Valproic Acid Regulates HR and Cell Cycle Through MUS81-pRPA2 Pathway in Response to Hydroxyurea

Breast cancer is the primary problem threatening women’s health. The combined application of valproic acid (VPA) and hydroxyurea (HU) has a synergistic effect on killing breast cancer cells, but the molecular mechanism remains elusive. Replication protein A2 phosphorylation (pRPA2), is essential for homologous recombination (HR) repair and cell cycle. Here we showed that in response to HU, the VPA significantly decreased the tumor cells survival, and promoted S-phase slippage, which was associated with the decrease of pCHK1 and WEE1/pCDK1-mediated checkpoint kinases phosphorylation pathway and inhibited pRPA2/Rad51-mediated HR repair pathway; the mutation of pRPA2 significantly diminished the above effect, indicating that VPA-caused HU sensitization was pRPA2 dependent. It was further found that VPA and HU combination treatment also resulted in the decrease of endonuclease MUS81. After MUS81 elimination, not only the level of pRPA2 was abolished in response to HU treatment, but also VPA-caused HU sensitization was significantly down-regulated through pRPA2-mediated checkpoint kinases phosphorylation and HR repair pathways. In addition, the VPA altered the tumor microenvironment and reduced tumor burden by recruiting macrophages to tumor sites; the Kaplan-Meier analysis showed that patients with high pRPA2 expression had significantly worse survival. Overall, our findings demonstrated that VPA influences HR repair and cell cycle through down-regulating MUS81-pRPA2 pathway in response to HU treatment.

Neurophysiology of slip sensation and grip reaction: insights for hand prosthesis control of slippage.

Sensory feedback is pivotal for a proficient dexterity of the hand. By modulating the grip force in function of the quick and not completely predictable change of the load force, grabbed objects are prevented to slip from the hand. Slippage control is an enabling achievement to all manipulation abilities. However, in hand prosthetics, the performance of even the most innovative research solutions proposed so far to control slippage remain distant from the human physiology. Indeed, slippage control involves parallel and compensatory activation of multiple mechanoceptors, spinal and supraspinal reflexes and higher-order voluntary behavioral adjustments. In this work, we reviewed the literature on physiological correlates of slippage to propose a three-phases model for the slip sensation and reaction. Furthermore, we discuss the main strategies employed so far in the research studies that tried to restore slippage control in amputees. In the light of the proposed three-phase slippage model, and from the weaknesses of already implemented solutions, we proposed several physiology-inspired solutions for slippage control, to be implemented in the future hand prostheses. Understanding the physiological basis of slip detection and perception and implementing them in novel hand feedback system would make prosthesis manipulation more efficient and would boost its perceived naturalness, fostering the sense of agency for the hand movements.

Lag, lock, sync, slip: the many ‘phases’ of coupled flagella

In a multitude of life's processes, cilia and flagella are found indispensable. Recently, the biflagellated chlorophyte alga Chlamydomonas has become a model organism for the study of ciliary motility and synchronization. Here, we use high-speed, high-resolution imaging of single pipette-held cells to quantify the rich dynamics exhibited by their flagella. Underlying this variability in behaviour are biological dissimilarities between the two flagella—termed cis and trans , with respect to a unique eyespot. With emphasis on the wild-type, we derive limit cycles and phase parametrizations for self-sustained flagellar oscillations from digitally tracked flagellar waveforms. Characterizing interflagellar phase synchrony via a simple model of coupled oscillators with noise, we find that during the canonical swimming breaststroke the cis flagellum is consistently phase-lagged relative to, while remaining robustly phase-locked with, the trans flagellum. Transient loss of synchrony, or phase slippage , may be triggered stochastically, in which the trans flagellum transitions to a second mode of beating with attenuated beat envelope and increased frequency. Further, exploiting this alga's ability for flagellar regeneration, we mechanically induced removal of one or the other flagellum of the same cell to reveal a striking disparity between the beatings of the cis and trans flagella, in isolation. These results are evaluated in the context of the dynamic coordination of Chlamydomonas flagella.

A Simple Model for Two-Phase Flow in Liquid-Cut Gas Wells

This paper presents a simple two-phase flow model for liquid-cut gas wells, which considers phase slippage and can be applied to various flow patterns. The model is developed from 312 measured pressure losses of gas wells in China, covering a wide range of flow patterns: annular flow, churn flow, and slug flow. Unlike most available methods, this new model introduces a derivation factor,ψ, to modify the void fraction, which not only considers the phase slippage but also unifies the slip model with the homogenous model. Parameter,ψ, is obtained from test data using the regression analyses method. It is a function of gas velocity number, liquid velocity number and liquid viscosity number. Frictional factor is estimated using the simple homogeneous modeling approach. The evaluation results using 145 published data indicate that the new model performed better than the other models.