Nonlinear dynamics of a flapping rotary wing: Modeling and optimal wing kinematic analysis

The analysis of the passive rotation feature of a micro Flapping Rotary Wing (FRW) applicable for Micro Air Vehicle (MAV) design is presented in this paper. The dynamics of the wing and its influence on aerodynamic performance of FRW is studied at low Reynolds number (∼103). The FRW is modeled as a simplified system of three rigid bodies: a rotary base with two flapping wings. The multibody dynamic theory is employed to derive the motion equations for FRW. A quasi-steady aerodynamic model is utilized for the calculation of the aerodynamic forces and moments. The dynamic motion process and the effects of the kinematics of wings on the dynamic rotational equilibrium of FWR and the aerodynamic performances are studied. The results show that the passive rotation motion of the wings is a continuous dynamic process which converges into an equilibrium rotary velocity due to the interaction between aerodynamic thrust, drag force and wing inertia. This causes a unique dynamic time-lag phenomena of lift generation for FRW, unlike the normal flapping wing flight vehicle driven by its own motor to actively rotate its wings. The analysis also shows that in order to acquire a high positive lift generation with high power efficiency and small dynamic time-lag, a relative high mid-up stroke angle within 7–15° and low mid-down stroke angle within −40° to −35° are necessary. The results provide a quantified guidance for design option of FRW together with the optimal kinematics of motion according to flight performance requirement

Differences in tissue distribution ability of evodiamine and dehydroevodiamine are due to the dihedral angle of the molecule stereo-structure

Introduction: This researcher focused at the evodiamine and dehydroevodiamine tissue distribution and structure-pharmacokinetics (PK) relationship after intravenous injection in mice.Methods: Using a transmembrane transport experiment, the permeability of evodiamine and dehydroevodiamine on Caco-2 cells was evaluated. The tissue distribution and pharmacokinetics (PK) of evodiamine and dehydroevodiamine in mice were studied. To comprehend the connection between structure and tissue distribution, physicochemical property evaluations and molecular electrostatic potential (MEP) calculations were performed.Results: Dehydroevodiamine’s Papp values in vitro were 10−5 cm/s, whereas evodiamine’s were 10−6 cm/s. At a dose of 5 mg/kg, the brain concentration of dehydroevodiamine was 6.44 times more than that of evodiamine. By MEP or physicochemical measures, the permeability difference between evodiamine and dehydroevodiamine is unaffected. The dihedral angle of the stereo-structure appears to be the main cause of the difference in tissue distribution ability between evodiamine and dehydroevodiamine.Discussion: Dehydroevodiamine has a dihedral angle of 3.71° compared to 82.34° for evodiamine. Dehydroevodiamine can more easily pass through the phospholipid bilayer than evodiamine because it has a more planar stereo-structure. Dehydroevodiamine is therefore more likely to pass cross the blood-brain barrier and enter the brain in a tissue-specific manner

Synthesis and biological evaluation of novel bi-gold mitocans in lung cancer cells

Mitochondria are promising drug target for cancer treatment. We previously demonstrated that a bi-gold compound BGC2a was more potent than the mono-gold drug auranofin in suppressing cancer cells due to increased gold atom number that led to higher drug accumulation in and thereby inhibition of mitochondria. To exploit the potential of this new strategy, we further designed and synthesized a series of bi-gold mitocans, the compounds targeting mitochondria. The results showed that most of the newly synthesized mitocans exhibited obviously lower IC50 than auranofin, an old drug that is repurposed in clinical trials for cancer treatment. The best mitocan C3P4 was nearly 2-fold more potent than BGC2a in human non-small cell lung cancer A549 cells and mantle cell lymphoma Jeko-1 cells, exhibiting substantial colony formation-suppressing and tumor-suppressing effects in A549 cells xenograft model. C3P4 induced apoptosis in a dose-dependent manner and arrested cell cycle at G0/G1 phase. The mechanistic study showed that C3P4 significantly increased the global reactive oxygen species and mitochondrial superoxide level, and reduced the mitochondrial membrane potential. C3P4 preferentially accumulated in mitochondria as measured by the gold content and substantially inhibited oxygen consumption rate and ATP production. These results further validated our hypothesis that targeting mitochondria would be promising to develop more potent anticancer agents. C3P4 may be further evaluated as a drug candidate for lung cancer treatment

