Orthogonal printing of uniform nanocomposite monolayer and oriented organic semiconductor crystals for high-performance nano-crystal floating gate memory

Inkjet printing is of great interest in the preparation of optoelectronic and microelectronic devices due to its low cost, low process temperature, versatile material compatibility, and ability to precisely manufacture multi-layer devices on demand. However, interlayer solvent erosion is a typical problem that limits the printing of organic semiconductor devices with multi-layer structures. In this study, we proposed a solution to address this erosion problem by designing polystyrene-block-poly(4-vinyl pyridine)-grafted Au nanoparticles (Au@PS-b-P4VP NPs). With a colloidal ink containing the Au@PS-b-P4VP NPs, we obtained a uniform monolayer of Au nano-crystal floating gates (NCFGs) embedded in the PS-b-P4VP tunneling dielectric (TD) layer using direct-ink-writing (DIW). Significantly, PS-b-P4VP has high erosion resistance against the semiconductor ink solvent, which enables multi-layer printing. An active layer of semiconductor crystals with high crystallinity and well-orientation was obtained by DIW. Moreover, we developed a strategy to improve the quality of the TD/semiconductor interface by introducing a polystyrene intermediate layer. We show that the NCFG memory devices exhibit a low threshold voltage (100 cycles), and long-term retention (>10 years). This study provides universal guidance for printing functional coatings and multi-layer devices

6-Substituted Hexamethylene Amiloride (HMA) Derivatives as Potent and Selective Inhibitors of the Human Urokinase Plasminogen Activator for Use in Cancer

Metastasis is the cause of death in the majority (∼90%) of malignant cancers. The oral potassium-sparing diuretic amiloride and its 5-substituted derivative 5-N,N-(hexamethylene)amiloride (HMA) reportedly show robust antitumor/metastasis effects in multiple in vitro and animal models. These effects are likely due, at least in part, to inhibition of the urokinase plasminogen activator (uPA), a key protease determinant of cell invasiveness and metastasis. This study reports the discovery of 6-substituted HMA analogs that show nanomolar potency against uPA, high selectivity over related trypsin-like serine proteases, and minimal inhibitory effects against epithelial sodium channels (ENaC), the diuretic and antikaliuretic target of amiloride. Reductions in lung metastases were demonstrated for two analogs in a late-stage experimental mouse metastasis model, and one analog completely inhibited formation of liver metastases in an orthotopic xenograft mouse model of pancreatic cancer. The results support further evaluation of 6-substituted HMA derivatives as uPA-targeting anticancer drugs

A cyclic peptidic serine protease inhibitor:increasing affinity by increasing peptide flexibility

Peptides are attracting increasing interest as protease inhibitors. Here, we demonstrate a new inhibitory mechanism and a new type of exosite interactions for a phage-displayed peptide library-derived competitive inhibitor, mupain-1 (CPAYSRYLDC), of the serine protease murine urokinase-type plasminogen activator (uPA). We used X-ray crystal structure analysis, site-directed mutagenesis, liquid state NMR, surface plasmon resonance analysis, and isothermal titration calorimetry and wild type and engineered variants of murine and human uPA. We demonstrate that Arg6 inserts into the S1 specificity pocket, its carbonyl group aligning improperly relative to Ser195 and the oxyanion hole, explaining why the peptide is an inhibitor rather than a substrate. Substitution of the P1 Arg with novel unnatural Arg analogues with aliphatic or aromatic ring structures led to an increased affinity, depending on changes in both P1 - S1 and exosite interactions. Site-directed mutagenesis showed that exosite interactions, while still supporting high affinity binding, differed substantially between different uPA variants. Surprisingly, high affinity binding was facilitated by Ala-substitution of Asp9 of the peptide, in spite of a less favorable binding entropy and loss of a polar interaction. We conclude that increased flexibility of the peptide allows more favorable exosite interactions, which, in combination with the use of novel Arg analogues as P1 residues, can be used to manipulate the affinity and specificity of this peptidic inhibitor, a concept different from conventional attempts at improving inhibitor affinity by reducing the entropic burden

Disruption of 5-hydroxytryptamine 1A receptor and orexin receptor 1 heterodimer formation affects novel G protein-dependent signaling pathways and has antidepressant effects in vivo

