Areal assessment of pine wood nematode invasion risk, based on import statistics, forest inventory data and grid-based spread model

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Trafficking and ethanol-induced inhibition of AMPA receptors

AMPA receptors are an important class of ionotropic glutamate receptors which participate in fast excitatory synaptic transmission in most brain areas. They have a pivotal role in adjustment of cell membrane excitability as their cell membrane expression levels is altered in brain physiology such as in learning and memory formation. AMPA receptor function and trafficking is regulated by several proteins, such as transmembrane AMPA receptor regulatory proteins (TARPs). NMDA-type glutamate receptors are important target molecules of ethanol. The role of AMPA receptors in the actions of ethanol has not been clarified as thoroughly. Furthermore, the regulation of AMPA receptor synthesis and their possible adaptation in neurons with altered inhibitory mechanisms are poorly understood. In this thesis work AMPA receptor pharmacology, trafficking and synaptic localization was studied using patch-clamp electrophysiology. Both native and recombinant AMPA receptors were studied. Hippocampal slices from transgenic Thy1alfa6 mice with altered inhibition were used to study adaptation of AMPA receptors. Ethanol was found to inhibit AMPA receptor function by increasing desensitization of the receptor, as the steady-state current was inhibited more than the peak current. Ethanol inhibition was reduced when cyclothiazide was used to block desensitization and when non-desensitizing mutant receptors were studied. Ethanol also increased the rate of desensitization, which was increased further by the coexpression of TARP-proteins. We found that the agonist binding capability is important for trafficking AMPA receptors from endoplasmic reticulum to the cell membrane. TARP rescues the surface expression of non-binding AMPA receptor mutants in HEK293 cells, but not in native neurons. Studies with Thy1alfa6 mice revealed that decreased inhibition decrease AMPA receptor mediated excitation keeping the neurotransmission in balance. Thy1alfa6 mice also had lower sensitivity to electroshock convulsions, presumably due to the decreased AMPA receptor function. The results suggest that during alcohol intoxication ethanol may inhibit AMPA receptors by increasing the rate and the extent of desensitization. TARPs appear to enhance ethanol inhibition. TARPs also participate in trafficking of AMPA receptors upon their synthesis in the cell. AMPA receptors mediate also long-term adaptation to altered neuronal excitability, which adds to their well-known role in synaptic plasticity.FM Tommi Möykkysen väitöstutkimuksessa tutkittiin aivojen yleisimmän kiihdyttävän välittäjäaineen, glutamaatin, AMPA-tyyppisten reseptorien kuljetusta ja ilmentymistä solukalvolla sekä alkoholin (etanolin) vaikutuksia kyseisiin reseptoreihin. AMPA reseptorit ovat keskeisiä hermosolujen toiminnassa, koska ne välittävät sähkösignaalien siirtymistä hermosolulta toiselle kaikkialla aivoissa. Niiden määrän ja ominaisuuksien säätely on tärkeää normaaleissa fysiologisissa tilanteissa, kuten muistin ja oppimisen yhteydessä. Tämän lisäksi AMPA reseptorien toiminnan on havaittu muuttuneen myös joissakin tautitiloissa ja huumausaineiden käytön yhteydessä. Hermosoluilla tehdyissä kokeissa etanolin todettiin lisäävän AMPA reseptoreiden inaktivaatiota, eli ei-aktiivista tilaa, mikä luonnollisesti estää reseptorien toimintaa. HEK-solulinjalla tehdyissä lisäkokeissa etanolin havaittiin nopeuttavan inaktiiviseen tilaan siirtymistä. Kokeissa havaittiin myös, että TARP-proteiinit nopeuttivat entisestään inaktiiviseen tilaan siirtymistä. Reseptorien solukalvoilmentymistä koskevissa tutkimuksissa osoitettiin, että reseptorien kyky sitoa välittäjäaine glutamaattia tarkastetaan solun sisällä ennen kuin ne kuljetetaan lopulliseen määränpäähänsä, solukalvolle. Vähentyneen estävän viestinvälityksen puolestaan todettiin vähentävän AMPA reseptorivälitteistä kiihdyttävää viestinvälitystä, mikä viittaa siihen, että hermosolut pitävät yllä tasapainotilaa hermoviestinvälityksessä. Etanolin on todettu vaikuttavat moniin aivojen välittäjäainesysteemeihin ja proteiineihin, ja onkin ollut vaikeaa osoittaa mitkä näistä vaikutuksista ovat tärkeitä humalatilassa ja alkoholin aiheuttamissa terveyshaitoissa. Glutamaattireseptorien on pitkään tiedetty olevan etanolin kohdemolekyylejä, mutta näistä vain NMDA reseptoreita on pidetty kliinisesti tärkeänä. Tämä väitöstutkimus paljastaa osaltaan miten etanoli estää AMPA reseptorien toimintaa ja paljastaa ne olosuhteet missä etanoli vaikuttaa myös AMPA reseptoreihin. Tutkimustulosten perusteella voidaan päätellä, että etanoli vaikuttaa AMPA reseptoreihin niillä aivoalueilla, missä inaktivaatiolla on merkitystä reseptoreiden toiminnassa. Tulokset osoittavat lisäksi, että AMPA reseptoreiden kanssa yhteydessä olevat TARP-proteiinit vaikuttavat reseptorien etanoliherkkyyteen. Tuloksista voivat osaltaan auttaa alkoholin terveyshaittojen selvittämisessä ja torjumisessa

