Identification of Four Potential Epigenetic Modulators from the NCI Structural Diversity Library Using a Cell-Based Assay

Epigenetic pathways help control the expression of genes. In cancer and other diseases, aberrant silencing or overexpression of genes, such as those that control cell growth, can greatly contribute to pathogenesis. Access to these genes by the transcriptional machinery is largely mediated by chemical modifications of DNA or histones, which are controlled by epigenetic enzymes, making these enzymes attractive targets for drug discovery. Here we describe the characterization of a locus derepression assay, a fluorescence-based mammalian cellular system which was used to screen the NCI structural diversity library for novel epigenetic modulators using an automated imaging platform. Four structurally unique compounds were uncovered that, when further investigated, showed distinct activities. These compounds block the viability of lung cancer and melanoma cells, prevent cell cycle progression, and/or inhibit histone deacetylase activity, altering levels of cellular histone acetylation

The TEMPO Survey I: Predicting Yields of the Transiting Exosatellites, Moons, and Planets from a 30-day Survey of Orion with the Nancy Grace Roman Space Telescope

We present design considerations for the Transiting Exosatellites, Moons, and Planets in Orion (TEMPO) Survey with the Nancy Grace Roman Space Telescope. This proposed 30-day survey is designed to detect a population of transiting extrasolar satellites, moons, and planets in the Orion Nebula Cluster (ONC). The young (1-3 Myr), densely-populated ONC harbors about a thousand bright brown dwarfs (BDs) and free-floating planetary-mass objects (FFPs). TEMPO offers sufficient photometric precision to monitor FFPs with ${\rm M}\geq1{\rm M}_{\rm J}$ for transiting satellites. The survey is also capable of detecting FFPs down to sub-Saturn masses via direct imaging, although follow-up confirmation will be challenging. TEMPO yield estimates include 14 (3-22) exomoons/satellites transiting FFPs and 54 (8-100) satellites transiting BDs. Of this population, approximately $50\%$ of companions would be "super-Titans" (Titan to Earth mass). Yield estimates also include approximately $150$ exoplanets transiting young Orion stars, of which $>50\%$ will orbit mid-to-late M dwarfs and approximately ten will be proto-habitable zone, terrestrial ($0.1{\rm M}_{\oplus} - 5{\rm M}_{\oplus}$) exoplanets. TEMPO would provide the first census demographics of small exosatellites orbiting FFPs and BDs, while simultaneously offering insights into exoplanet evolution at the earliest stages. This detected exosatellite population is likely to be markedly different from the current census of exoplanets with similar masses (e.g., Earth-mass exosatellites that still possess H/He envelopes). Although our yield estimates are highly uncertain, as there are no known exoplanets or exomoons analogous to these satellites, the TEMPO survey would test the prevailing theories of exosatellite formation and evolution, which limit the certainty surrounding detection yields.Comment: Submitted to PAS

Rethinking the patient: using Burden of Treatment Theory to understand the changing dynamics of illness

<b>Background</b> In this article we outline Burden of Treatment Theory, a new model of the relationship between sick people, their social networks, and healthcare services. Health services face the challenge of growing populations with long-term and life-limiting conditions, they have responded to this by delegating to sick people and their networks routine work aimed at managing symptoms, and at retarding - and sometimes preventing - disease progression. This is the new proactive work of patient-hood for which patients are increasingly accountable: founded on ideas about self-care, self-empowerment, and self-actualization, and on new technologies and treatment modalities which can be shifted from the clinic into the community. These place new demands on sick people, which they may experience as burdens of treatment.<p></p> <b>Discussion</b> As the burdens accumulate some patients are overwhelmed, and the consequences are likely to be poor healthcare outcomes for individual patients, increasing strain on caregivers, and rising demand and costs of healthcare services. In the face of these challenges we need to better understand the resources that patients draw upon as they respond to the demands of both burdens of illness and burdens of treatment, and the ways that resources interact with healthcare utilization.<p></p> <b>Summary</b> Burden of Treatment Theory is oriented to understanding how capacity for action interacts with the work that stems from healthcare. Burden of Treatment Theory is a structural model that focuses on the work that patients and their networks do. It thus helps us understand variations in healthcare utilization and adherence in different healthcare settings and clinical contexts

South African research in the Southern Ocean: New opportunities but serious challenges