New tranylcypromine derivatives containing sulfonamide motif as potent LSD1 inhibitors to target acute myeloid leukemia: design, synthesis and biological evaluation

Lysine-specific demethylase 1 (LSD1) is frequently elevated in acute myeloid leukemia (AML) and often leads to tumorigenesis. In recent years, numerous LSD1 inhibitors based on tranylcypromine (TCP) scaffolding have reached clinical trials. Most TCP derivatives were modified at the amino site of cyclopropane motif. Herein, we for the first time introduced a sulfonamide group in TCP benzene ring of series a compounds and performed a systematical study on structure and activity relationships by varying sulfonamide groups. The introduction of sulfonamide significantly increased the targeting capacity of TCP against LSD1. Moreover, we discovered that the Boc attached LSD1 inhibitors (labelled as series b compounds) substantially improved their anti-proliferation capacity towards AML cells. The intracellular thermal shift and LC-MS/MS results implied that Boc enhanced the drug lipophilicity and might be removed under the cancerous acidic environment to release the real pharmacophore, evidenced by the fact that a structurally similar but acidic inert pivaloyl to replace Boc dramatically dropped the cellular anti-proliferation effect. Finally, a benzyl group installed at the amino site to appropriately increase lipophilicity led to trans-4-(2-(benzylamino)-cyclopropyl)-N,N-diethylbenzenesulfonamide a10 that showed better anti-proliferation activity in AML cells and enzymatic inhibition against LSD1. Taken together, our work offers a novel TCP-based structure and provides a prodrug strategy for the discovery of potent LSD1 inhibitors by having appropriate lipophilicity

Effect of the structure of Ni nanoparticles on the electrocatalytic activity of Ni@Pd/C for formic acid oxidation

Ni@Pd/C catalysts were synthesized, using Ni/C with different crystalline structures prepared with various ligands. A series of characterizations were performed by transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy. The results indicated the electrocatalysts with amorphous/crystalline (denoted as Nia and Nic) Ni structures decorated with Pd. The formic acid electrocatalytic oxidation results showed that the peak current of Nia@Pd/C was about 1.2 times higher than that of Nic@Pd/C. The good electrochemical performance and stability of Pd-modified amorphous Ni substrate reveals that the core structure plays an important role in the electrocatalytic activity and the change of the structure can improve the activity and stability of electrocatalysts.Web of Scienc

Flat edge modes of graphene and of Z2 topological insulator

A graphene nano-ribbon in the zigzag edge geometry exhibits a specific type of gapless edge modes with a partly flat band dispersion. We argue that the appearance of such edge modes are naturally understood by regarding graphene as the gapless limit of a Z2 topological insulator. To illustrate this idea, we consider both Kane-Mele (graphene-based) and Bernevig-Hughes-Zhang models: the latter is proposed for HgTe/CdTe 2D quantum well. Much focus is on the role of valley degrees of freedom, especially, on how they are projected onto and determine the 1D edge spectrum in different edge geometries

Evasion of anti-growth signaling: a key step in tumorigenesis and potential target for treatment and prophylaxis by natural compounds

