The centrosomal Deubiquitylase USP21 regulates Gli1 transcriptional activity and stability

USP21 is a centrosome-associated deubiquitylase (DUB) that has been implicated in the formation of primary cilia – crucial organelles for the regulation of the Hedgehog (Hh) signaling pathway in vertebrates. Here, we identify KCTD6 – a cullin-3 E3-ligase substrate adapter that has been previously linked to Hh signaling – as well as Gli1, the key transcription factor responsible for Hh signal amplification, as new interacting partners of USP21. We identify a cryptic structured protein interaction domain in KCTD6, which is predicted to have a similar fold to Smr domains. Importantly, we show that both depletion and overexpression of catalytically active USP21 suppress Gli1-dependent transcription. Gli proteins are negatively regulated through protein kinase A (PKA)-dependent phosphorylation. We provide evidence that USP21 recruits and stabilises Gli1 at the centrosome where it promotes its phosphorylation by PKA. By revealing an intriguing functional pairing between a spatially restricted deubiquitylase and a kinase, our study highlights the centrosome as an important hub for signal coordination

East Midlands Research into Ageing Network (EMRAN) Discussion Paper Series

Academic geriatric medicine in Leicester . There has never been a better time to consider joining us. We have recently appointed a Professor in Geriatric Medicine, alongside Tom Robinson in stroke and Victoria Haunton, who has just joined as a Senior Lecturer in Geriatric Medicine. We have fantastic opportunities to support students in their academic pursuits through a well-established intercalated BSc programme, and routes on through such as ACF posts, and a successful track-record in delivering higher degrees leading to ACL post. We collaborate strongly with Health Sciences, including academic primary care. See below for more detail on our existing academic set-up. Leicester Academy for the Study of Ageing We are also collaborating on a grander scale, through a joint academic venture focusing on ageing, the ‘Leicester Academy for the Study of Ageing’ (LASA), which involves the local health service providers (acute and community), De Montfort University; University of Leicester; Leicester City Council; Leicestershire County Council and Leicester Age UK. Professors Jayne Brown and Simon Conroy jointly Chair LASA and have recently been joined by two further Chairs, Professors Kay de Vries and Bertha Ochieng. Karen Harrison Dening has also recently been appointed an Honorary Chair. LASA aims to improve outcomes for older people and those that care for them that takes a person-centred, whole system perspective. Our research will take a global perspective, but will seek to maximise benefits for the people of Leicester, Leicestershire and Rutland, including building capacity. We are undertaking applied, translational, interdisciplinary research, focused on older people, which will deliver research outcomes that address domains from: physical/medical; functional ability, cognitive/psychological; social or environmental factors. LASA also seeks to support commissioners and providers alike for advice on how to improve care for older people, whether by research, education or service delivery. Examples of recent research projects include: ‘Local History Café’ project specifically undertaking an evaluation on loneliness and social isolation; ‘Better Visits’ project focused on improving visiting for family members of people with dementia resident in care homes; and a study on health issues for older LGBT people in Leicester. Clinical Geriatric Medicine in Leicester We have developed a service which recognises the complexity of managing frail older people at the interface (acute care, emergency care and links with community services). There are presently 17 consultant geriatricians supported by existing multidisciplinary teams, including the largest complement of Advance Nurse Practitioners in the country. Together we deliver Comprehensive Geriatric Assessment to frail older people with urgent care needs in acute and community settings. The acute and emergency frailty units – Leicester Royal Infirmary This development aims at delivering Comprehensive Geriatric Assessment to frail older people in the acute setting. Patients are screened for frailty in the Emergency Department and then undergo a multidisciplinary assessment including a consultant geriatrician, before being triaged to the most appropriate setting. This might include admission to in-patient care in the acute or community setting, intermediate care (residential or home based), or occasionally other specialist care (e.g. cardiorespiratory). Our new emergency department is the county’s first frail friendly build and includes fantastic facilities aimed at promoting early recovering and reducing the risk of hospital associated harms. There is also a daily liaison service jointly run with the psychogeriatricians (FOPAL); we have been examining geriatric outreach to oncology and surgery as part of an NIHR funded study. We are home to the Acute Frailty Network, and those interested in service developments at the national scale would be welcome to get involved. Orthogeriatrics There are now dedicated hip fracture wards and joint care with anaesthetists, orthopaedic surgeons and geriatricians. There are also consultants in metabolic bone disease that run clinics. Community work Community work will consist of reviewing patients in clinic who have been triaged to return to the community setting following an acute assessment described above. Additionally, primary care colleagues refer to outpatients for sub-acute reviews. You will work closely with local GPs with support from consultants to deliver post-acute, subacute, intermediate and rehabilitation care services. Stroke Medicine 24/7 thrombolysis and TIA services. The latter is considered one of the best in the UK and along with the high standard of vascular surgery locally means one of the best performances regarding carotid intervention

A Tumbling Top-Quark Condensate Model

We propose a renormalizable model with no fundamental scalars which breaks itself in the manner of a "tumbling" gauge theory down to the standard model with a top-quark condensate. Because of anomaly cancellation requirements, this model contains two color sextet fermions (quixes), which are vector-like with respect to the standard model gauge group. The model also has a large number of pseudo-Nambu-Goldstone bosons, some of which can be light. The top-quark condensate is responsible for breaking the electroweak gauge symmetry and gives the top quark a large mass. We discuss the qualitative features and instructive shortcomings of the model in its present form. We also show that this model can be naturally embedded into an aesthetically pleasing model in which the standard model fermion families appear symmetrically.Comment: 16 pages. v2: TeX formatting fixed, no other change

