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"Gao, Zhan"
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Historical and Current Adenosine Receptor Agonists in Preclinical and Clinical Development
Adenosine receptors (ARs) function in the body's response to conditions of pathology and stress associated with a functional imbalance, such as in the supply and demand of energy/oxygen/nutrients. Extracellular adenosine concentrations vary widely to raise or lower the basal activation of four subtypes of ARs. Endogenous adenosine can correct an energy imbalance during hypoxia and other stress, for example, by slowing the heart rate by A
AR activation or increasing the blood supply to heart muscle by the A
AR. Moreover, exogenous AR agonists, antagonists, or allosteric modulators can be applied for therapeutic benefit, and medicinal chemists working toward that goal have reported thousands of such agents. Thus, numerous clinical trials have ensued, using promising agents to modulate adenosinergic signaling, most of which have not succeeded. Currently, short-acting, parenteral agonists, adenosine and Regadenoson, are the only AR agonists approved for human use. However, new concepts and compounds are currently being developed and applied toward preclinical and clinical evaluation, and initial results are encouraging. This review focuses on key compounds as AR agonists and positive allosteric modulators (PAMs) for disease treatment or diagnosis. AR agonists for treating inflammation, pain, cancer, non-alcoholic steatohepatitis, angina, sickle cell disease, ischemic conditions and diabetes have been under development. Multiple clinical trials with two A
AR agonists are ongoing.
Journal Article
A2B Adenosine Receptor and Cancer
There are four subtypes of adenosine receptors (ARs), named A1, A2A, A2B and A3, all of which are G protein-coupled receptors (GPCRs). Locally produced adenosine is a suppressant in anti-tumor immune surveillance. The A2BAR, coupled to both Gαs and Gαi G proteins, is one of the several GPCRs that are expressed in a significantly higher level in certain cancer tissues, in comparison to adjacent normal tissues. There is growing evidence that the A2BAR plays an important role in tumor cell proliferation, angiogenesis, metastasis, and immune suppression. Thus, A2BAR antagonists are novel, potentially attractive anticancer agents. Several antagonists targeting A2BAR are currently in clinical trials for various types of cancers. In this review, we first describe the signaling, agonists, and antagonists of the A2BAR. We further discuss the role of the A2BAR in the progression of various cancers, and the rationale of using A2BAR antagonists in cancer therapy.
Journal Article
Thin, soft, wearable system for continuous wireless monitoring of artery blood pressure
Continuous monitoring of arterial blood pressure (BP) outside of a clinical setting is crucial for preventing and diagnosing hypertension related diseases. However, current continuous BP monitoring instruments suffer from either bulky systems or poor user-device interfacial performance, hampering their applications in continuous BP monitoring. Here, we report a thin, soft, miniaturized system (TSMS) that combines a conformal piezoelectric sensor array, an active pressure adaptation unit, a signal processing module, and an advanced machine learning method, to allow real wearable, continuous wireless monitoring of ambulatory artery BP. By optimizing the materials selection, control/sampling strategy, and system integration, the TSMS exhibits improved interfacial performance while maintaining Grade A level measurement accuracy. Initial trials on 87 volunteers and clinical tracking of two hypertension individuals prove the capability of the TSMS as a reliable BP measurement product, and its feasibility and practical usability in precise BP control and personalized diagnosis schemes development.
Continuous monitoring of arterial blood pressure is limited by bulky connecting systems and poor interfacial contact. Here, Li et al. report a wearable thin, soft, miniaturized system that integrates sensing, active pressure adaptation, and signal processing for improved performance and accuracy.
Journal Article
Highly stretchable organic electrochemical transistors with strain-resistant performance
Realizing fully stretchable electronic materials is central to advancing new types of mechanically agile and skin-integrable optoelectronic device technologies. Here we demonstrate a materials design concept combining an organic semiconductor film with a honeycomb porous structure with biaxially prestretched platform that enables high-performance organic electrochemical transistors with a charge transport stability over 30–140% tensional strain, limited only by metal contact fatigue. The prestretched honeycomb semiconductor channel of donor–acceptor polymer poly(2,5-bis(2-octyldodecyl)-3,6-di(thiophen-2-yl)-2,5-diketo-pyrrolopyrrole-alt-2,5-bis(3-triethyleneglycoloxy-thiophen-2-yl) exhibits high ion uptake and completely stable electrochemical and mechanical properties over 1,500 redox cycles with 10
4
stretching cycles under 30% strain. Invariant electrocardiogram recording cycles and synapse responses under varying strains, along with mechanical finite element analysis, underscore that the present stretchable organic electrochemical transistor design strategy is suitable for diverse applications requiring stable signal output under deformation with low power dissipation and mechanical robustness.
Highly stretchable organic electrochemical transistors with stable charge transport under severe tensional strains are demonstrated using a honeycomb semiconducting polymer morphology, thereby enabling controllable signal output for diverse stretchable bioelectronic applications.
