RBR E3 ubiquitin ligases: new structures, new insights, new questions

The RBR (RING-BetweenRING-RING) or TRIAD [two RING fingers and a DRIL (double RING finger linked)] E3 ubiquitin ligases comprise a group of 12 complex multidomain enzymes. This unique family of E3 ligases includes parkin, whose dysfunction is linked to the pathogenesis of early-onset Parkinson's disease, and HOIP (HOIL-1-interacting protein) and HOIL-1 (haem-oxidized IRP2 ubiquitin ligase 1), members of the LUBAC (linear ubiquitin chain assembly complex). The RBR E3 ligases share common features with both the larger RING and HECT (homologous with E6-associated protein C-terminus) E3 ligase families, directly catalysing ubiquitin transfer from an intrinsic catalytic cysteine housed in the C-terminal domain, as well as recruiting thioester-bound E2 enzymes via a RING domain. Recent three-dimensional structures and biochemical findings of the RBRs have revealed novel protein domain folds not previously envisioned and some surprising modes of regulation that have raised many questions. This has required renaming two of the domains in the RBR E3 ligases to more accurately reflect their structures and functions: the C-terminal Rcat (required-for-catalysis) domain, essential for catalytic activity, and a central BRcat (benign-catalytic) domain that adopts the same fold as the Rcat, but lacks a catalytic cysteine residue and ubiquitination activity. The present review discusses how three-dimensional structures of RBR (RING1-BRcat-Rcat) E3 ligases have provided new insights into our understanding of the biochemical mechanisms of these important enzymes in ubiquitin biology. INTRODUCTIO

Equality, Security and Sustainability: In Search of Virtuous Circles

Many people and institutions are conducting research on inequality, security, or environmental sustainability. Some are looking at two of these issues together. None, to our knowledge, are examining all three simultaneously, or looking in detail at the interactions between them. This matters. Of the 17 Sustainable Development Goals (SDGs), nine relate directly to these subjects, and eight have strong indirect linkages. Crucially, while each SDG can be considered on its own terms, they should really be viewed as interdependent objectives: the level and nature of growth and industrialisation, for example, is inextricably linked with environment goals. The same is true of the three objectives that form the title of this report. From a development perspective, the aim is not to foster societies that are equal or secure or sustainable, but to understand the pathways that could potentially lead to societies with all of these characteristics. As a prerequisite, we need to identify the ways that these goals can interact during the development process, both negatively and positively, and understand better how negative interactions might be reduced and positive synergies enhanced.UK Department for International Developmen

Adjunctive strategies in the management of resistant, 'undilatable' coronary lesions after successfully crossing a CTO with a guidewire.

Successful revascularisation of chronic total occlusions (CTOs) remains one of the greatest challenges in the era of contemporary percutaneous coronary intervention (PCI). Such lesions are encountered with increasing frequency in current clinical practice. A predictable increase in the future burden of CTO management can be anticipated given the ageing population, increased rates of renal failure, graft failure and diabetes mellitus. Given recent advances and developments in CTO PCI management, successful recanalisation can be anticipated in the majority of procedures undertaken at high-volume centres when performed by expert operators. Despite advances in device technology, the management of resistant, calcific lesions remains one of the greatest challenges in successful CTO intervention. Established techniques to modify calcific lesions include the use of high-pressure non-compliant balloon dilation, cutting-balloons, anchor balloons and high speed rotational atherectomy (HSRA). Novel approaches have proven to be safe and technically feasible where standard approaches have failed. A step-wise progression of strategies is demonstrated, from well-recognised techniques to techniques that should only be considered when standard manoeuvres have proven unsuccessful. These methods will be described in the setting of clinical examples and include use of very high-pressure non-compliant balloon dilation, intentional balloon rupture with vessel dissection or balloon assisted micro-dissection (BAM), excimer coronary laser atherectomy (ECLA) and use of HSRA in various 'offlabel' settings

A Phenomenological Study of Implementing Social-Emotional Learning Skills Virtually and Its Influence on the Teacher-Student Relationship

This transcendental phenomenological research design seeks to investigate the experience of teachers in Illinois urban school districts who have virtually implemented Social-Emotional Learning skill sets and describe any impact virtual implementation has had on the teacher-student relationship. This data was viewed through teachers who implemented the social and emotional learning skill sets in an urban middle school. Social-emotional learning is often implemented in a classroom while teaching students regular academic requirements. The theory used to guide this study was Maslow’s hierarchy of needs, with self-actualization being the ultimate achievement goal on the pyramid. The theory explained the connection between the basic needs in Maslow’s pyramid and social-emotional learning, as explained by CASEL (Collaborative for Academic, Social, and Emotional Learning). Five research questions guided this study. The study used purposeful sampling to select 10 participants from Illinois urban middle schools. The data was collected using individual and group interviews. Three overarching themes emerged from the study, and five sub-themes were generated. This research aimed to bring knowledge and add to the limited research on the lived experience of urban middle school teachers in Illinois regarding implementing social-emotional skills virtually during a pandemic and describe any impact it has had on the teacher-student relationship. Future research should investigate how parents\u27 and students’ perceptions differ from teachers regarding implementing social-emotional learning skill sets virtually and its effectiveness in establishing and keeping the teacher-student relationship intact

