The impact of fretting wear on structural dynamics: Experiment and simulation

This paper investigates the effects of fretting wear on frictional contacts. A high frequency friction rig is used to measure the evolution of hysteresis loops, friction coefficient and tangential contact stiffness over time. This evolution of the contact parameters is linked to significant changes in natural frequencies and damping of the rig. Hysteresis loops are replicated by using a Bouc-Wen modified formulation, which includes wear to simulate the evolution of contact parameters and to model the evolving dynamic behaviour of the rig. A comparison of the measured and predicted dynamic behaviour demonstrates the feasibility of the proposed approach and highlights the need to consider wear to accurately capture the dynamic response of a system with frictional joints over its lifetime

The impact of fretting wear on structural dynamics: Experiment and simulation

This paper investigates the effects of fretting wear on frictional contacts. A high frequency friction rig is used to measure the evolution of hysteresis loops, friction coefficient and tangential contact stiffness over time. This evolution of the contact parameters is linked to significant changes in natural frequencies and damping of the rig. Hysteresis loops are replicated by using a Bouc-Wen modified formulation, which includes wear to simulate the evolution of contact parameters and to model the evolving dynamic behaviour of the rig. A comparison of the measured and predicted dynamic behaviour demonstrates the feasibility of the proposed approach and highlights the need to consider wear to accurately capture the dynamic response of a system with frictional joints over its lifetime

Risk factors for pre-eclampsia in clinical practice guidelines: comparison with the evidence.

OBJECTIVE: To compare pre-eclampsia risk factors identified by clinical practice guidelines (CPGs) with risk factors from hierarchical evidence review, to guide pre-eclampsia prevention. DESIGN: Our search strategy provided hierarchical evidence of relationships between risk factors and pre-eclampsia, using Medline (Ovid), January 2010-January 2021. SETTING: Published studies and CPGs. POPULATION: Pregnant women. METHODS: We evaluated strength of association and quality of evidence (GRADE). CPGs (N=15) were from previous systematic review. MAIN OUTCOME MEASURE: Pre-eclampsia. RESULTS: Of 78 pre-eclampsia risk factors, 13 (16.5%) arise only during pregnancy. Strength of association was usually 'probable' (n=40, 51.3%), and quality of evidence low (n=35, 44.9%). The 'major' and 'moderate' risk factors proposed by 8/15 CPGs were not well-aligned with evidence; of 10 'major' risk factors (alone warranting aspirin prophylaxis), associations with pre-eclampsia were definite (n=4), probable (n=5), or possible (n=1), based on moderate (n=4), low (n=5), or very-low (n=1) quality evidence. Obesity ('moderate' risk factor), was definitely associated with pre-eclampsia (high-quality evidence). The other ten 'moderate' risk factors had probable (n=8), possible (n=1), or no (n=1) association with pre-eclampsia, based on moderate (n=1), low (n=5), or very-low (n=4) quality evidence. Three risk factors not identified by CPGs had probable associations (high-quality): overweight, booking 'prehypertension', and early pregnancy BP 130-139/80-89mmHg. CONCLUSIONS: Pre-eclampsia risk factors in CPGs are poorly aligned with evidence, particularly for the strongest risk factor, obesity. There is a lack of distinction between risk factors identifiable in early pregnancy and those arising later. A refresh of strategies advocated by CPGs is needed

Benfotiamine increases glucose oxidation and downregulates NADPH oxidase 4 expression in cultured human myotubes exposed to both normal and high glucose concentrations