South Africa has a long track record in Southern Ocean and Antarctic research and has recently invested considerable funds in acquiring new infrastructure for ongoing support of this research. This infrastructure includes a new base at Marion Island and a purpose-built ice capable research vessel, which greatly expand research opportunities. Despite this investment, South Africa's standing as a participant in this critical field is threatened by confusion, lack of funding, lack of consultation and lack of transparency. The research endeavour is presently bedevilled by political manoeuvring among groups with divergent interests that too often have little to do with science, while past and present contributors of research are excluded from discussions that aim to formulate research strategy. This state of affairs is detrimental to the country's aims of developing a leadership role in climate change and Antarctic research and squanders both financial and human capital

A Sound Approach to Language Matters: In Honor of Ocke-Schwen Bohn

The contributions in this Festschrift were written by Ocke’s current and former PhD-students, colleagues and research collaborators. The Festschrift is divided into six sections, moving from the smallest building blocks of language, through gradually expanding objects of linguistic inquiry to the highest levels of description - all of which have formed a part of Ocke’s career, in connection with his teaching and/or his academic productions: “Segments”, “Perception of Accent”, “Between Sounds and Graphemes”, “Prosody”, “Morphology and Syntax” and “Second Language Acquisition”. Each one of these illustrates a sound approach to language matters

Synthesising practice guidelines for the development of community-based exercise programmes after stroke

This is a freely-available open access publication. Please cite the published version which is available via the DOI link in this record.Multiple guidelines are often available to inform practice in complex interventions. Guidance implementation may be facilitated if it is tailored to particular clinical issues and contexts. It should also aim to specify all elements of interventions that may mediate and modify effectiveness, including both their content and delivery. We conducted a focused synthesis of recommendations from stroke practice guidelines to produce a structured and comprehensive account to facilitate the development of community-based exercise programmes after stroke.National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsul

Clinical associations and prognostic value of MRI-visible perivascular spaces in patients with ischemic stroke or TIA: a pooled analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH

Anhydrobiosis and Freezing-Tolerance:Adaptations That Facilitate the Establishment of Panagrolaimus Nematodes in Polar Habitats

<div><p>Anhydrobiotic animals can survive the loss of both free and bound water from their cells. While in this state they are also resistant to freezing. This physiology adapts anhydrobiotes to harsh environments and it aids their dispersal. <i>Panagrolaimus davidi</i>, a bacterial feeding anhydrobiotic nematode isolated from Ross Island Antarctica, can survive intracellular ice formation when fully hydrated. A capacity to survive freezing while fully hydrated has also been observed in some other Antarctic nematodes. We experimentally determined the anhydrobiotic and freezing-tolerance phenotypes of 24 <i>Panagrolaimus</i> strains from tropical, temperate, continental and polar habitats and we analysed their phylogenetic relationships. We found that several other <i>Panagrolaimus</i> isolates can also survive freezing when fully hydrated and that tissue extracts from these freezing-tolerant nematodes can inhibit the growth of ice crystals. We show that <i>P. davidi</i> belongs to a clade of anhydrobiotic and freezing-tolerant panagrolaimids containing strains from temperate and continental regions and that <i>P. superbus</i>, an early colonizer at Surtsey island, Iceland after its volcanic formation, is closely related to a species from Pennsylvania, USA. Ancestral state reconstructions show that anhydrobiosis evolved deep in the phylogeny of <i>Panagrolaimus</i>. The early-diverging <i>Panagrolaimus</i> lineages are strongly anhydrobiotic but weakly freezing-tolerant, suggesting that freezing tolerance is most likely a derived trait. The common ancestors of the <i>davidi</i> and the <i>superbus</i> clades were anhydrobiotic and also possessed robust freezing tolerance, along with a capacity to inhibit the growth and recrystallization of ice crystals. Unlike other endemic Antarctic nematodes, the life history traits of <i>P. davidi</i> do not show evidence of an evolved response to polar conditions. Thus we suggest that the colonization of Antarctica by <i>P. davidi</i> and of Surtsey by <i>P. superbus</i> may be examples of recent “ecological fitting” of freezing-tolerant anhydrobiotic propagules to the respective abiotic conditions in Ross Island and Surtsey.</p></div

Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction. AIMS: To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline. METHODS: We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI 24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site. RESULTS: We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) 24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34-1.68) and multivariable (OR 1.27, 95%CI 1.10-1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline. CONCLUSIONS: The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/