Unveiling the molecular determinants of mammalian skin ageing: A proteomic and transcriptomic approach

As the limits of human lifespan continue to expand, ageing biologists must address the decline in the integrity of bodily tissues with time. Our skin is drastically impacted by both intrinsic and extrinsic ageing processes, driven by gradual accumulation of cellular damage and environmental insults like ultra-violet irradiation. Together intrinsic and extrinsic skin ageing give rise to clinical issues such as xerosis, pruritus and neoplasms. Cosmetic issues, such as unsightly wrinkling, thinning and sagging of the skin also impact human psychological and social wellbeing. Given these issues, studying the molecular mechanisms of intrinsic and extrinsic skin ageing processes is an important element of biological research, as a better understanding of how these processes contribute to reduced tissue integrity will allow us to develop therapies to attenuate the ageing process. Using tissues taken from C57BL/6 male mice and female humans as our models, we analysed skin at early, middle and late stages within both the murine and human lifespans to assess the impact of ageing on changes in the epidermis, dermis and at the basement membrane. By considering tissue taken from photo-protected and photo-exposed sites of humans, we additionally studied the differential changes occurring during intrinsic and extrinsic skin ageing (photo-ageing). Our studies showed that several morphometric changes occur to the epidermis with age in mouse skin, where we observed thinning and cellular loss. Cell proliferation and lamin B1 levels declined, which was coupled with decreased expression of dermal and basement membrane collagens. Many of these observations were ubiquitous in intrinsically aged human skin, where we additionally show unique transcriptional changes at the basement membrane. One little studied pathway in skin ageing is the Hippo pathway, which has crucial roles in epidermal development through its control of epidermal cell proliferation. We identify a novel modulation of the Hippo pathway effector YAP1 in aged mouse and human skin, where we show that nuclear localisation of YAP1 increases during epidermal ageing. Together this body of work demonstrates that C57BL/6 mouse skin ageing shares common mechanisms of intrinsic human skin ageing. Additionally, we show that YAP1 localisation is altered during epidermal ageing, which suggests that the Hippo pathway is sensitive to both changes in the extra-cellular matrix content, and cell-proliferation properties of skin over time

An investigation into the role of Lamin A in cell motility and Epithelial to Mesenchymal Transition in Colorectal Cancer

The Lamin A protein has a number of structural and gene-regulatory roles. Recently novel functions for Lamin A have been established in colorectal cancer, where expression of Lamin A is a biomarker of poor patient prognosis. Colorectal cancer is the fourth most frequent cause of cancer-related death world-wide, therefore understanding the molecular mechanisms behind the disease is of importance in the development of future therapeutic strategies to reduce mortality rates. SW480 colorectal cancer cells that artificially express Lamin A (SW480/Lamin A cells) demonstrate increased cell motility and a mesenchymal-like morphology, suggesting a more aggressive cancer cell phenotype in the presence of Lamin A expression. The aims of this project were to further explore how Lamin A expression contributes to a more aggressive cancer cell phenotype in SW480 cells. Herein cell density experiments show that at low cell density, SW480/Lamin A cells express the mesenchymal markers Slug and Vimentin. Scratch wounding assays of SW480/Lamin A cells show that cell junctions are absent from these cells at high cell density and the cytoskeletons of SW480/Lamin A cells are able to form motile structures. Finally silencing of Lamin A in SW480/Lamin A cells caused some of these changes to reversed. Together this data indicate that transfection of SW480 cells with Lamin A permits a signalling environment conducive to EMT and thus patients with high levels of Lamin A in the cells in their tumours may have a poorer prognosis due to increased cellular metastatic potential as a result of EMT

Modeling an Integrated Public Transportation System - a case study in Dublin, Ireland