The evasion of anti-growth signaling is an important characteristic of cancer cells. In order to continue to proliferate, cancer cells must somehow uncouple themselves from the many signals that exist to slow down cell growth. Here, we define the anti-growth signaling process, and review several important pathways involved in growth signaling: p53, phosphatase and tensin homolog (PTEN), retinoblastoma protein (Rb), Hippo, growth differentiation factor 15 (GDF15), AT-rich interactive domain 1A (ARID1A), Notch, insulin-like growth factor (IGF), and Krüppel-like factor 5 (KLF5) pathways. Aberrations in these processes in cancer cells involve mutations and thus the suppression of genes that prevent growth, as well as mutation and activation of genes involved in driving cell growth. Using these pathways as examples, we prioritize molecular targets that might be leveraged to promote anti-growth signaling in cancer cells. Interestingly, naturally-occurring phytochemicals found in human diets (either singly or as mixtures) may promote anti-growth signaling, and do so without the potentially adverse effects associated with synthetic chemicals. We review examples of naturally-occurring phytochemicals that may be applied to prevent cancer by antagonizing growth signaling, and propose one phytochemical for each pathway. These are: epigallocatechin-3-gallate (EGCG) for the Rb pathway, luteolin for p53, curcumin for PTEN, porphyrins for Hippo, genistein for GDF15, resveratrol for ARID1A, withaferin A for Notch and diguelin for the IGF1-receptor pathway. The coordination of anti-growth signaling and natural compound studies will provide insight into the future application of these compounds in the clinical setting

Mining expression and prognosis of topoisomerase isoforms in non-small-cell lung cancer by using Oncomine and Kaplan-Meier plotter.

DNA topoisomerases are essential to modulate DNA topology during various cellular genetic processes. The expression and distinct prognostic value of topoisomerase isoforms in non-small-cell lung cancer (NSCLC) is not well established. In the current study, we have examined the mRNA expression of topoisomerase isoforms by using Oncomine analysis and investigated their prognostic value via the Kaplan-Meier plotter database in NSCLC patients. Our analysis indicated that the expression level of topoisomerases in lung cancer was higher compared with normal tissues. Especially, high expression of two topoisomerase isoforms, TOP2A and TOP3A, was found to be correlated to worse overall survival (OS) in all NSCLC and lung adenocarcinoma (Ade) patients, but not in lung squamous cell carcinoma (SCC) patients. In a contrast, high expression of isoforms TOP1 and TOP2B indicated better OS in all NSCLC and Ade, but not in SCC patients. Meanwhile, high expression of TOP1MT and TOP3B was not correlated with OS in NSCLC patients. Furthermore, we also demonstrated a relationship between topoisomerase isoforms and the clinicopathological features for the NSCLC patients, such as grades, clinical stages, lymph node status, smoking status, gender, chemotherapy and radiotherapy. These results support that TOP2A and TOP3A are associated with worse prognosis in NSCLC patients. In addition, our study also shows that TOP1 and TOP2B contribute to favorable prognosis in NSCLC patients. The exact prognostic significance of TOP1MT and TOP3B need to be further elucidated. Comprehensive evaluation of expression and prognosis of topoisomerase isoforms will be a benefit for the better understanding of heterogeneity and complexity in the molecular biology of NSCLC, paving a way for more accurate prediction of prognosis and discovery of potential drug targets for NSCLC patients

Optimization of Inhibitors of Mycobacterium tuberculosis Pantothenate Synthetase Based on Group Efficiency Analysis.

Ligand efficiency has proven to be a valuable concept for optimization of leads in the early stages of drug design. Taking this one step further, group efficiency (GE) evaluates the binding efficiency of each appendage of a molecule, further fine-tuning the drug design process. Here, GE analysis is used to systematically improve the potency of inhibitors of Mycobacterium tuberculosis pantothenate synthetase, an important target in tuberculosis therapy. Binding efficiencies were found to be distributed unevenly within a lead molecule derived using a fragment-based approach. Substitution of the less efficient parts of the molecule allowed systematic development of more potent compounds. This method of dissecting and analyzing different groups within a molecule offers a rational and general way of carrying out lead optimization, with potential broad application within drug discovery.Acknowledgements: This research was supported by the Bill & Melinda Gates Foundation[“Integrated Methods for TB Drug Development(IMTB)” Accelerator Grant], the UK Biotechnology and Biological Sciences Research Council (Grant BB/D006104/1), the Fundação para a Ciência e Tecnologia (PhD sponsorship to H.L.S.), and Homerton College (Junior Research Fellowship to A.C.).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/cmdc.20150041