The aim of the present work was to study the effects of benfotiamine (S-benzoylthiamine O-monophosphate) on glucose and lipid metabolism and gene expression in differentiated human skeletal muscle cells (myotubes) incubated for 4 days under normal (5.5 mM glucose) and hyperglycemic (20 mM glucose) conditions. Myotubes established from lean, healthy volunteers were treated with benfotiamine for 4 days. Glucose and lipid metabolism were studied with labeled precursors. Gene expression was measured using real-time polymerase chain reaction (qPCR) and microarray technology. Benfotiamine significantly increased glucose oxidation under normoglycemic (35 and 49% increase at 100 and 200 μM benfotiamine, respectively) as well as hyperglycemic conditions (70% increase at 200 μM benfotiamine). Benfotiamine also increased glucose uptake. In comparison, thiamine (200 μM) increased overall glucose metabolism but did not change glucose oxidation. In contrast to glucose, mitochondrial lipid oxidation and overall lipid metabolism were unchanged by benfotiamine. The expression of NADPH oxidase 4 (NOX4) was significantly downregulated by benfotiamine treatment under both normo- and hyperglycemic conditions. Gene set enrichment analysis (GSEA) showed that befotiamine increased peroxisomal lipid oxidation and organelle (mitochondrial) membrane function. In conclusion, benfotiamine increases mitochondrial glucose oxidation in myotubes and downregulates NOX4 expression. These findings may be of relevance to type 2 diabetes where reversal of reduced glucose oxidation and mitochondrial capacity is a desirable goal

The miR-183/ItgA3 axis is a key regulator of prosensory area during early inner ear development

MicroRNAs are important regulators of gene expression and are involved in cellular processes such as proliferation or differentiation, particularly during development of numerous organs including the inner ear. However, it remains unknown if miRNAs are required during the earliest stages of otocyst and cochlear duct development. Here, we report that a conditional loss of Dicer expression in the otocyst impairs the early development of the inner ear as a result of the accumulation of DNA damage that trigger p53-mediated apoptosis. Moreover, cochlear progenitors in the prosensory domain do not exit the cell cycle. Our unbiased approach identified ItgA3 as a target of miR-183, which are both enriched in the otic vesicle. We observed that the repression of integrin alpha 3 by miR-183 controls cell proliferation in the developing cochlea. Collectively, our results reveal that Dicer and miRNAs play essential roles in the regulation of early inner ear development.Cell Death and Differentiation advance online publication, 4 August 2017; doi:10.1038/cdd.2017.127

MiRNAs in early brain development and pediatric cancer

The size and organization of the brain are determined by the activity of progenitor cells early in development. Key mechanisms regulating progenitor cell biology involve miRNAs. These small noncoding RNA molecules bind mRNAs with high specificity, controlling their abundance and expression. The role of miRNAs in brain development has been studied extensively, but their involvement at early stages remained unknown until recently. Here, recent findings showing the important role of miRNAs in the earliest phases of brain development are reviewed, and it is discussed how loss of specific miRNAs leads to pathological conditions, particularly adult and pediatric brain tumors. Let-7 miRNA downregulation and the initiation of embryonal tumors with multilayered rosettes (ETMR), a novel link recently discovered by the laboratory, are focused upon. Finally, it is discussed how miRNAs may be used for the diagnosis and therapeutic treatment of pediatric brain tumors, with the hope of improving the prognosis of these devastating diseases.A.P. was funded by a predoctoral fellowship from Fundación Tatiana Pérez de Guzmán el Bueno. Work in the lab was supported by grants from the European Research Council (309633) and the Spanish State Research Agency (PGC2018-102172-B-I00, as well as through the “Severo Ochoa” Programme for Centers of Excellence in R&D, ref. SEV-2017-0723).Peer reviewe

MicroRNAs tune cerebral cortical neurogenesis

peer reviewedMicroRNAs (miRNAs) are non-coding RNAs that promote post-transcriptional silencing of genes involved in a wide range of developmental and pathological processes. It is estimated that most protein-coding genes harbor miRNA recognition sequences in their 3' untranslated region and are thus putative targets. While functions of miRNAs have been extensively characterized in various tissues, their multiple contributions to cerebral cortical development are just beginning to be unveiled. This review aims to outline the evidence collected to date demonstrating a role for miRNAs in cerebral corticogenesis with a particular emphasis on pathways that control the birth and maturation of functional excitatory projection neurons