Journal Article
Condition monitoring and life prediction of the turning tool based on extreme learning machine and transfer learning
When the turning tool has worn and failed but the failure is not found, if it continues to be used for processing, it will break, and cause the workpiece to be scrapped, and even damage the machine tool. In order to avoid the loss caused by turning tool wear, the remaining useful life (RUL) prediction of turning tool wear has become a hot research topic in recent years. For RUL prediction in turning tools, the traditional machine is difficult to acquire sufficient degradation data and inconsistent data distribution among different turning tools in engineering, and they cannot provide better prediction accuracy to some extent. To solve the above problems, this paper proposes a multi-granularity feature extraction (MGFE) method based on the gray-level co-occurrence matrix (GLCM) and random forest (RF). Moreover, a health indicator (HI) of turning tools in the source domain was obtained. The common representative features in HI sequence of target domain was transferred to source domain and builds the condition monitoring and life prediction system of turning tools based on extreme learning machine and transfer learning. Finally, extreme vector machine (ELM) is used to construct the RUL prediction model. The research results show that the model constructed in this paper is effective in RUL prediction and can significantly improve the prediction accuracy of remaining useful life.
Journal Article
Purinergic Signaling in Mast Cell Degranulation and Asthma
Mast cells are responsible for the majority of allergic conditions. It was originally thought that almost all allergic events were mediated directly only via the high-affinity immunoglobulin E receptors. However, recent evidence showed that many other receptors, such as G protein-coupled receptors and ligand-gated ion channels, are also directly involved in mast cell degranulation, the release of inflammatory mediators such as histamine, serine proteases, leukotrienes, heparin, and serotonin. These mediators are responsible for the symptoms in allergic conditions such as allergic asthma. In recent years, it has been realized that purinergic signaling, induced via the activation of G protein-coupled adenosine receptors and P2Y nucleotide receptors, as well as by ATP-gated P2X receptors, plays a significant role in mast cell degranulation. Both adenosine and ATP can induce degranulation and bronchoconstriction on their own and synergistically with allergens. All three classes of receptors, adenosine, P2X and P2Y are involved in tracheal mucus secretion. This review will summarize the currently available knowledge on the role of purinergic signaling in mast cell degranulation and its most relevant disease, asthma.
Journal Article
Anionic phospholipids control mechanisms of GPCR-G protein recognition
G protein-coupled receptors (GPCRs) are embedded in phospholipids that strongly influence drug-stimulated signaling. Anionic lipids are particularly important for GPCR signaling complex formation, but a mechanism for this role is not understood. Using NMR spectroscopy, we explore the impact of anionic lipids on the function-related conformational equilibria of the human A
2A
adenosine receptor (A
2A
AR) in bilayers containing defined mixtures of zwitterionic and anionic phospholipids. Anionic lipids prime the receptor to form complexes with G proteins through a conformational selection process. Without anionic lipids, signaling complex formation proceeds through a less favorable induced fit mechanism. In computational models, anionic lipids mimic interactions between a G protein and positively charged residues in A
2A
AR at the receptor intracellular surface, stabilizing a pre-activated receptor conformation. Replacing these residues strikingly alters the receptor response to anionic lipids in experiments. High sequence conservation of the same residues among all GPCRs supports a general role for lipid-receptor charge complementarity in signaling.
In cell membranes, lipids are ubiquitous regulators of protein function. Here, Thakur et al. observe anionic phospholipids impact the conformational dynamics of a class A human GPCR.
Journal Article
Structure of an Agonist-Bound Human A2A Adenosine Receptor
Activation of G protein-coupled receptors upon agonist binding is a critical step in the signaling cascade for this family of cell surface proteins. We report the crystal structure of the A(2A) adenosine receptor (A(2A)AR) bound to an agonist UK-432097 at 2.7 angstrom resolution. Relative to inactive, antagonist-bound A(2A)AR, the agonist-bound structure displays an outward tilt and rotation of the cytoplasmic half of helix VI, a movement of helix V, and an axial shift of helix III, resembling the changes associated with the active-state opsin structure. Additionally, a seesaw movement of helix VII and a shift of extracellular loop 3 are likely specific to A(2A)AR and its ligand. The results define the molecule UK-432097 as a \"conformationally selective agonist\" capable of receptor stabilization in a specific active-state configuration.
Journal Article
The effects of nanoscale nuclei on cavitation
Under certain conditions, experimental values of the tensile strength of water are found to be much lower than theoretical values, even when the water is purified and degassed as much as possible. The discrepancy could be ascribed to stabilized nanobubbles or nanoparticles suspended in the liquid, as such contaminants cannot be eliminated completely from a substantial liquid volume. Thus, the present study aims at elucidating the effects of such nanoscale nuclei on cavitation. A parameter-free mathematical model is derived to predict the cavitation arising from nanoscale nuclei, based on classical nucleation theory. To verify the model, molecular dynamics is used to simulate cavitation at nuclei of different sizes, embedded either in water or in liquid copper at different temperatures. The cavitation pressures calculated from the molecular dynamics results are compared with the predictions of the present mathematical model, with a good agreement between them. The results show that nanoscale nuclei significantly promote cavitation, i.e. the tensile strength is reduced notably by the presence of nanoscale nuclei. The tensile strength decreases when the size of nuclei increases, and the change rule of cavitation pressure is also affected by the liquid properties, such as liquid temperature. The present study may provide an acceptable explanation of the discrepancy between theory and experiment on the cavitation pressure in liquids purified and degassed as much as possible.
Journal Article