Developmental changes in mouse placental cells from several stages of pregnancy in vivo and in vitro

Developmental changes in mouse placentae from the 6th to the 18th day of pregnancy were studied in vivo and in vitro. Placental volume increased from the 6th to the 18th day of pregnancy; however, the total number of cells per placenta reached a plateau on the 14th day. Decidual cells were predominant in the placenta on the 6th day. Placentae obtained from the 10th to the 18th day contained decidual cells, trophoblastic (labyrinth and spongiotrophoblast) cells, and trophoblast giant cells. Decidual cells increased in number from the 6th to the 10th but decreased on the 14th day, whereas trophoblastic cells increased linearly until the 14th day. Two types of placental cells were distinguished in vitro: small fibroblast-like cells and large flattened cells containing 2-3 nuclei. The large cells reacted to anti-desmin antibody, indicating their decidual character. The small cells reacting to anti-keratin antibody appeared to be trophoblastic cells. Decidual cells from all days of gestation were nonproliferative, regressing with time in culture. 17 beta-Estradiol (E, 10(-9) and 10(-8) M), progesterone (P, 10(-10), 10(-9), and 10(-8) M), and a combination of E and P (10(-9) M each) stimulated proliferation of the trophoblastic cells only from the 6th and the 10th days. Keoxifene (2 x 10(-7) M), but not tamoxifen, significantly inhibited the E-induced proliferation of the trophoblastic cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Study on Lubricant Depletion Induced by Laser Heating in Thermally Assisted Magnetic Recording Systems: Effect of Lubricant Thickness and Bonding Ratio

In this study, we have carried out fundamental research on lubricant depletion due to laser heating in thermally assisted magnetic recording. In particular, we investigated the effects of lubricant film thickness and lubricant bonding ratio on lubricant depletion. Conventional lubricants Zdol2000 and Ztetraol2000 were used. The lubricant depletion characteristics due to laser heating were found to depend largely on the lubricant film thickness and material. That is, for films thicker than one monolayer, the lubricant depletion depth increased with the laser-irradiation duration, whereas the thickness of the lubricant after laser irradiation on the diamond-like carbon (DLC) films tended to remain at a constant film thickness of one monolayer. The lubricant depletion width gradually increased as the laser irradiation duration increased. The increasing trends for the lubricant depletion width were quantitatively very similar and almost independent of the initial lubricant film thickness. However, for lubricant films with thicknesses less than one monolayer, the lubricant depletion depth was very small. The lubricant depletion width increased remarkably to several hundred micrometers as the laser irradiation duration increased. The lubricant depletion depth and width were much smaller for Ztetraol2000 than Zdol2000. In addition, the lubricant-bonding ratio was found to greatly affect the lubricant depletion characteristics due to laser heating. In other words, the lubricant depletion depth and width decreased as the bonding ratio increased. The lubricant depletion mechanism involves the evaporation of mobile lubricant molecules when the maximum attained temperature is less than 100 °C. Another suggested lubricant depletion mechanism involves the thermocapillary stress effect, which is induced by the disk surface temperature gradient resulting from the non-uniformity of the laser spot intensity distribution.     

Circular tunnel in a semi-infinite aquifer

The steady gravity flow that is generated by a circular tunnel disturbing the hydrostatic state of a semi-infinite, homogeneous and isotropic aquifer is solved exactly. Many aspects of the flow are found in closed analytical forms such as the water inflow, pressure, leakage and recharging infiltration, which give a complete view of the aquifer in the drained steady state. It is found that the maximum value of the recharging infiltration does not exceed the hydraulic conductivity allowing stating a criteria for recharge intervention to ensure the stability of the aquifer. In addition to the main results, two aspects of the water inflow are treated. These are the necessary modifications that are to be considered in the case of an inclined water table and in the case of a lined tunnel that develops a constant internal pressure. It is also found that under an inclined water table a tunnel may cease to drain on its complete circumferential edge and a limiting condition is stated. Furthermore, the Muskat–Goodman and other water inflow predictions are compared to the exact gravity water inflow.     