The Hybrid Approach to Intervention of Chronic Total Occlusions

The "hybrid" approach to chronic total occlusion (CTO) percutaneous coronary intervention (PCI) was developed to provide guidance on optimal crossing strategy selection. Dual angiography remains the cornerstone of clinical decision making in CTO PCI. Four angiographic parameters are assessed: (a) morphology of the proximal cap (clear-cut or ambiguous); (b) occlusion length; (c) distal vessel size and presence of bifurcations beyond the distal cap; and (d) location and suitability of location and suitability of a retrograde conduit (collateral channels or bypass grafts) for retrograde access. Antegrade wire escalation is favored for short (<20 mm) occlusions, usually escalating rapidly from a soft tapered-tip polymer-jacketed guidewire to a stiff polymer-jacketed or tapered-tip guidewire. Antegrade dissection/re-entry is favored in long (≥20 mm long) occlusions, trying to minimize the dissection length by re-entering into the distal true lumen immediately after the occlusion. Primary retrograde approach is preferred for lesions with an ambiguous proximal cap, poor distal target, good interventional collaterals, and heavy calcification,as well as chronic kidney disease. The "hybrid" approach advocates early change between strategies to enable CTO crossing in the most efficacious, efficient, and safe way. Several early studies are demonstrating high success and low complication rates with use of the "hybrid" approach, supporting its expanding use in CTO PCI

Maximisation of Benefits for the Poor of Investments in Renewable Electricity: A Policy Tool for Project Planning

Energy poverty is a major development issue: nearly 1.2 billion people, or close to one-fifth of the world’s population, have no access to electricity. Close to 85 per cent of them live in rural areas (Banerjee et al. 2013). After falling out of favour in the 1980s, electrification is again seen as central to poverty reduction efforts. Electricity improves users’ quality of life and can enable income generation when used for productive activities, hence supporting an escape from the poverty trap. Where generation comes from renewable sources, it also makes a positive contribution to low-carbon development; for many, this is a classic ‘win-win’ situation. This report uses the evidence collected through a comprehensive literature review to develop a policy tool to maximise the poverty impact of electrification projects. It can be of use for development and climate finance institutions funding renewable energy projects in developing countries, and keen to enhance the poverty impacts of these projects.UK Department for International Developmen

Probing the nanoadhesion of Streptococcus sanguinis to titanium implant surfaces by atomic force microscopy

The authors would kindly like to thank the BecasChile PhD Scholarship Programme for funding this research

p19/Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis.

The ability of tumor cells to metastasize is increasingly viewed as an interaction between the primary tumor and host tissues. Deletion of the p19/Arf or p53 tumor suppressor genes accelerates malignant progression and metastatic spread of 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced squamous cell carcinomas, providing a model system to address mechanisms of metastasis. Here, we show that benign pre-metastatic papillomas from wild-type mice trigger lymphangiogenesis within draining lymph nodes, whereas there is no growth of primary tumor lymphatic vessels. Lymph node lymphangiogenesis is greatly accelerated in papilloma-bearing p19/Arf- or p53-deficient mice, which coincides with the greater propensity of these tumors to progress to carcinomas and to metastasize. The extent of accumulation of B cells within the tumor-draining lymph nodes of wild-type mice predicted the level of lymph node lymphangiogenesis and metastatic potential. Arf or p53 deficiency strongly accelerated lymph node immune cell accumulation, in a manner that was associated with the extent of lymph node lymphatic sinus growth. This immune cell accumulation and lymph node lymphangiogenesis phenotype identifies host anti-tumor responses that could drive metastatic spread of cancers via the lymphatics

A Multi-scale Biophysical Approach to Develop Structure-Property Relationships in Oral Biofilms

Over the last 5-10 years, optical coherence tomography (OCT) and atomic force microscopy (AFM) have been individually applied to monitor the morphological and mechanical properties of various single-species biofilms respectively. This investigation looked to combine OCT and AFM as a multi-scale approach to understand the role sucrose concentration and age play in the morphological and mechanical properties of oral, microcosm biofilms, in-vitro. Biofilms with low (0.1% w/v) and high (5% w/v) sucrose concentrations were grown on hydroxyapatite (HAP) discs from pooled human saliva and incubated for 3 and 5 days. Distinct mesoscale features of biofilms such as regions of low and high extracellular polymeric substances (EPS) were identified through observations made by OCT. Mechanical analysis revealed increasing sucrose concentration decreased Young's modulus and increased cantilever adhesion (p < 0.0001), relative to the biofilm. Increasing age was found to decrease adhesion only (p < 0.0001). This was due to mechanical interactions between the indenter and the biofilm increasing as a function of increased EPS content, due to increasing sucrose. An expected decrease in EPS cantilever contact decreased adhesion due to bacteria proliferation with biofilm age. The application OCT and AFM revealed new structure-property relationships in oral biofilms, unattainable if the techniques were used independently

Detecting foraminiferal photosymbionts in the fossil record: a combined micropalaeontological and geochemical approach

Poster from International Conference on Paleoceanography 12 (ICP 12). See the above link for more information on the conference