Screening of DUB activity and specificity by MALDI-TOF mass spectrometry

Deubiquitylases (DUBs) are key regulators of the ubiquitin system which cleave ubiquitin moieties from proteins and polyubiquitin chains. Several DUBs have been implicated in various diseases and are attractive drug targets. We have developed a sensitive and fast assay to quantify in vitro DUB enzyme activity using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Unlike other current assays, this method uses unmodified substrates, such as diubiquitin topoisomers. By analyzing 42 human DUBs against all diubiquitin topoisomers we provide an extensive characterization of DUB activity and specificity. Our results confirm the high specificity of many members of the OTU and JAMM DUB families and highlight that all USPs tested display low linkage selectivity. We also demonstrate that this assay can be deployed to assess the potency and specificity of DUB inhibitors by profiling 11 compounds against a panel of 32 DUBs

Cellular localization, accumulation and trafficking of double-walled carbon nanotubes in human prostate cancer cells

Carbon nanotubes (CNTs) are at present being considered as potential nanovectors with the ability to deliver therapeutic cargoes into living cells. Previous studies established the ability of CNTs to enter cells and their therapeutic utility, but an appreciation of global intracellular trafficking associated with their cellular distribution has yet to be described. Despite the many aspects of the uptake mechanism of CNTs being studied, only a few studies have investigated internalization and fate of CNTs inside cells in detail. In the present study, intracellular localization and trafficking of RNA-wrapped, oxidized double-walled CNTs (oxDWNT–RNA) is presented. Fixed cells, previously exposed to oxDWNT–RNA, were subjected to immunocytochemical analysis using antibodies specific to proteins implicated in endocytosis; moreover cell compartment markers and pharmacological inhibitory conditions were also employed in this study. Our results revealed that an endocytic pathway is involved in the internalization of oxDWNT–RNA. The nanotubes were found in clathrin-coated vesicles, after which they appear to be sorted in early endosomes, followed by vesicular maturation, become located in lysosomes. Furthermore, we observed co-localization of oxDWNT–RNA with the small GTP-binding protein (Rab 11), involved in their recycling back to the plasma membrane via endosomes from the trans-golgi network

Constructing a new understanding of the environment under postsocialism

This paper introduces a special grouping of papers on the theme of the environment and postsocialism. After the collapse of state socialism in Europe between 1989 and 1991, many immediate approaches to environmental reconstruction assumed that economic liberalisation and democratisation would alleviate problems. Since then, critics have argued that these proposed solutions were themselves problematic, and too closely reflected Western European and North American conceptions of environmental quality and democracy. The result has been a counterreaction focusing on detail and specificity at national levels and below. In this paper, we summarise debates about the environment and postsocialism since the period 1989 - 91. In particular, we examine whether an essentialistic link can be made between state socialism and environmental problems, and how far civil society -- or environmentalism -- may result in an improvement in perceived environmental quality. Finally, we consider the possibility for developing an approach to the environment and postsocialism that lies between crude generalisation and microscale studies

Model-based Processing of Microcantilever Sensor Arrays

We have developed a model-based processor (MBP) for a microcantilever-array sensor to detect target species in solution. We perform a proof-of-concept experiment, fit model parameters to the measured data and use them to develop a Gauss-Markov simulation. We then investigate two cases of interest, averaged deflection data and multi-channel data. For this evaluation we extract model parameters via a model-based estimation, perform a Gauss-Markov simulation, design the optimal MBP and apply it to measured experimental data. The performance of the MBP in the multi-channel case is evaluated by comparison to a ''smoother'' (averager) typically used for microcantilever signal analysis. It is shown that the MBP not only provides a significant gain ({approx} 80dB) in signal-to-noise ratio (SNR), but also consistently outperforms the smoother by 40-60 dB. Finally, we apply the processor to the smoothed experimental data and demonstrate its capability for chemical detection. The MBP performs quite well, apart from a correctable systematic bias error

Stress Field Interactions Between Overlapping Shield Volcanoes : Borehole Breakout Evidence From the Island of Hawai'i, USA

Acknowledgments: This PTA2 borehole investigation was funded by the International Continental Scientific Drilling Program (ICDP) and by VMAPP (Volcanic Margin Petroleum Prospectivity) project (VBPR/DougalEARTH/TGS) in collaboration with the Humu'ula Groundwater Research Project. D. A. J. and S. P. are partly funded through a Norwegian Research Council Centres of Excellence project (project number 223272, CEED). We thank Marco Groh for the logging operations. We thank two anonymous reviewers for the comments and suggestions. We are particularly grateful to the Associate Editor Mike Poland for his valuable comments and his critical review that greatly improved the manuscript.Peer reviewedPublisher PD

The 28 November 2020 Landslide, Tsunami, and Outburst Flood – A Hazard Cascade Associated With Rapid Deglaciation at Elliot Creek, British Columbia, Canada

We describe and model the evolution of a recent landslide, tsunami, outburst flood, and sediment plume in the southern Coast Mountains, British Columbia, Canada. On November 28, 2020, about 18 million m3 of rock descended 1,000 m from a steep valley wall and traveled across the toe of a glacier before entering a 0.6 km2 glacier lake and producing >100-m high run-up. Water overtopped the lake outlet and scoured a 10-km long channel before depositing debris on a 2-km2 fan below the lake outlet. Floodwater, organic debris, and fine sediment entered a fjord where it produced a 60+km long sediment plume and altered turbidity, water temperature, and water chemistry for weeks. The outburst flood destroyed forest and salmon spawning habitat. Physically based models of the landslide, tsunami, and flood provide real-time simulations of the event and can improve understanding of similar hazard cascades and the risk they pose