Inhibition of the FGF/FGFR System Induces Apoptosis in Lung Cancer Cells via c-Myc Downregulation and Oxidative Stress

Lung cancer represents an extremely diffused neoplastic disorder with different histological/molecular features. Among the different lung tumors, non-small-cell lung cancer (NSCLC) is the most represented histotype, characterized by various molecular markers, including the expression/overexpression of the fibroblast growth factor receptor-1 (FGFR1). Thus, FGF/FGFR blockade by tyrosine kinase inhibitors (TKi) or FGF-ligand inhibitors may represent a promising therapeutic approach in lung cancers. In this study we demonstrate the potential therapeutic benefit of targeting the FGF/FGFR system in FGF-dependent lung tumor cells using FGF trapping (NSC12) or TKi (erdafitinib) approaches. The results show that inhibition of FGF/FGFR by NSC12 or erdafitinib induces apoptosis in FGF-dependent human squamous cell carcinoma NCI-H1581 and NCI-H520 cells. Induction of oxidative stress is the main mechanism responsible for the therapeutic/pro-apoptotic effect exerted by both NSC12 and erdafitinib, with apoptosis being abolished by antioxidant treatments. Finally, reduction of c-Myc protein levels appears to strictly determine the onset of oxidative stress and the therapeutic response to FGF/FGFR inhibition, indicating c-Myc as a key downstream effector of FGF/FGFR signaling in FGF-dependent lung cancers.     

Synthesis,Molecular Modeling and Biological Evaluation of Metabolically Stable Analogues of the Endogenous Fatty Acid Amide Palmitoylethanolamide

Palmitoylethanolamide (PEA) belongs to the class of N-acylethanolamine and is an endogenous lipid potentially useful in a wide range of therapeutic areas; products containing PEA are licensed for use in humans as a nutraceutical, a food supplement, or food for medical purposes for its analgesic and anti-inflammatory properties demonstrating efficacy and tolerability. However, the exogenously administered PEA is rapidly inactivated; in this process, fatty acid amide hydrolase (FAAH) plays a key role both in hepatic metabolism and in intracellular degradation. So, the aim of the present study was the design and synthesis of PEA analogues that are more resistant to FAAH-mediated hydrolysis. A small library of PEA analogues was designed and tested by molecular docking and density functional theory calculations to find the more stable analogue. The computational investigation identified RePEA as the best candidate in terms of both synthetic accessibility and metabolic stability to FAAH-mediated hydrolysis. The selected compound was synthesized and assayed ex vivo to monitor FAAH-mediated hydrolysis and to confirm its anti-inflammatory properties. ¹H-NMR spectroscopy performed on membrane samples containing FAAH in integral membrane protein demonstrated that RePEA is not processed by FAAH, in contrast with PEA. Moreover, RePEA retains PEA’s ability to inhibit LPS-induced cytokine release in both murine N9 microglial cells and human PMA-THP-1 cells.     

The Emerging Role of Tetrazines in Drug-Activation Chemistries

Traditionally, prodrug activation has been limited to enzymatic triggers or gross physiological aberrations, such as pH, that offer low selectivity and control over dosage. In recent years, the field of prodrug activation chemistry has been transformed by the use of bioorthogonal reactions that can be carried out under biological conditions at sub-millimolar concentrations, with the tetrazine-mediated inverse electron demand Diels–Alder reaction amongst the most recognised. Their high reaction rates, chemoselectivity and excellent biocompatibility make tetrazines ideal small molecules for activating prodrugs. Recently the tetrazine moiety has been used as a prodrug for a pyridazine thus broadening the scope of prodrug systems. This article discusses the concept of using tetrazines as small-molecule activators for prodrugs, and provides an overview of tetrazine-based prodrug systems, with a particular focus on the recently reported prodrug–prodrug activation strategy.