A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain

Maladaptive plasticity involving increased expression of AMPA‐type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell‐permeable, high‐affinity (~2 nM) peptide inhibitor, Tat‐P$_4$‐(C5)$_2$, of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat‐P$_4$‐(C5)$_2$ disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA‐receptor surface expression in vivo. Moreover, Tat‐P$_4$‐(C5)$_2$ administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat‐P$_4$‐(C5)$_2$ as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non‐tandem protein–protein interaction domains

The Danish National Child Health Register

Aim of the Database: The aim of the National Child Health Registry is to provide comprehensive insight into children’s health and growth on a national scale by continuously monitoring the health status of Danish children. Through this effort, the registry assists the health authorities in prioritizing preventive efforts to promote better child health outcomes.Study Population: The registry includes all Danish children, however, incomplete coverage persists.Main Variables: The National Child Health Registry contains information on exposure to secondhand smoking, breastfeeding duration, and anthropometric measurements through childhood. The information in the registry is divided into three datasets: Smoking, Breastfeeding, and Measurements. Beside specific information on the three topics, all datasets include information on CPR-number, date of birth, sex, municipality, and region of residence.Database Status: The National Child Health Registry was established in 2009 and contains health information on children from all Danish municipalities, collected through routinely performed health examinations conducted by general practitioners and health nurses.Conclusion: The National Child Health Register is an asset to epidemiological and health research with nationwide information on children’s health and growth in Denmark. Due to the unique Danish Civil Registration System, it is possible to link data from the National Child Health Register to information from several other national health and social registers which enables longitudinal unambiguous follow-up

Sediment resuspension and deposition on seagrass leaves impedes internal plant aeration and promotes phytotoxic H<inf>2</inf>S intrusion

© 2017 Brodersen, Hammer, Schrameyer, Floytrup, Rasheed, Ralph, Kühl and Pedersen. Anthropogenic activities leading to sediment re-suspension can have adverse effects on adjacent seagrass meadows, owing to reduced light availability and the settling of suspended particles onto seagrass leaves potentially impeding gas exchange with the surrounding water. We used microsensors to determine O2 fluxes and diffusive boundary layer (DBL) thickness on leaves of the seagrass Zostera muelleri with and without fine sediment particles, and combined these laboratory measurements with in situ microsensor measurements of tissue O2 and H2 S concentrations. Net photosynthesis rates in leaves with fine sediment particles were down to ∼20% of controls without particles, and the compensation photon irradiance increased from a span of 20–53 to 109–145 µmol photons m−2 s−1. An ∼2.5-fold thicker DBL around leaves with fine sediment particles impeded O2 influx into the leaves during darkness. In situ leaf meristematic O2 concentrations of plants exposed to fine sediment particles were lower than in control plants and exhibited long time periods of complete meristematic anoxia during night-time. Insufficient internal aeration resulted in H2 S intrusion into the leaf meristematic tissues when exposed to sediment resuspension even at relatively high night-time water-column O2 concentrations. Fine sediment particles that settle on seagrass leaves thus negatively affect internal tissue aeration and thereby the plants’ resilience against H2 S intrusion

A high‐affinity, bivalent PDZ domain inhibitor complexes PICK 1 to alleviate neuropathic pain

Maladaptive plasticity involving increased expression of AMPA‐type glutamate receptors is involved in several pathologies, including neuropathic pain, but direct inhibition of AMPARs is associated with side effects. As an alternative, we developed a cell‐permeable, high‐affinity (~2 nM) peptide inhibitor, Tat‐P$_4$‐(C5)$_2$, of the PDZ domain protein PICK1 to interfere with increased AMPAR expression. The affinity is obtained partly from the Tat peptide and partly from the bivalency of the PDZ motif, engaging PDZ domains from two separate PICK1 dimers to form a tetrameric complex. Bivalent Tat‐P$_4$‐(C5)$_2$ disrupts PICK1 interaction with membrane proteins on supported cell membrane sheets and reduce the interaction of AMPARs with PICK1 and AMPA‐receptor surface expression in vivo. Moreover, Tat‐P$_4$‐(C5)$_2$ administration reduces spinal cord transmission and alleviates mechanical hyperalgesia in the spared nerve injury model of neuropathic pain. Taken together, our data reveal Tat‐P$_4$‐(C5)$_2$ as a novel promising lead for neuropathic pain treatment and expand the therapeutic potential of bivalent inhibitors to non‐tandem protein–protein interaction domains