The role of geometric stiffness in momentum and energy conserving time integration

In this paper, a number of recently proposed implicit and explicit composite time integration schemes are reviewed and critically evaluated. To give suitable guidelines of using them in practical transient analyses of structural problems, numerical performances of these schemes are compared through illustrative examples. Meaningful insights into computational aspects of the composite schemes are also provided. In the discussion, the role of the splitting ratio of the recent composite schemes is also investigated through a different point of view, and similarities and differences of various composite schemes are also studied. It is shown that the explicit composite scheme proposed recently by the authors can noticeably increase the efficiency and the accuracy of linear and nonlinear transient analyses when compared with other well-known composite schemes.

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Hypoxia Regulation of ndrgs

10.1101/2020.12.16.422782 ◽

2020 ◽

Author(s):

Nguyet Le ◽

Timothy Hufford ◽

Rachel Brewster

Keyword(s):

De Novo ◽

Cell Damage ◽

Normal Function ◽

Transport Chain ◽

Energy Conserving ◽

Underlying Mechanisms ◽

Conserved Gene ◽

Excessive Oxygen

ABSTRACTMany organisms rely on oxygen to generate energy in the form of adenosine triphosphate (ATP). During severe hypoxia, the production of ATP decreases due to diminished activity of the electron transport chain, leading to cell damage or death. Conversely, excessive oxygen causes oxidative stress that is equally damaging to cells. To mitigate pathological outcomes, organisms have evolved mechanisms to adapt to fluctuations in oxygen levels. Zebrafish embryos are remarkably hypoxia-tolerant, surviving anoxia (zero oxygen) for hours in a hypometabolic, energy-conserving state. To begin to unravel underlying mechanisms, we analyze here the distribution and hypoxia-dependent regulation of members of the N-myc Downstream Regulated Gene (Ndrg) family, Ndrg 1-4. These genes have primarily been studied in cancer cells, and hence little is understood about their normal function. We show here using in situ hybridization that, under normoxic conditions, ndrgs are expressed in metabolically-demanding organs of the zebrafish embryo, such as the brain, kidney, and heart. Following exposure of embryos to different severity and durations of hypoxia, we observed that ndrgs are differentially regulated and that ndrg1a is the most responsive member of this family, with nine-fold upregulation following prolonged anoxia. We further show that this treatment resulted in de novo expression of ndrg1a in tissues where it is not observed under normoxia, such as head vasculature, the inner ear, and somites. These findings provide an entry point into understanding the role of this conserved gene family in hypoxia adaptation of normal cells.

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Cardiac myosin super relaxation (SRX): a perspective on fundamental biology, human disease and therapeutics

Biology Open ◽

10.1242/bio.057646 ◽

2021 ◽

Vol 10 (2) ◽

pp. bio057646

Author(s):

Manuel Schmid ◽

Christopher N. Toepfer

Keyword(s):

Human Disease ◽

Energy Use ◽

Force Production ◽

Monogenic Disease ◽

Regulation Of Contraction ◽

Therapeutic Development ◽

Energy Conserving ◽

Health And Disease ◽

Fundamental Biology

ABSTRACTThe fundamental basis of muscle contraction ‘the sliding filament model’ (Huxley and Niedergerke, 1954; Huxley and Hanson, 1954) and the ‘swinging, tilting crossbridge-sliding filament mechanism’ (Huxley, 1969; Huxley and Brown, 1967) nucleated a field of research that has unearthed the complex and fascinating role of myosin structure in the regulation of contraction. A recently discovered energy conserving state of myosin termed the super relaxed state (SRX) has been observed in filamentous myosins and is central to modulating force production and energy use within the sarcomere. Modulation of myosin function through SRX is a rapidly developing theme in therapeutic development for both cardiovascular disease and infectious disease. Some 70 years after the first discoveries concerning muscular function, modulation of myosin SRX may bring the first myosin targeted small molecule to the clinic, for treating hypertrophic cardiomyopathy (Olivotto et al., 2020). An often monogenic disease HCM afflicts 1 in 500 individuals, and can cause heart failure and sudden cardiac death. Even as we near therapeutic translation, there remain many questions about the governance of muscle function in human health and disease. With this review, we provide a broad overview of contemporary understanding of myosin SRX, and explore the complexities of targeting this myosin state in human disease.This article has an associated Future Leaders to Watch interview with the authors of the paper.

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