 μm, P \u3c 0.001). The 10 disc areas of retinal ischemia was more common in patients with perivascular (80.0%) and peripapillary (31.3%) versus deep hemorrhages alone (16.1%, P \u3c 0.001). Neovascularization of the iris was more common, although this differrence was not significant, in the groups with peripapillary (14.3%) and perivascular (2.0%) NFL versus deep hemorrhages alone (0.0%). CONCLUSIONS. NFL retinal hemorrhages at baseline correlate with more severe forms of CRVO, with greater macular edema, poorer visual outcomes, and greater risk of ischemia and neovascularization. This may be related to the organization of the retinal capillary plexus. The depth and pattern of distribution of retinal hemorrhages in CRVO may provide an easily identifiable early biomarker of CRVO prognosis