The MAPK Pathway-Based Drug Therapeutic Targets in Pituitary Adenomas

Mitogen-activated protein kinases (MAPKs) include ERK, p38, and JNK MAPK subfamilies, which are crucial regulators of cellular physiology, cell pathology, and many diseases including cancers. For the MAPK signaling system in pituitary adenomas (PAs), the activation of ERK signaling is generally thought to promote cell proliferation and growth; whereas the activations of p38 and JNK signaling are generally thought to promote cell apoptosis. The role of MAPK in treatment of PAs is demonstrated through the effects of currently used medications such as somatostatin analogs such as SOM230 and OCT, dopamine agonists such as cabergoline and bromocriptine, and retinoic acid which inhibit the MAPK pathway. Further, there are potential novel therapies based on putative molecular targets of the MAPK pathway, including 18beta-glycyrrhetinic acid (GA), dopamine-somatostatin chimeric compound (BIM-23A760), ursolic acid (UA), fulvestrant, Raf kinase inhibitory protein (RKIP), epidermal growth factor pathway substrate number 8 (Eps8), transmembrane protein with EGF-like and two follistatin-like domains (TMEFF2), cold inducible RNA-binding protein (CIRP), miR-16, and mammaliansterile-20-like kinase (MST4). The combined use of ERK inhibitor (e.g., SOM230, OCT, or dopamine) plus p38 activator (e.g., cabergoline, bromocriptine, and fulvestrant) and/or JNK activator (e.g., UA), or the development of single drug (e.g., BIM-23A760) to target both ERK and p38 or JNK pathways, might produce better anti-tumor effects on PAs. This article reviews the advances in understanding the role of MAPK signaling in pituitary tumorigenesis, and the MAPK pathway-based potential therapeutic drugs for PAs

Poly[[bis(μ2-4-amino­benzene­sul­fon­ato-κ2 N:O)diaqua­manganese(II)] dihydrate]

The title compound, {[Mn(NH2C6H4SO3)2(H2O)2]·2H2O}n, was prepared under mild hydro­thermal conditions. The unique MnII ion is located on a crystallographic inversion center and is coordinated by two –NH2 and two –SO3 groups from four 4-amino­benzene­sulfonate ligands and by two water mol­ecules in the axial positions, forming a slightly distorted octa­hedral coordination environment. The 4-amino­benzene­sulfonate anions behave as μ2-bridging ligands to produce a two-dimensional structure. In the crystal structure, inter­molecular N—H⋯O, O—H⋯O and C—H⋯O hydrogen bonds link the layers into a three-dimensional network

Query-Policy Misalignment in Preference-Based Reinforcement Learning

Preference-based reinforcement learning (PbRL) provides a natural way to align RL agents' behavior with human desired outcomes, but is often restrained by costly human feedback. To improve feedback efficiency, most existing PbRL methods focus on selecting queries to maximally improve the overall quality of the reward model, but counter-intuitively, we find that this may not necessarily lead to improved performance. To unravel this mystery, we identify a long-neglected issue in the query selection schemes of existing PbRL studies: Query-Policy Misalignment. We show that the seemingly informative queries selected to improve the overall quality of reward model actually may not align with RL agents' interests, thus offering little help on policy learning and eventually resulting in poor feedback efficiency. We show that this issue can be effectively addressed via near on-policy query and a specially designed hybrid experience replay, which together enforce the bidirectional query-policy alignment. Simple yet elegant, our method can be easily incorporated into existing approaches by changing only a few lines of code. We showcase in comprehensive experiments that our method achieves substantial gains in both human feedback and RL sample efficiency, demonstrating the importance of addressing query-policy misalignment in PbRL tasks.Comment: The first two authors contributed equall