G protein-coupled receptor (GPCR) heterodimers are new targets for the treatment of depression. Increasing evidence supports the importance of serotonergic and orexin-producing neurons in numerous physiological processes, possibly via a crucial interaction between 5-hydroxytryptamine 1A receptor (5-HT1AR) and orexin receptor 1 (OX1R). However, little is known about the function of 5-HT1AR/OX1R heterodimers. It is unclear how the transmembrane domains (TMs) of the dimer affect its function and whether its modulation mediates antidepressant-like effects. Here, we examined the mechanism of 5-HT1AR/OX1R dimerization and downstream G protein-dependent signaling. We found that 5-HT1AR and OX1R form constitutive heterodimers that induce novel G protein-dependent signaling, and that this heterodimerization does not affect recruitment of β-arrestins to the complex. In addition, we found that the structural interface of the active 5-HT1AR/OX1R dimer transforms from TM4/TM5 in the basal state to TM6 in the active conformation. We also used mutation analyses to identify key residues at the interface (5-HT1AR R1514.40, 5-HT1AR Y1985.41, and OX1R L2305.54). Injection of chronic unpredictable mild stress (CUMS) rats with TM4/TM5 peptides improved their depression-like emotional status and decreased the number of endogenous 5-HT1AR/OX1R heterodimers in the rat brain. These antidepressant effects may be mediated by upregulation of BDNF levels and enhanced phosphorylation and activation of CREB in the hippocampus and medial prefrontal cortex. This study provides evidence that 5-HT1AR/OX1R heterodimers are involved in the pathological process of depression. Peptides including TMs of the 5-HT1AR/OX1R heterodimer interface are candidates for the development of compounds with fast-acting antidepressant-like effects

Motion and Load Analysis of the Flexible Platform Based on Noncontact Processing

In this paper, we explore the applicability of the positioning stage based on flexible hinges for noncontact processing. According to the actual application of the positioning stage, Hooke’s law, the Euler–Bernoulli beam theory, and the geometric relationship of the structure are applied to analyze the coupled displacement in the movement of the positioning stage and the changes in the performance of the positioning stage caused by external loads. The coupled-displacement matrix and the external-load matrix obtained from the analysis are substituted into the ideal-displacement expression of the positioning stage to obtain the displacement expression of the platform in noncontact machining. The platform trajectory obtained by the referenced curve is analyzed. In addition, the coupled displacement in the X- and Y-directions and the coupled displacement caused by the external load in the Z-direction are nanoscales and about one-thousandth of the output displacement, which meets the requirement of tracking accuracy for micron-level machining. Finally, we use finite element analysis (FEA) and experiments to prove the correctness of the theoretical analysis

Strategies to Manage Stress and Fatigue in Athletes

High level athletes frequently travel for competition, participate in heavy training loads, have dense competitive schedules, and have to manage pressure to perform. All of these are sources of stress and if not strategically managed could lead to fatigue, decreased performance, and increased risk for injury. The purpose of this review is to provide the reader scientifically based strategies to manage stress and promote performance. Specific attention will focus on the influence of travel, sleep, and training load

Microorganism Assisted Synthesized Nanoparticles for Catalytic Applications

Metal and metalloid nanoparticles (NPs) have attracted substantial attention from research communities over the past few decades. Traditional methodologies for NP fabrication have also been intensely explored. However, drawbacks such as the use of toxic agents and the high energy consumption involved in chemical and physical processes hinder their further application in various fields. It is well known that some bacteria are capable of binding and concentrating dissolved metal and metalloid ions, thereby detoxifying their environments. Bioinspired fabrication of NPs is environmentally friendly and inexpensive and requires only low energy consumption. Some biosynthesized NPs are usually used as heterogeneous catalysts in environmental remediation and show higher catalytic efficiency because of their enhanced biocompatibility, stability and large specific surface areas. Therefore, bacteria used as nanofactories can provide a novel approach for removing metal or metalloid ions and fabricating materials with unique properties. Even though a wide range of NPs have been biosynthesized, and their synthetic mechanisms have been proposed, some of these mechanisms are not known in detail. This review focuses on the synthesis and catalytic applications of NPs obtained using bacteria. The known mechanisms of bioreduction and prospects in the design of NPs for catalytic applications are also discussed