ABNORMAL EMBRYONIC DEVELOPMENT OF THE AMERICAN SEA URCHIN FOLLOWING ILLUMINATION OF GAMETES WITH VISIBLE LIGHT FROM A PHOTOTHERAPY UNIT

Abstract— The unfertilized oocytes and spermatozoa of the American sea urchin ( Arbacia punctulata ) were exposed to phototherapy lights in order to determine the effect of this treatment regimen on post-irradiation fertilization and embryonic development. Light treatment revealed dose-dependent abnormalities in fertilization and subsequent embryonic development.     

Activation of Sperm EGFR by Light Irradiation is Mediated by Reactive Oxygen Species

To acquire fertilization competence, spermatozoa must undergo several biochemical and motility changes in the female reproductive tract, collectively called capacitation. Actin polymerization and the development of hyperactivated motility (HAM) are part of the capacitation process. In a recent study, we showed that irradiation of human sperm with visible light stimulates HAM through a mechanism involving reactive‐oxygen‐species (ROS), Ca²⁺ influx, protein kinases A (PKA), and sarcoma protein kinase (Src). Here, we showed that this effect of light on HAM is mediated by ROS‐dependent activation of the epidermal growth factor receptor (EGFR). Interestingly, ROS‐mediated HAM even when the EGFR was activated by EGF, the physiological ligand of EGFR. Light irradiation stimulated ROS‐dependent actin polymerization, and this effect was abrogated by PBP10, a peptide which activates the actin‐severing protein, gelsolin, and causes actin‐depolymerization in human sperm. Light‐stimulated tyrosine phosphorylation of Src‐dependent gelsolin, resulting in enhanced HAM. Thus, light irradiation stimulates HAM through a mechanism involving Src‐mediated actin polymerization. Light‐stimulated HAM and in vitro‐fertilization (IVF) rate in mouse sperm, and these effects were mediated by ROS and EGFR. In conclusion, we show here that irradiation of sperm with visible light, enhances their fertilization capacity via a mechanism requiring ROS, EGFR and HAM.     

Propellanes-LXXIV: Bis-alkylation at nitrogen of a [4.3.3] propellene-bis-imide

-Various halides were used to alkylate at both nitrogen atoms of [4.3.3]propell-3-ene-bis-imidi     

Drugs Targeting the A3 Adenosine Receptor: Human Clinical Study Data

The A3 adenosine receptor (A3AR) is overexpressed in pathological human cells. Piclidenoson and namodenoson are A3AR agonists with high affinity and selectivity to A3AR. Both induce apoptosis of cancer and inflammatory cells via a molecular mechanism entailing deregulation of the Wnt and the NF-κB signaling pathways. Our company conducted phase I studies showing the safety of these 2 molecules. In the phase II studies in psoriasis patients, piclidenoson was safe and demonstrated efficacy manifested in significant improvements in skin lesions. Namodenoson is currently being developed to treat liver cancer, where prolonged overall survival was observed in patients with advanced liver disease and a Child–Pugh B score of 7. A pivotal phase III study in this patient population has been approved by the FDA and the EMA and is currently underway. Namodenoson is also being developed to treat non-alcoholic steatohepatitis (NASH). A Phase IIa study has been successfully concluded and showed that namodenoson has anti-inflammatory, anti-fibrosis, and anti-steatosis effects. A phase IIb study in NASH is currently enrolling patients. In conclusion, A3AR agonists are promising drug candidates in advanced stages of clinical development and demonstrate safety and efficacy in their targeted indications.     

Propellanes. Part LXXXII. Preparation and Labelling of [20.3.3]Propellane-24,27-dione

The title diketone has been prepared by a synthetic sequence beginning with decane-1,10-dicarboxylic acid.     

Propellanes. LXVII. Reactions of 1, 6-bridged [10]annulenes with 4-methyl-1,2,4-triazoline-3, 5-dione

Reactions of 11-substituted-1, 6-methano [10]annulenes and 1, 6-methano [10]-annulenes substituted in the aromatic ring with the title dienophile are described.     

Propellanes. LXVI. Exo- and Endo-Diels-Alder adducts of 4-substituted 1,2,4-triazoline-3, 5-diones with various 1, 6-methano [10]annulenes

Relatively few exo-adducts have been obtained from the title compounds. Only one such mono-adduct, 3 , is known. Several exo-endo-bis-adducts have been obtained but the structure of one of these, 5 , has been proved unequivocally by X-ray structural determination.     

Live cell labeling of native intracellular bacterial receptors using aniline-catalyzed oxime ligation

Live cell fluorescent labeling of proteins has become a seminal tool in biology and has led to hallmark discoveries in diverse research areas such as protein trafficking, cell-to-cell interactions, and intracellular network dynamics. One of the main challenges, however, remains the ability to label intracellular proteins using fluorescent ligands with high specificity, all the while retaining viability of the targeted cells. Here, we present the first example of live cell labeling and imaging of an intracellular bacterial receptor involved in cell-to-cell communication (i.e., quorum sensing), using a novel two-step approach involving covalent attachment of a reactive mimic of the primary endogenous Pseudomonas aeruginosa quorum-sensing signal to its receptor, LasR, followed by aniline-catalyzed oxime formation between the modified receptor and a fluorescent BODIPY derivative. Our results indicate that LasR is not distributed evenly throughout the cytoplasmic membrane but is instead concentrated at the poles of the P. aeruginosa cell.