Mechanical identification of layer-specific properties of mouse carotid arteries using 3D-DIC and a hyperelastic anisotropic constitutive model

The role of mechanics is known to be of primary order in many arterial diseases; however, determining mechanical properties of arteries remains a challenge. This paper discusses the identifiability of the passive mechanical properties of a mouse carotid artery, taking into account the orientation of collagen fibres in the medial and adventitial layers. On the basis of 3D digital image correlation measurements of the surface strain during an inflation/extension test, an inverse identification method is set up. It involves a 3D finite element mechanical model of the mechanical test and an optimisation algorithm. A two-layer constitutive model derived from the Holzapfel model is used, with five and then seven parameters. The five-parameter model is successfully identified providing layer-specific fibre angles. The seven-parameter model is over parameterised, yet it is shown that additional data from a simple tension test make the identification of refined layer-specific data reliable.Comment: PB-CMBBE-15.pd

Validity of a wrist-worn consumer-grade wearable for estimating energy expenditure, sedentary behaviour and physical activity in manual wheelchair users with spinal cord injury

Data availability statement: The datasets supporting the conclusions of this article are available in Figshare (https://figshare.com/s/e1db69ec9f38bdd1ab16), DOI: 10.17633/rd.brunel.24551791.Purpose: To evaluate the validity of a consumer-grade wearable for estimating energy expenditure, sedentary behaviour, and physical activity in manual wheelchair users with spinal cord injury (SCI). Materials and methods: Fifteen manual wheelchair users with SCI (C5-L1, four female) completed activities of daily living and wheelchair propulsion (2–8 km·h−1). Wrist-worn accelerometry data were collected using consumer-grade (z-Track) and research-grade (ActiGraph GT9X) devices. Energy expenditure was measured via indirect calorimetry. Linear regression was used to evaluate the prediction of criterion metabolic equivalent of task (MET) by each accelerometer’s vector magnitude (VM). Area under the receiver operating characteristic curve (ROC-AUC) evaluated the accuracy of VM for discriminating between physical activity intensities and for identifying accelerometer cut-points. Results: Standardised β-coefficients for the association between z-Track and ActiGraph VM for criterion MET were 0.791 (p < 0.001) and 0.774 (p < 0.001), respectively. The z-Track had excellent accuracy for classifying time in sedentary behaviour (ROC-AUC = 0.95) and moderate-to-vigorous physical activity (ROC-AUC = 0.93); similar values to the ActiGraph (ROC-AUC = 0.96 and 0.88, respectively). Cut-points for the z-Track were ≤37 g·min−1 for sedentary behaviour and ≥222 g·min−1 for moderate-to-vigorous physical activity. Conclusions: This study supports the validity of a consumer-grade wearable to measure sedentary time and physical activity in manual wheelchair users with SCI.No external funding was received in support of the stud

Stressed out symbiotes:hypotheses for the influence of abiotic stress on arbuscular mycorrhizal fungi

Abiotic stress is a widespread threat to both plant and soil communities. Arbuscular mycorrhizal (AM) fungi can alleviate effects of abiotic stress by improving host plant stress tolerance, but the direct effects of abiotic stress on AM fungi are less well understood. We propose two hypotheses predicting how AM fungi will respond to abiotic stress. The stress exclusion hypothesis predicts that AM fungal abundance and diversity will decrease with persistent abiotic stress. The mycorrhizal stress adaptation hypothesis predicts that AM fungi will evolve in response to abiotic stress to maintain their fitness. We conclude that abiotic stress can have effects on AM fungi independent of the effects on the host plant. AM fungal communities will change in composition in response to abiotic stress, which may mean the loss of important individual species. This could alter feedbacks to the plant community and beyond. AM fungi will adapt to abiotic stress independent of their host plant. The adaptation of AM fungi to abiotic stress should allow the maintenance of the plant-AM fungal mutualism in the face of changing climates. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00442-016-3673-7) contains supplementary material, which is available to authorized users

Population‐based cohort study of outcomes following cholecystectomy for benign gallbladder diseases

Background The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all‐cause 30‐day readmissions and complications in a prospective population‐based cohort. Methods Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all‐cause 30‐day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two‐level hierarchical structure with patients (level 1) nested within hospitals (level 2). Results Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. Conclusion Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics

How policy impacts on practice and how practice does not impact on policy

Our project attempts to understand how the Learning and Skills Sector functions. It traces how education and training policy percolates down through many levels in the English system and how these levels interact, or fail to interact. Our first focus is upon how policy impacts upon the interests of three groups of learners: unemployed people in adult and community learning centres, adult employees in work-based learning and younger learners on Level 1 and Level 2 courses in further education. Our next focus is upon how professionals in these three settings struggle to cope with two sets of pressures upon them: those exerted by government and a broader set of professional, institutional and local factors. We describe in particular how managers and tutors mediate national policy and translate it (and sometimes mistranslate it) into local plans and practices. Finally we criticise the new government model of public service reform for failing to harness the knowledge, good will and energy of staff working in the sector, and for ignoring what constitutes the main finding of our research: the central importance of the relationship between tutor and students