The efficiency of the public transport system in any city depends on integration of its major public transport modes. Suburban railway and public buses are the modes normally used by the majority of commuters in metropolitan cities of developed and developing countries. Integration of these two services reduces overall journey time of an individual. In this research, a model is developed for operational integration of suburban trains and public buses. The model has two sub models: a Routing Sub Model and a Scheduling Sub Model. In the Routing Sub Model, feeder routes are generated for public buses which originate from a railway station. A Heuristic Feeder Route Generation Algorithm is developed for generation of feeder routes. In the Scheduling Sub Model, optimal coordinated schedules for feeder buses are developed for the given schedules of suburban trains. As a case study the Dun Laoghaire DART (Dublin Area Rapid Transit) (heavy rail suburban service) station of Dublin in Ireland is selected. Feeder bus services are coordinated with existing schedules of the DART on the developed feeder route network. Genetic Algorithms, which are known to be a robust optimization technique for this type of problem, are used in the Scheduling Sub Model. Finally the outcome of the research is a generated feeder route network and coordinated services of feeder buses on it for the DART station

Teachers as knowledge creators

Explore how teachers are connecting with each other through use of online learning technologies. • Demonstrate how teachers are creating learning artefacts for use in their own practice contexts. • Show how teachers are integrating their educational values in practice by asking, researching and answering the question, 'how can I improve my practice?

Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2):a multicentre observational cohort study

Background: Cerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack. Methods: Our observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316. Findings: Between Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0–20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1–5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27–10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29–0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53–0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60–0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07–0·43, p=0·0065; and 0·33, 0·14–0·51, p=0·00059, respectively). Interpretation: In patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from oral anticoagulation. Funding: The Stroke Association and the British Heart Foundation

Creative destruction in science

Drawing on the concept of a gale of creative destruction in a capitalistic economy, we argue that initiatives to assess the robustness of findings in the organizational literature should aim to simultaneously test competing ideas operating in the same theoretical space. In other words, replication efforts should seek not just to support or question the original findings, but also to replace them with revised, stronger theories with greater explanatory power. Achieving this will typically require adding new measures, conditions, and subject populations to research designs, in order to carry out conceptual tests of multiple theories in addition to directly replicating the original findings. To illustrate the value of the creative destruction approach for theory pruning in organizational scholarship, we describe recent replication initiatives re-examining culture and work morality, working parents\u2019 reasoning about day care options, and gender discrimination in hiring decisions. Significance statement It is becoming increasingly clear that many, if not most, published research findings across scientific fields are not readily replicable when the same method is repeated. Although extremely valuable, failed replications risk leaving a theoretical void\u2014 reducing confidence the original theoretical prediction is true, but not replacing it with positive evidence in favor of an alternative theory. We introduce the creative destruction approach to replication, which combines theory pruning methods from the field of management with emerging best practices from the open science movement, with the aim of making replications as generative as possible. In effect, we advocate for a Replication 2.0 movement in which the goal shifts from checking on the reliability of past findings to actively engaging in competitive theory testing and theory building. Scientific transparency statement The materials, code, and data for this article are posted publicly on the Open Science Framework, with links provided in the article

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study

Summary Background: Cerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack. Methods: Our observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316. Findings: Between Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0–20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1–5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27–10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29–0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53–0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60–0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07–0·43, p=0·0065; and 0·33, 0·14–0·51, p=0·00059, respectively). Interpretation In patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from oral anticoagulation. Funding The Stroke Association and the British Heart Foundation

A model for development of optimized feeder routes and coordinated schedules--A genetic algorithms approach

Many attempts have been made to solve bus route network design problems by splitting it in two stages, one for routing and the other for scheduling. Some researchers have made attempts to solve network design problems using non-traditional optimization techniques also, but not much has been done on modelling coordinated operations involving transfers from one mode to another. In this research, feeder routes and frequencies leading to schedule coordination of feeder buses with main transit are developed simultaneously using genetic algorithms. The coordinated schedules of feeder buses are determined for the existing given schedules of main transit. Thus the developed feeder routes and schedules are complementary to each other. As a case study the Dun Laoghaire Dublin Area Rapid Transit (DART) (heavy rail suburban service) station of Dublin in Ireland is selected. Finally the outcome of the research is a generated feeder route network for feeder buses and coordinated schedules of feeder buses for the existing schedules of DART at the selected station. The results of the proposed model indicate improved load factors on developed routes and also the overall load factor is also improved considerably as compared to the authors' earlier model.