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Biology subjects

Finke, A.

Publications and source records attributed to Finke, A..

2 recordsLinked to original sources

Modelling human endurance: Power laws vs critical power

The power-duration relationship describes the time to exhaustion for exercise at different intensities. It is generally believed to be a "fundamental bioenergetic property of living systems" that this relationship is hyperbolic. Indeed, the hyperbolic (a.k.a. critical-power) model which formalises this belief is the dominant tool for describing and predicting high-intensity exercise performance, e.g. in cycling, running, rowing, or swimming. However, the hyperbolic model is now the focus of two heated debates in the literature because: (a) it unrealistically represents efforts that are short (< 2 minutes) or long (> 15 minutes); (b) it contradicts widely-used performance predictors such as the so-called functional threshold power (FTP) in cycling. We contribute to both debates by demonstrating that the power-duration relationship is more adequately represented by an alternative, power-law model. In particular, we show that the often observed good fit of the hyperbolic model between 2 and 15 minutes should not be taken as proof that the power-duration relationship is hyperbolic. Rather, in this range, a hyperbolic function just happens to approximate a power law fairly well. We also prove mathematical results which suggest that the power-law model is a safer tool for pace selection than the hyperbolic model and that the former better models fatigue than the latter. Finally, we use the power-law model to shed light on popular performance predictors in cycling, running and rowing such as FTP and Jack Daniels "VDOT" calculator.

physiology↗

New Insights into the Mechanisms Used by Inhibitors Targeting Glutamine Metabolism in Cancer Cells

Many cancer cells become dependent on glutamine metabolism to compensate for glycolysis being uncoupled from the TCA cycle. The mitochondrial enzyme Glutaminase C (GAC) satisfies this glutamine addiction by catalyzing the first step in glutamine metabolism, making it an attractive drug target. Despite one of the allosteric inhibitors (CB-839) being in clinical trials, none of the drugs targeting GAC are approved for cancer treatment and their mechanism of action is not well understood. A major challenge has been the rational design of better drug candidates: standard cryo-cooled X-ray crystal structures of GAC bound to CB-839 and its analogs fail to explain their potency differences. Here, we address this problem by using an emerging technique, serial room temperature crystallography, which enabled us to observe clear differences between the binding conformations of inhibitors with significantly different potencies. A computational model was developed to further elucidate the molecular basis of inhibitor potency. We then corroborated the results from our modeling efforts by using recently established fluorescence assays that directly read-out inhibitor binding to GAC. Together, these findings provide new insights into the mechanisms used by a major class of allosteric GAC inhibitors and for the future rational design of more potent drug candidates.

biochemistry↗