Plasma gelsolin levels and outcomes after aneurysmal subarachnoid hemorrhage

INTRODUCTION: Lower gelsolin levels have been associated with the severity and poor outcome of critical illness. Nevertheless, their link with clinical outcomes of aneurysmal subarachnoid hemorrhage is unknown. Therefore, we aimed to investigate the relationship between plasma gelsolin levels and clinical outcomes in patients with aneurysmal subarachnoid hemorrhage. METHODS: A total of 262 consecutive patients and 150 healthy subjects were included. Plasma gelsolin levels were measured by enzyme-linked immunosorbent assay. Mortality and poor long-term outcome (Glasgow Outcome Scale score of 1-3) at 6 months were recorded. RESULTS: Plasma gelsolin levels on admission were substantially lower in patients than in healthy controls (66.9 (26.4) mg/L vs. 126.4 (35.4) mg/L, P < 0.001), and negatively associated with World Federation of Neurological Surgeons score (r = -0.554, P < 0.001) and Fisher score (r = -0.538, P < 0.001), and identified as an independent predictor of poor functional outcome (odds ratio, 0.957; 95% confidence interval (CI), 0.933-0.983; P = 0.001) and death (odds ratio, 0.953; 95% CI, 0.917-0.990; P = 0.003) after 6 months. The areas under the ROC curve of gelsolin for functional outcome and mortality were similar to those of World Federation of Neurological Surgeons score and Fisher score (all P > 0.05). Gelsolin improved the predictive values of World Federation of Neurological Surgeons score and Fisher score for functional outcome (both P < 0.05), but not for mortality (both P > 0.05). CONCLUSIONS: Gelsolin levels are a useful, complementary tool to predict functional outcome and mortality 6 months after aneurysmal subarachnoid hemorrhage

Quantitative measurement of cell membrane receptor internalization by the nanoluciferase reporter: Using the G protein-coupled receptor RXFP3 as a model

AbstractNanoluciferase (NanoLuc) is a newly developed small luciferase reporter with the brightest bioluminescence to date. In the present work, we developed NanoLuc as a sensitive bioluminescent reporter to measure quantitatively the internalization of cell membrane receptors, based on the pH dependence of the reporter activity. The G protein-coupled receptor RXFP3, the cognate receptor of relaxin-3/INSL7, was used as a model receptor. We first generated stable HEK293T cells that inducibly coexpressed a C-terminally NanoLuc-tagged human RXFP3 and a C-terminally enhanced green fluorescent protein (EGFP)-tagged human RXFP3. The C-terminal EGFP-tag and NanoLuc-tag had no detrimental effects on the ligand-binding potency and intracellular trafficking of RXFP3. Based on the fluorescence of the tagged EGFP reporter, the ligand-induced RXFP3 internalization was visualized directly under a fluorescence microscope. Based on the bioluminescence of the tagged NanoLuc reporter, the ligand-induced RXFP3 internalization was measured quantitatively by a convenient bioluminescent assay. Coexpression of an EGFP-tagged inactive [E141R]RXFP3 had no detrimental effect on the ligand-binding potency and ligand-induced internalization of the NanoLuc-tagged wild-type RXFP3, suggesting that the mutant RXFP3 and wild-type RXFP3 worked independently. The present bioluminescent internalization assay could be extended to other G protein-coupled receptors and other cell membrane receptors to study ligand–receptor and receptor–receptor interactions

Surface Metallization of Polyimide as a Photoanode Substratefor Rear-Illuminated Dye-Sensitized Solar Cells

Plastic film is promising as a photoanode substrate of dye-sensitized solar cell (DSSC) for flexible applications, while a lowtemperaturesintering process is generally adopted for the TiO2 mesoporous film due to unstable thermal property of general plastics.This study demonstrates that typical high-temperature TiO2 sintering can be adopted for preparing the photoanode when using asurface-metallized polyimide (PI) film. A Sn/Ni bi-layer is formed on a PI film via a chemical process as the conductive layer. TheSn/Ni-coated PI photoanode can withstand high-temperature TiO2 sintering at a peak temperature of 430◦C for 30 min withoutsignificant visual deformation due to high thermal stability of PI and strength reinforcement caused by surface metallization. TheDSSC employing the Sn/Ni-coated PI film as the photoanode substrate reaches an energy conversion efficiency of 3.44% under1 sun rear-side illumination