Prostate cancer is a major cause of cancer-related mortality in men. Even though current therapeutic management has contributed to reducing mortality, additional intervention strategies are warranted to further improve the outcomes. To this end, we have investigated the efficacy of dicaffeoylquinic acids, ingredients in Yerba Mate (Ilex paraguariensis), an evergreen cultivated in South America, the leaves of which are used to prepare a tea/coffee-like drink. Of the various analogs tested, 4,5-dicaffeoylquinic acid (4,5-diCQA) was the most active molecule against DU-145 prostate cancer cells with a 50% inhibitory concentration (IC50) of 5 μM. 4,5-diCQA was active both under normoxic and hypoxic conditions. The effect of 72-hour treatment on DU-145 cells persisted for an extended time period as assessed by clonogenic assay. Mechanistic studies revealed that the toxic effect was not due to induction of programmed cell death but through cell cycle arrest at S phase. Additionally, 4,5-diCQA did not impact PI3K/MAPK signaling pathway nor did it affect the depolarization of the mitochondrial membrane. 4,5-diCQA-induced accumulation of cells in the S-phase also seems to negatively impact Bcl-2 expression. 4,5-diCQA also exhibited inhibitory activity on LNCaP and PC-3 prostate cancer cells suggesting that it has therapeutic potential on a broad range of prostate cancers. Taken together, the novel inhibitory activity and mechanism of action of 4,5-diCQA opens up potential therapeutic options for using this molecule as monotherapy as well as in combinatorial therapies for the clinical management of prostate cancer.

Muscle mediates movement but movement is typically unsteady and perturbed. Muscle is known to behave non-linearly and with historydependent properties during steady locomotion, but the importance of history dependence in mediating muscle function during perturbations remains less clear. To explore the capacity of muscles to mitigate perturbations during locomotion, we constructed a series of perturbations that varied only in kinematic history, keeping instantaneous position, velocity and time from stimulation constant. We found that the response of muscle to a perturbation is profoundly history dependent, varying 4-fold as baseline frequency changes, and dissipating energy equivalent to ∼6 times the kinetic energy of all the limbs in 5 ms (nearly 2400 W kg −1 ). Muscle energy dissipation during a perturbation is predicted primarily by the force at the onset of the perturbation. This relationship holds across different frequencies and timings of stimulation. This history dependence behaves like a viscoelastic memory producing perturbation responses that vary with the frequency of the underlying movement.

Statement: The response of muscles to rapid, identical strain perturbations is history 9 dependent, but is captured by a viscoelastic model with memory. Muscle function during pertur-10 bations therefore depends on locomotor frequency. 11 1 1 Abstract 12Muscle mediates movement but movement is typically unsteady and perturbed. Muscle is known 13 to behave non-linearly and with history dependent properties during steady locomotion, but the 14 importance of history dependence in mediating muscles function during perturbations remains less 15 clear. To explore muscle's capacity to mitigate perturbations, we constructed a series of perturba- 16 tions that varied only in kinematic history, keeping instantaneous position, velocity and time from 17 stimulation constant. We discovered that muscle's perturbation response is profoundly history de-18 pendent, varying by four fold as baseline frequency changes, and dissipating energy equivalent to 19 ∼ 6 times the kinetic energy of all the limbs (nearly 2400 W Kg −1 ). Muscle's energy dissipation 20 during a perturbation is predicted primarily by the force at the onset of the perturbation. This 21 relationship holds across different frequencies and timings of stimulation. This history dependence 22 behaves like a viscoelastic memory producing perturbation responses that vary with the frequency 23 of the underlying movement. 24 2 Introduction 25Muscle produces, dissipates, stores, returns, and transits mechanical energy to adopt diverse func-26 tions during locomotion (Dickinson et al., 2000). Even the same muscle can adopt different functions 27 in unsteady or perturbed conditions (Biewener and Daley, 2007;Azizi and Roberts, 2010). A sin-28 gle muscle in the leg of cockroach normally dissipates energy during steady-state running (Ahn 29 et al., 2006;Full et al., 1998). Yet when the animal is perturbed, neural feedback can categorically 30 switch the muscle's function from one stride to the next (Sponberg, Spence, Mullens and Full, 31 2011). Under unsteady conditions the muscle can dissipate more than ten times the energy that it 32 does in steady state or convert its function to that of non-linear motor (Sponberg, Libby, Mullens 33 and Full, 2011). It remains challenging to predict function from the quasi-static length-tension 34 and force-velocity relationships, especially under unsteady conditions. Nonetheless such conditions 35 likely pose greater performance demands than steady-state. 36Strain history-dependent muscle properties are well known to affect muscle's stress develop-37 ment. These properties include force depression during shortening and force enhancement during 38 lengthening. While the specific mechanisms for history dependence remain controversial and are 39 likely multifaceted (Rassier, 2012), there are established consequences for steady, transition, and 40 impulsive behaviors (Josephson, 1999;Roberts and Azizi, 2011;Herzog et al., 2015; Nishikawa, 41 2016). However, muscle function during perturbations during movement is much less explo...