The Role of Cell Cycle Regulators in Cell Survival—Dual Functions of Cyclin-Dependent Kinase 20 and p21Cip1/Waf1

The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21^Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies.     

Abrasive waterjet micro-machining of channels in metals: Comparison between machining in air and submerged in water

Abrasive water jet technology can be used for micro-milling using recently developed miniaturized nozzles. Abrasive water jet (AWJ) machining is often used with both the nozzle tip and workpiece submerged in water to reduce noise and contain debris. This paper compares the performance of submerged and unsubmerged abrasive water jet micro-milling of channels in 316L stainless steel and 6061-T6 aluminum at various nozzle angles and standoff distances. The effect of submergence on the diameter and effective footprint of AWJ erosion footprints was measured and compared. It was found that the centerline erosion rate decreased with channel depth due to the spreading of the jet as the effective standoff distance increased, and because of the growing effect of stagnation as the channel became deeper. The erosive jet spread over a larger effective footprint in air than in water, since particles on the jet periphery were slowed much more quickly in water due to increased drag. As a result, the width of a channel machined in air was wider than that in water. Moreover, it was observed that the instantaneous erosion rate decreased with channel depth, and that this decrease was a function only of the channel cross-sectional geometry, being independent of the type of metal, the jet angle, the standoff distance, and regardless of whether the jet was submerged or in air, in either the forward or backward directions. It is shown that submerged AWJM results in narrower features than those produced while machining in air, without a decrease in centerline etch rate.     

Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together

Histone deacetylase inhibitors (HDIs) are promising anti-cancer agents that inhibit proliferation of many types of cancer cells including breast carcinoma (BC) cells. In the present study, we investigated the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two HDIs, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), in luminal-like BC cells. The type of drug–drug interaction between CDDP and HDIs was determined by isobolographic analysis. MCF7 cells were genetically modified to express differential levels of Notch1 activity. The cytotoxic effect of SAHA or VPA was higher on cells with decreased Notch1 activity and lower for cells with increased Notch1 activity than native BC cells. The isobolographic analysis demonstrated that combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive or additive with tendency toward synergism interactions. Therefore, treatment of CDDP with HDIs could be used to optimize a combined therapy based on CDDP against Notch1-altered luminal BC. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of luminal-type BC with altered Notch1 activity.     

Migraine: Calcium Channels and Glia

Migraine is a common neurological disease that affects about 11% of the adult population. The disease is divided into two main clinical subtypes: migraine with aura and migraine without aura. According to the neurovascular theory of migraine, the activation of the trigeminovascular system (TGVS) and the release of numerous neuropeptides, including calcitonin gene-related peptide (CGRP) are involved in headache pathogenesis. TGVS can be activated by cortical spreading depression (CSD), a phenomenon responsible for the aura. The mechanism of CSD, stemming in part from aberrant interactions between neurons and glia have been studied in models of familial hemiplegic migraine (FHM), a rare monogenic form of migraine with aura. The present review focuses on those interactions, especially as seen in FHM type 1, a variant of the disease caused by a mutation in CACNA1A, which encodes the α1A subunit of the P/Q-type voltage-gated calcium channel.     

Salivary Proteome Changes in Response to Acute Psychological Stress Due to an Oral Exam Simulation in University Students: Effect of an Olfactory Stimulus

The autonomic nervous system (ANS) plays a crucial role both in acute and chronic psychological stress eliciting changes in many local and systemic physiological and biochemical processes. Salivary secretion is also regulated by ANS. In this study, we explored salivary proteome changes produced in thirty-eight University students by a test stress, which simulated an oral exam. Students underwent a relaxation phase followed by the stress test during which an electrocardiogram was recorded. To evaluate the effect of an olfactory stimulus, half of the students were exposed to a pleasant odor diffused in the room throughout the whole session. Saliva samples were collected after the relaxation phase (T0) and the stress test (T1). State anxiety was also evaluated at T0 and T1. Salivary proteins were separated by two-dimensional electrophoresis, and patterns at different times were compared. Spots differentially expressed were trypsin digested and identified by mass spectrometry. Western blot analysis was used to validate proteomic results. Anxiety scores and heart rate changes indicated that the fake exam induced anxiety. Significant changes of α-amylase, polymeric immunoglobulin receptor (PIGR), and immunoglobulin α chain (IGHA) secretion were observed after the stress test was performed in the two conditions. Moreover, the presence of pleasant odor reduced the acute social stress affecting salivary proteome changes. Therefore, saliva proteomic analysis was a useful approach to evaluate the rapid responses associated to an acute stress test also highlighting known biomarkers.     

Toughness enhancement and equivalent initial fracture toughness of cementitious composite reinforced with aligned steel fibres

Based on theoretical analysis and numerical simulation, the impact of steel fibres on the stress intensity factor (SIF) at the crack tip for cementitious composite was studied. The enhanced toughness of steel fibre reinforced cementitious composite (SFRC) in resisting cracks was explained by the decrement of SIF caused by steel fibre inclusions at the crack tip of the composite. The equivalent initial fracture toughness was used to characterize the crack initiation of SFRC. A simplified method for determining the of SFRC was proposed based on a linear regression method. Fracture tests were conducted on three‐point bending notched beams with different steel fibre volume fractions and specimen sizes to study the crack initiation behaviour of aligned steel fibre reinforced cementitious composite (ASFRC). of ASFRC was calculated, and the size effect of was analysed. The results showed that slightly increased with the steel fibre volume fraction and gradually became stable. For the tested specimens, whose heights varied between 40 and 100 mm, the specimen size had little impact on the .     

Damage mechanism at different transpassive potentials of solution-annealed 316 and 316l stainless steels

Electrochemical impedance spectroscopy (EIS), anodic polarization and scanning electron microscopy techniques were used to investigate the damage mechanism in the transpassive potential region of AISI ...