Theory of dynamic crack branching in brittle materials

The problem of dynamic symmetric branching of an initial single brittle crack propagating at a given speed under plane loading conditions is studied within a continuum mechanics approach. Griffith's energy criterion and the principle of local symmetry are used to determine the cracks paths. The bifurcation is predicted at a given critical speed and at a specific branching angle: both correlated very well with experiments. The curvature of the subsequent branches is also studied: the sign of $T$, with $T$ being the non singular stress at the initial crack tip, separates branches paths that diverge from or converge to the initial path, a feature that may be tested in future experiments. The model rests on a scenario of crack branching with some reasonable assumptions based on general considerations and in exact dynamic results for anti-plane branching. It is argued that it is possible to use a static analysis of the crack bifurcation for plane loading as a good approximation to the dynamical case. The results are interesting since they explain within a continuum mechanics approach the main features of the branching instabilities of fast cracks in brittle materials, i.e. critical speeds, branching angle and the geometry of subsequent branches paths.Comment: 41 pages, 15 figures. Accepted to International Journal of Fractur

Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): Study protocol

Background: Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). Methods: iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m2. At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. Discussion: iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D. Trial registration: Clinicaltrials.gov (NCT03716401)

The simulation of transport processes in cementitious materials with embedded healing systems

A new model for simulating the transport of healing agents in self-healing (SH) cementitious materials is presented. The model is applicable to autonomic SH material systems in which embedded channels, or vascular networks, are used to supply healing agents to damaged zones. The essential numerical components of the model are a crack flow model, based on the Navier-Stokes equations, which is coupled to the mass balance equation for simulating unsaturated matrix flow. The driving forces for the crack flow are the capillary meniscus force and the force derived from an external (or internal) pressure applied to the liquid healing agent. The crack flow model component applies to non-uniform cracks and allows for the dynamic variation of the meniscus contact angle, as well as accounting for inertial terms. Particular attention is paid to the effects of curing on the flow characteristics. In this regard, a kinetic reaction model is presented for simulating the curing of the healing agent and a set of relationships established for representing the variation of rheological properties with the degree of cure. Data obtained in a linked experimental programme of work is employed to justify the choice and form of the constitutive relationships, as well as to calibrate the model’s evolution functions. Finally, a series of validation examples are presented that include the analysis of a series of concrete beam specimens with an embedded vascular network. These examples demonstrate the ability of the model to capture the transport behaviour of this type of SH cementitious material system

VEGF-A isoforms differentially regulate ATF-2-dependent VCAM-1 gene expression and endothelial-leukocyte interactions

Vascular endothelial growth factor A (VEGF-A) regulates many aspects of vascular physiology. VEGF-A stimulates signal transduction pathways that modulate endothelial outputs such as cell migration, proliferation, tubulogenesis, and cell-cell interactions. Multiple VEGF-A isoforms exist, but the biological significance of this is unclear. Here we analyzed VEGF-A isoform-specific stimulation of VCAM-1 gene expression, which controls endothelial-leukocyte interactions, and show that this is dependent on both ERK1/2 and activating transcription factor-2 (ATF-2). VEGF-A isoforms showed differential ERK1/2 and p38 MAPK phosphorylation kinetics. A key feature of VEGF-A isoform-specific ERK1/2 activation and nuclear translocation was increased phosphorylation of ATF-2 on threonine residue 71 (T71). Using reverse genetics, we showed ATF-2 to be functionally required for VEGF-A-stimulated endothelial VCAM-1 gene expression. ATF-2 knockdown blocked VEGF-A-stimulated VCAM-1 expression and endothelial-leukocyte interactions. ATF-2 was also required for other endothelial cell outputs, such as cell migration and tubulogenesis. In contrast, VCAM-1 was essential only for promoting endothelial-leukocyte interactions. This work presents a new paradigm for understanding how soluble growth factor isoforms program complex cellular outputs and responses by modulating signal transduction pathways

A Criterion for Brittle Failure of Rocks Using the Theory of Critical Distances

This paper presents a new analytical criterion for brittle failure of rocks and heavily overconsolidated soils. Griffith’s model of a randomly oriented defect under a biaxial stress state is used to keep the criterion simple. The Griffith’s criterion is improved because the maximum tensile strength is not evaluated at the boundary of the defect but at a certain distance from the boundary, known as the critical distance. This fracture criterion is known as the Point Method, and is part of the Theory of Critical Distances, which is utilized in fracture mechanics. The proposed failure criterion has two parameters: the inherent tensile strength, ó0, and the ratio of the half-length of the initial crack/flaw to the critical distance, a/L. These parameters are difficult to measure but they may be correlated with the uniaxial compressive and tensile strengths, óc and ót. The proposed criterion is able to reproduce the common range of strength ratios for rocks and heavily overconsolidated soils (óc/ót=3-50) and the influence of several microstructural rock properties, such as texture and porosity. Good agreement with laboratory tests reported in the literature is found for tensile and low confining stresses.The work presented was initiated during a research project on “Structural integrity assessments of notch-type defects", for the Spanish Ministry of Science and Innovation (Ref.: MAT2010-15721)

Angiogenesis and chronic kidney disease

The number of patients requiring renal replacement therapy due to end-stage renal disease (ESRD) is increasing worldwide. The prevalence of chronic kidney disease (CKD), and the importance of CKD as a risk factor in development of ESRD and in complicating cardiovascular disease (CVD) have been confirmed. In recent years, the involvement of angiogenesis-related factors in the progression of CKD has been studied, and the potential therapeutic effects on CKD of modulating these factors have been identified. Vascular endothelial growth factor (VEGF)-A, a potent pro-angiogenic factor, is involved in the development of the kidney, in maintenance of the glomerular capillary structure and filtration barrier, and in the renal repair process after injury. VEGF-A is also involved in the development of early diabetic nephropathy, demonstrated by the therapeutic effects of anti-VEGF-A antibody. Angiopoietin (Ang)-1 induces the maturation of newly formed blood vessels, and the therapeutic effects of Ang-1 in diabetic nephropathy have been described. In experimental models of diabetic nephropathy, the therapeutic effects of angiogenesis inhibitors, including angiostatin, endostatin and tumstatin peptides, the isocoumarin NM-3, and vasohibin-1, have been reported

Prognostic imaging biomarkers for diabetic kidney disease (iBEAt): study protocol

Background: Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). Methods: iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR >= 30 ml/min/1.73m(2). At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H2O15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. Discussion: iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D.</div