The importance of N-linked glycosylation on the N-domain of angiotensin-I converting enzyme

Angiotensin-I converting enzyme (ACE) is an important drug target in the treatment of heart disease due to its role in the regulation of blood pressure. ACE contains two domains, the N- and C-domains, both of which are catalytically active and heavily glycosylated. Glycosylation is one of the most important forms of post-translational modification, having a wide range of functions including protein folding, modulation of the immune response, and providing targeting signals. Glycosylation is required for the expression of active ACE and structural studies of ACE have been fraught with severe difficulties because of surface N-glycosylation of the protein. This problem has been addressed to a large extent with respect to the C-domain, where the role of glycosylation has been extensively characterised and a minimally glycosylated form was able to crystallise reproducibly. As yet, little is known about the degree and importance of N-linked glycosylation on the N-domain. The generation of minimally glycosylated N-domain, however, requires a greater understanding of the relative importance of the individual N-linked glycosylation sites

Characteristics and Prognostic Importance of Myocardial Fibrosis in Patients with Dilated Cardiomyopathy Assessed by Contrast-Enhanced Cardiac Magnetic Resonance Imaging

Introduction Dilated cardiomyopathy (DCM) is associated with significant morbidity and mortality. Contrast-enhanced cardiac MRI (CE-CMR) can detect potentially prognostic myocardial fibrosis in DCM. We investigated the role of CE-CMR in New Zealand patients with DCM, both Maori and non-Maori, including the characteristics and prognostic importance of fibrosis. Methods One hundred and three patients (mean age 58 ± 13, 78 male) referred for CMR assessment of DCM were followed for 660 ± 346 days. Major adverse cardiac events (MACE) were defined as death, infarction, ventricular arrhythmias or rehospitalisation. CE-CMR used cines for functional analysis, and delayed enhancement to assess fibrosis. Results Myocardial fibrosis was present in 30% of patients, the majority of which was mid-myocardial (63%). Volumetric parameters were similar in patients with or without fibrosis. At 2 years patients with fibrosis had an increased rate of MACE (HR = 0.77, 95% CI 0.3-2.0). Patients with full thickness or subendocardial fibrosis had the highest MACE, even in the absence of CAD). More Maori had fibrosis on CE-CMR (40% vs. 28% for non-Maori), and the majority (75%) was mid-myocardial. Maori and non-Maori had similar outcomes (25% vs. 24% with events during follow-up). Conclusions DCM patients frequently have myocardial fibrosis detected on CE-CMR, the majority of which is mid-myocardial. Fibrosis is associated with worse outcome in the medium term. The information obtained using CE-CMR in DCM may be of incremental clinical benefit

Characterising encapsulated nuclear waste using cosmic-ray muon tomography

Tomographic imaging techniques using the Coulomb scattering of cosmic-ray muons have been shown previously to successfully identify and characterise low- and high-Z materials within an air matrix using a prototype scintillating-fibre tracker system. Those studies were performed as the first in a series to assess the feasibility of this technology and image reconstruction techniques in characterising the potential high-Z contents of legacy nuclear waste containers for the UK Nuclear Industry. The present work continues the feasibility study and presents the first images reconstructed from experimental data collected using this small-scale prototype system of low- and high-Z materials encapsulated within a concrete-filled stainless-steel container. Clear discrimination is observed between the thick steel casing, the concrete matrix and the sample materials assayed. These reconstructed objects are presented and discussed in detail alongside the implications for future industrial scenarios.Comment: 6 pages, 4 figure

Epochs, events and episodes: Marking the geological impact of humans

Event stratigraphy is used to help characterise the Anthropocene as a chronostratigraphic concept, based on analogous deep-time events, for which we provide a novel categorization. Events in stratigraphy are distinct from extensive, time-transgressive ‘episodes’ – such as the global, highly diachronous record of anthropogenic change, termed here an Anthropogenic Modification Episode (AME). Nested within the AME are many geologically correlatable events, the most notable being those of the Great Acceleration Event Array (GAEA). This isochronous array of anthropogenic signals represents brief, unique events evident in geological deposits, e.g.: onset of the radionuclide ‘bomb-spike’; appearance of novel organic chemicals and fuel ash particles; marked changes in patterns of sedimentary deposition, heavy metal contents and carbon/nitrogen isotopic ratios; and ecosystem changes leaving a global fossil record; all around the mid-20th century. The GAEA reflects a fundamental transition of the Earth System to a new state in which many parameters now lie beyond the range of Holocene variability. Globally near-instantaneous events can provide robust primary guides for chronostratigraphic boundaries. Given the intensity, magnitude, planetary significance and global isochroneity of the GAEA, it provides a suitable level for recognition of the base of the Anthropocene as a series/epoch

Response to Merritts et al. (2023): The Anthropocene is complex. Defining it is not

Merritts et al. (2023) misrepresent Paul Crutzen’s Anthropocene concept as encompassing all significant anthropogenic impacts, extending back many millennia. Crutzen's definition reflects massively enhanced, much more recent human impacts that transformed the Earth System away from the stability of Holocene conditions. His concept of an epoch (hence the ‘cene’ suffix) is more consistent with the strikingly distinct sedimentary record accumulated since the mid-20th century. Waters et al. (2022) highlighted a Great Acceleration Event Array (GAEA) of stratigraphic event markers that are indeed diverse and complex but also tightly clustered around 1950 CE, allowing ultra-high resolution characterization and correlation of a clearly recognisable Anthropocene chronostratigraphic base. The ‘Anthropocene event’ offered by Merritts et al., following Gibbard et al. (2021, 2022), is a highly nuanced concept that obfuscates the transformative human impact of the chronostratigraphic Anthropocene. Waters et al. (2022) restricted the meaning of the term ‘event’ in geology to conform with usual Quaternary practice and improve its utility. They simultaneously recognized an evidence-based Anthropogenic Modification Episode that is more explicitly defined than the highly interpretive interdisciplinary ‘Anthropocene event’ of Gibbard et al. (2021, 2022). The advance of science is best served through clearly developed concepts supported by tightly circumscribed terminology; indeed, improvements to stratigraphy over recent decades have been achieved through increasingly precise definitions, especially for chronostratigraphic units, and not by retaining vague terminology

Planning for Sustainability in Small Municipalities: The Influence of Interest Groups, Growth Patterns, and Institutional Characteristics

How and why small municipalities promote sustainability through planning efforts is poorly understood. We analyzed ordinances in 451 Maine municipalities and tested theories of policy adoption using regression analysis.We found that smaller communities do adopt programs that contribute to sustainability relevant to their scale and context. In line with the political market theory, we found that municipalities with strong environmental interests, higher growth, and more formal governments were more likely to adopt these policies. Consideration of context and capacity in planning for sustainability will help planners better identify and benefit from collaboration, training, and outreach opportunities

An evaluation of Minor Groove Binders as anti- Trypanosoma brucei brucei therapeutics

A series of 32 structurally diverse MGBs, derived from the natural product distamycin, was evaluated for activity against Trypanosoma brucei brucei. Four compounds have been found to possess significant activity, in the nanomolar range, and represent hits for further optimisation towards novel treatments for Human and Animal African Trypanosomiases. Moreover, SAR indicates that the head group linking moiety is a significant modulator of biological activit