MicroRNAs: Beyond Post-transcriptional Regulation of mRNAs

MicroRNAs (miRNAs), small non-coding RNAs, participate in the transcriptional and post-transcriptional regulation of eukaryotic genes, and are potential biomarkers for diseases. Mature miRNAs can be located in both the nucleus and cytoplasm, where they perform their regulatory function. The discovery of new miRNAs and the identification of their targets and functions are fundamental to understanding the biological processes regulated by them, as well as the role they play in diseases. This present study researched miRNAs function at nuclear level and as circulating molecules.

Nuclear level densities away from line of β-stability

The variation of total nuclear level densities (NLDs) and level density parameters with proton number Z are studied around the β-stable isotope, Z0, for a given mass number. We perform our analysis for a mass range A=40 to 180 using the NLDs from popularly used databases obtained with the single-particle energies from two different microsopic mass-models. These NLDs which include microscopic structural effects such as collective enhancement, pairing and shell corrections, do not exhibit inverted parabolic trend with a strong peak at Z0 as predicted earlier. We also compute the NLDs using the single-particle energies from macroscopic-microscopic mass-model. Once the collective and pairing effects are ignored, the inverted parabolic trends of NLDs and the corresponding level density parameters become somewhat visible. Nevertheless, the factor that governs the (Z-Z0) dependence of the level density parameter, leading to the inverted parabolic trend, is found to be smaller by an order of magnitude. We further find that the (Z-Z0) dependence of NLDs is quite sensitive to the shell effects.

TPH1 and 5-HT7 Receptor Overexpression Leading to Gemcitabine-Resistance Requires Non-Canonical Permissive Action of EZH2 in Pancreatic Ductal Adenocarcinoma

In the present study, we investigated the regulatory mechanisms underlying overexpression of EZH2, tryptophan hydroxylase 1 (TPH1), and 5-HT7, in relation to gemcitabine resistance and CSC survival in PDAC cells. In aggressive PANC-1 and MIA PaCa-2 cells, knock-down (KD) of EZH2, TPH1, or HTR7 induced a decrease in CSCs and recovery from gemcitabine resistance, while preconditioning of less aggressive Capan-1 cells with 5-HT induced gemcitabine resistance with increased expression of EZH2, TPH1, and 5-HT7. Such effects of the gene KD and 5-HT treatment were mediated through PI3K/Akt and JAK2/STAT3 signaling pathways. EZH2 KD or GSK-126 (an EZH2 inhibitor) inhibited activities of these signaling pathways which altered nuclear level of NF-kB, Sp1, and p-STAT3, accompanied by downregulation of TPH1 and 5-HT7. Co-immunoprecipation with EZH2 and pan-methyl lysine antibodies revealed that auto-methylated EZH2 served as a scaffold for binding with methylated NF-kB and Sp1 as well as unmethylated p-STAT3. Furthermore, the inhibitor of EZH2, TPH1, or 5-HT7 effectively regressed pancreatic tumor growth in a xenografted mouse tumor model. Overall, the results revealed that long-term exposure to 5-HT upregulated EZH2, and the noncanonical action of EZH2 allowed the expression of TPH1-5-HT7 axis leading to gemcitabine resistance and CSC population in PDAC.

THE TWOFOLD MEANING OF BRINKMANSHIP: EXPLAINING STRATEGIC AMBIGUITY IN RUSSIA’S NUCLEAR POLICY

Discussions and debates about whether or not the role of Russia’s Non-Strategic Nuclear Weapons underpins a so-called “Escalation to De-Escalation” strategy culminated in the 2018 Nuclear Posture Review, which declared the need for deploying a new low-yield nuclear warhead for submarine-launched ballistic missiles in order to prevent Russia from escalating to the limited nuclear level and successfully terminate the conflict. While unofficial evidence barely suggests that Russia may exhort to its NSNWs in order to stave off the adversary in crisis situations, common Western discussions on Escalation to De-Escalation revolve around the alleged existence of an “offensive” Escalation to De-Escalation strategy. Thereby, Moscow would pre-emptively escalate to the limited nuclear level over NATO's Eastern flank in order to take over it while leaving Western countries without no escalation options, given the doubts surrounding the ability of B61s’ delivery systems at going beyond Russian air-defence. However, while Western countries are often busy with self-deterrence, thus perceiving immediate threats at each deployment by the adversary, they tend to overlook strategic manipulation of deployed capabilities. That is why analysis of ambiguity surrounding Russian NSNWs have been less popular in Western contexts. Based upon critical analysis of Escalation to De-Escalation and classic deterrence and escalation studies, this paper argues that ambiguity surrounding Russia’s NSNWs is part of a brinkmanship strategy, which inadvertently triggered destabilizing dynamics in US-Russia relations. The article proceeds as follows. First, an introduction sets the scene and the aim of the article, as well as the methodology, including the scope and background of facts. Second, the Escalation to De-escalation debate is broken down in the attempt of shedding light on the ambiguity it builds on. Third, it is argued that ambiguity surrounding NSNWs is strategically exploited according to Schelling’s concept of brinkmanship, though exacerbating the risk of inadvertent escalation with Western countries. Finally, a conclusion wraps up the argument and indicates its implications.

Hibernoma-like Changes and TFE3 Expression in Mesothelioma Mimicking TFE3-Translocation Renal Cell Carcinoma: A Diagnostic Pitfall

The long delay between asbestos exposure and the development of mesothelioma will likely result in an increased incidence of mesothelioma in our industrialized societies. Radiation therapy is another factor known to induce these tumors. We describe a rare case of foamy looking mesothelioma in a 63-year-old patient with a long oncology history of a supposed peritoneal carcinomatosis. The pathologist was faced with a diagnostic pitfall as this peritoneal clear cell tumor expressed transcription factor binding to immunoglobulin heavy constant mu enhancer 3 (TFE3) at the nuclear level. Fortunately, the pathologist performed an extensive panel of immunomarkers, leading to a final diagnosis of epithelioid mesothelioma. Thus, we describe the first case of mesothelioma expressing TFE3. Note that there was no rearrangement of TFE3 in fluorescence in situ hybridization.

Updated nuclear level density parameters of 153Sm nucleus within the back-shifted Fermi gas model

The present work re-evaluates the level density parameter a, asymptotic level density parameter aasy, and back-shifted energy parameter E1 within the back-shifted Fermi gas model (BSFG) for the 153Sm nucleus. This reevaluation is based on the experimental nuclear level scheme extracted from the ENSDF library, the average level spacing at the neutron binding energy (D0 value), and the latest updated nuclear level scheme obtained from an experimental gamma cascade experiment, which was performed at the Dalat Nuclear Research Reactor using the thermal neutron beam. The updated values of the BSFG level parameters are: (1) a=18.09±0.25 MeV-1and E1=-0.92±0.07 MeV for the energy-independent level density parameter; and (2) aasy=15.00±0.20 MeV-1and E1=-0.81±0.08 MeV for the energy-dependent level density parameter. It has been found that the total nuclear level densities calculated using these updated parameters agree with the experimental data better than those using parameters taken from the nuclear reference database RIPL-3. These updated parameters are more accurate and reliable than those extracted from RIPL-3 and are, therefore, highly recommended for all the applications hereafter.