A Fast, Convenient, Polarizable Electrostatic Model for Molecular Dynamics.

We present an efficient polarizable electrostatic model, utilizing typed, atom-centered polarizabilities and the fast direct approximation, designed for efficient use in molecular dynamics (MD) simulations. The model provides two convenient approaches for assigning partial charges in the context of atomic polarizabilities. One is a generalization of RESP, called RESP-dPol, and the other, AM1-BCC-dPol, is an adaptation of the widely used AM1-BCC method. Both are designed to accurately replicate gas-phase quantum mechanical electrostatic potentials. Benchmarks of this polarizable electrostatic model against gas-phase dipole moments, molecular polarizabilities, bulk liquid densities, and static dielectric constants of organic liquids show good agreement with the reference values. Of note, the model yields markedly more accurate dielectric constants of organic liquids, relative to a matched nonpolarizable force field. MD simulations with this method, which is currently parametrized for molecules containing elements C, N, O, and H, run only about 3.6-fold slower than fixed charge force fields, while simulations with the self-consistent mutual polarization average 4.5-fold slower. Our results suggest that RESP-dPol and AM1-BCC-dPol afford improved accuracy relative to fixed charge force fields and are good starting points for developing general, affordable, and transferable polarizable force fields. The software implementing these approaches has been designed to utilize the force field fitting frameworks developed and maintained by the Open Force Field Initiative, setting the stage for further exploration of this approach to polarizable force field development.

Artificial potential function based spacecraft proximity maneuver 6-DOF control under multiple pyramid-type constraints.

This paper addresses the problem of spacecraft six degree of freedom (6-DOF) pose tracking control with collision avoidance and field of view (FOV) pyramid-type constraints during the autonomous proximity maneuver. The constraints are modeled as pyramid envelopes, which can better represent some real cases with less conservativeness comparing with commonly used cone-shaped model. A novel modeling method is proposed to describe the pyramid-type constraints in the dual-quaternion frame. Based on the specific geometric property of the pyramid constraints, a new convex artificial potential function (APF) with only one global minimum is designed, which incorporates the pose constraints into the control design procedure. Then, an integrated APF based control law is presented to simultaneously control the rotational and translational motion of the spacecraft without violating the pyramid constraints. The stability of the closed-loop system is demonstrated through the Lyapunov theory, and numerical simulation results are carried out to show the effectiveness of the proposed control law.

Discovering High Potent Hsp90 Inhibitors as Antinasopharyngeal Carcinoma Agents through Fragment Assembling Approach.

Hsp90 is a new promising target for cancer treatment. Many inhibitors have been discovered as therapeutic agents, and some have passed Phase I and II. However, no one is approved by FDA yet. Novel and druggable Hsp90 inhibitors are still demanding. Here, we report a new way to discover high potent Hsp90 inhibitors as antinasopharyngeal carcinoma agents through assembling fragments. With chemotyping analysis, we extract seven chemotypes from 3482 known Hsp90 inhibitors, screen 500 fragments that are compatible with the chemotypes, and confirm 15 anti-Hsp90 fragments. Click chemistry is employed to construct 172 molecules and synthesize 21 compounds among them. The best inhibitor 3d was further optimized and resulted in more potent 4f (IC50 = 0.16 µM). In vitro and in vivo experiments confirmed that 4f is a promising agent against nasopharyngeal carcinoma. This study may provide a strategy in discovering new ligands against targets without well-understood structures.

Reactive oxygen species altering the metabolite profile of the marine-derived fungus Dichotomomyces cejpii F31-1.

To investigate the influence of reactive oxygen species (ROS) on the secondary metabolites of the marine-derived fungus Dichotomomyces cejpii F31-1, hydrogen peroxide (H2O2) was added to the GPY culture medium. The HPLC chromatogram of the EtOAc extract of the culture broth was distinct from that of the H2O2 free GPY medium. Further study of the metabolites in the GPY medium with H2O2 resulted in the discovery of eight known compounds. Among them, (22E)-5α, 8α-epidioxyergosta-6, 22-dien-3ß-ol (2) and ergosta-4,6,8(14),22-tetraene-3-one (3) were present in the highest concentration, while ergosterol and diketopiperazines are abundant in the H2O2 free medium. Additionally, a new compound, dichocetide D (1) containing a chlorine element and a known ergosterol (10) were isolated from the H2O2 free medium. (22E)-5α, 8α-epidioxyergosta-6, 22-dien-3ß-ol (2) exhibited moderate cytotoxic activity against human prostate cancer cell line LNCaP-C4-2B.

Human adipose liquid extract induces angiogenesis and adipogenesis: a novel cell-free therapeutic agent.

BACKGROUND: Taking advantage of cellular paracrine mechanisms, the secretome of adipose-derived stem cells (ADSCs) and adipose tissue has been demonstrated to induce tissue repair and regeneration in various ischemic and impaired conditions. However, these cell-based therapies have been hindered by issues, such as inherent safety and cost-efficiency for clinical applications. In this study, we prepared a liquid cell-free extract from human adipose tissue [adipose liquid extract (ALE)] and evaluated its potential therapeutic efficacy. METHODS: ALE was prepared from human subcutaneous adipose tissue using a rapid and physical approach, and the protein components in ALE were identified using mass spectrometry analysis. In vivo, the therapeutic effect of this agent was investigated on wound healing in C57BL/6 mice, and wound healing rate, vessel density, and neo-adipocyte formation in wounded skins were measured at days 3, 7, 11, and 14. In vitro, the effect of ALE on the viability of human ADSCs, tube formation of human umbilical vein endothelial cells (HUVECs), and adipogenic differentiation of ADSCs were tested. RESULTS: The results demonstrated that ALE contained a variety of growth factors and did not affect cell viability. ALE-treated wounds exhibited accelerated wound healing with increased vessel density and formation of neo-adipocytes compared to that of control wounds. Moreover, when added as a cell culture supplement, ALE effectively induced tube formation of HUVECs and lipid accumulation in ADSCs. ALE-treated ADSCs also exhibited elevated levels of adipogenic gene expression. CONCLUSIONS: ALE is a novel growth-rich therapeutic agent that is cell-free and easy to produce. Besides, it is also able to induce angiogenesis and adipogenesis both in vitro and in vivo, thus indicating that it could be used for wound repair and soft tissue regeneration.

Treatment of human chronic wounds with autologous extracellular matrix/stromal vascular fraction gel: A STROBE-compliant study.

Stem cell therapy is considered as the most promising treatment for chronic wounds. Extracellular matrix/stromal vascular fraction gel (ECM/SVF gel), an adipose-derived stem cell-based cytotherapy, has shown healing potential in experimental wounds in animal models. However, the effects of ECM/SVF gel on human chronic wounds have not been investigated. The aim of the present study is to investigate the therapeutic effect of ECM/SVF gel on human chronic wounds.Autologous ECM/SVF gel was prepared and used to treat patients with chronic wounds in clinics, with negative pressure wound therapy as the positive control. Wound healing rate per week and histological changes were performed.The average wound healing rate per week in the ECM/SVF gel group was 34.55 ±â€Š11.18% compared with 10.16 ±â€Š2.67% in the negative pressure wound therapy group (P < .001). Histological analysis with hematoxylin and eosin, Masson's trichrome staining, and CD31 immunohistochemistry showed less lymphocyte infiltration, more collagen accumulation, and more newly formed vessels in the ECM/SVF gel group treated skins compared to the control.ECM/SVF gel is an effective therapeutic option for chronic wound healing in clinics.