Towards Alignment Independent Quantitative Assessment of Homology Detection

Identification of homologous proteins provides a basis for protein annotation. Sequence alignment tools reliably identify homologs sharing high sequence similarity. However, identification of homologs that share low sequence similarity remains a challenge. Lowering the cutoff value could enable the identification of diverged homologs, but also introduces numerous false hits. Methods are being continuously developed to minimize this problem. Estimation of the fraction of homologs in a set of protein alignments can help in the assessment and development of such methods, and provides the users with intuitive quantitative assessment of protein alignment results. Herein, we present a computational approach that estimates the amount of homologs in a set of protein pairs. The method requires a prevalent and detectable protein feature that is conserved between homologs. By analyzing the feature prevalence in a set of pairwise protein alignments, the method can estimate the number of homolog pairs in the set independently of the alignments' quality. Using the HomoloGene database as a standard of truth, we implemented this approach in a proteome-wide analysis. The results revealed that this approach, which is independent of the alignments themselves, works well for estimating the number of homologous proteins in a wide range of homology values. In summary, the presented method can accompany homology searches and method development, provides validation to search results, and allows tuning of tools and methods

Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines

In the treatment of breast cancer, combination chemotherapy is used to overcome drug resistance. Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission. Alterations in protein kinase-mediated signal transduction and p53 mutations may play a role in drug resistance with cross-talk between signal transduction and p53 pathways. The aim of this study was to establish the effects of doxorubicin and vinorelbine, as single agents, in combination, and as sequential treatments, on signal transduction and p53 in the breast cancer cell lines MCF-7 and MDA-MB-468. In both cell lines, increased p38 activity was demonstrated following vinorelbine but not doxorubicin treatment, whether vinorelbine was given prior to or simultaneously with doxorubicin. Mitogen-activated protein kinase (MAPK) activity and p53 expression remained unchanged following vinorelbine treatment. Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity. These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms. This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer

Activation of adherent vascular neutrophils in the lung during acute endotoxemia

BACKGROUND: Neutrophils constitute the first line of defense against invading microorganisms. Whereas these cells readily undergo apoptosis under homeostatic conditions, their survival is prolonged during inflammatory reactions and they become biochemically and functionally activated. In the present study, we analyzed the effects of acute endotoxemia on the response of a unique subpopulation of neutrophils tightly adhered to the lung vasculature. METHODS: Rats were treated with 5 mg/kg lipopolysaccharide (i.v.) to induce acute endotoxemia. Adherent neutrophils were isolated from the lung vasculature by collagenase digestion and sequential filtering. Agarose gel electrophoresis, RT-PCR, western blotting and electrophoretic mobility shift assays were used to evaluate neutrophil activity. RESULTS: Adherent vascular neutrophils isolated from endotoxemic animals exhibited decreased apoptosis when compared to cells from control animals. This was associated with a marked increase in expression of the anti-apoptotic protein, Mcl-1. Cells isolated 0.5–2 hours after endotoxin administration were more chemotactic than cells from control animals and expressed increased tumor necrosis factor-alpha and cyclooxygenase-2 mRNA and protein, demonstrating that they are functionally activated. Endotoxin treatment of the animals also induced p38 and p44/42 mitogen activated protein kinases in the adherent lung neutrophils, as well as nuclear binding activity of the transcription factors, NF-κB and cAMP response element binding protein. CONCLUSION: These data demonstrate that adherent vascular lung neutrophils are highly responsive to endotoxin and that pathways regulating apoptosis and cellular activation are upregulated in these cells

Rationale for combination therapy of chronic myelogenous leukaemia with imatinib and irradiation or alkylating agents: implications for pretransplant conditioning

The tyrosine kinase activity of the BCR–ABL oncoprotein results in reduced apoptosis and thus prolongs survival of chronic myelogenous leukaemia cells. The tyrosine kinase inhibitor imatinib (formerly STI571) was reported to selectively suppress the proliferation of BCR–ABL-positive cells. Assuming that imatinib could be included in pretransplantation conditioning therapies, we tested whether combinations of imatinib and γ-irradiation or alkylating agents such as busulfan or treosulfan would display synergistic activity in BCR–ABL-positive chronic myelogenous leukaemia BV173 and EM-3 cell lines. Further, primary cells of untreated chronic myelogenous leukaemia patients were assayed for colony forming ability under combination therapy with imatinib. Additionally, the cytotoxic effect of these combinations on BCR–ABL-negative cells was investigated. In the cell lines a tetrazolium based MTT assay was used to quantify growth inhibition after exposure to cytotoxic drugs alone or to combinations with imatinib. Irradiation was applied prior to exposure to imatinib. Interaction of drugs was analysed using the median-effect method of Chou and Talalay. The combination index was calculated according to the classic isobologram equation. The combination imatinib + γ-irradiation proved to be significantly synergistic over a broad range of cell growth inhibition levels in both BCR–ABL-positive cell lines and produced the strongest reduction in primary chronic myelogenous leukaemia colony-forming progenitor cells. Combinations of imatinib + busulfan and imatinib + treosulfan showed merely additive to antagonistic effects. Imatinib did not potentiate the effects of irradiation or cytotoxic agents in BCR–ABL-negative cells. Our data provide the basis to further develop imatinib-containing conditioning therapies for stem cell transplantation in chronic myelogenous leukaemia