L-Cysteine Containing Vitamin Supplement Which Prevents or Alleviates Alcohol-related Hangover Symptoms : Nausea, Headache, Stress and Anxiety

Correction ALCOHOL AND ALCOHOLISM Volume: 55 Issue: 6 Pages: 705-705 DOI: 10.1093/alcalc/agaa088 Published: NOV 2020Aims: Alcohol-related hangover symptoms: nausea, headache, stress and anxiety cause globally considerable amount of health problems and economic losses. Many of these harmful effects are produced by alcohol and its metabolite, acetaldehyde, which also is a common ingredient in alcohol beverages. The aim of the present study is to investigate the effect of the amino acid L-cysteine on the alcohol/acetaldehyde related aftereffects. Methods: Voluntary healthy participants were recruited through advertisements. Volunteers had to have experience of hangover and/or headache. The hangover study was randomized, double-blind and placebo-controlled. Nineteen males randomly swallowed placebo and L-cysteine tablets. The alcohol dose was 1.5 g/kg, which was consumed during 3 h. Results: The primary results based on correlational analysis showed that L-cysteine prevents or alleviates hangover, nausea, headache, stress and anxiety. For hangover, nausea and headache the results were apparent with the L-cysteine dose of 1200 mg and for stress and anxiety already with the dose of 600 mg. Conclusions: L-cysteine would reduce the need of drinking the next day with no or less hangover symptoms: nausea, headache, stress and anxiety. Altogether, these effects of L-cysteine are unique and seem to have a future in preventing or alleviating these harmful symptoms as well as reducing the risk of alcohol addiction.Peer reviewe

Aggregation Limits Surface Expression of Homomeric GluA3 Receptors

AMPA receptors are glutamate-gated cation channels assembled from GluA1-4 subunits and have properties that are strongly dependent on the subunit composition. The subunits have different propensities to form homomeric or various heteromeric receptors expressed on cell surface, but the underlying mechanisms are still poorly understood. Here, we examined the biochemical basis for the poor ability of GluA3 subunits to form homomeric receptors, linked previously to two amino acid residues, Y454 and R461, in its ligand-binding domain (LBD). Surface expression of GluA3 was improved by co-assembly with GluA2 but not with stargazin, a trafficking chaperone and modulator of AMPA receptors. The secretion efficiency of GluA2 and GluA3 LBDs paralleled the transport difference between the respective full-length receptors and was similarly dependent on Y454/R461, but not on LBD stability. In comparison to GluA2, GluA3 homomeric receptors showed a strong and Y454/R461-dependent tendency to aggregate both in the macroscopic scale measured as lower solubility in nonionic detergent and in the microscopic scale evident as the preponderance of hydrodynamically large structures in density gradient centrifugation and native gel electrophoresis. We conclude that the impaired surface expression of homomeric GluA3 receptors is caused by nonproductive assembly and aggregation to which LBD residues Y454 and R461 strongly contribute. This aggregation inhibits the entry of newly synthesized GluA3 receptors to the secretory pathway

Autoinactivation of the Stargazin–AMPA Receptor Complex: Subunit-Dependency and Independence from Physical Dissociation

are modulated by transmembrane accessory proteins. Stargazin, the prototypical accessory protein, decreases desensitization and increases agonist potency at AMPA receptors. Furthermore, in the presence of stargazin, the steadystate responses of AMPA receptors show a gradual decline at higher glutamate concentrations. This ‘‘autoinactivation’’ has been assigned to physical dissociation of the stargazin-AMPA receptor complex and suggested to serve as a protective mechanism against overactivation. Here, we analyzed autoinactivation of GluA1–A4 AMPA receptors (all flip isoform) expressed in the presence of stargazin. Homomeric GluA1, GluA3, and GluA4 channels showed pronounced autoinactivation indicated by the bell-shaped steady-state dose response curves for glutamate. In contrast, homomeric GluA2i channels did not show significant autoinactivation. The resistance of GluA2 to autoinactivation showed striking dependence on the splice form as GluA2-flop receptors displayed clear autoinactivation. Interestingly, the resistance of GluA2-flip containing receptors to autoinactivation was transferred onto heteromeric receptors in a dominant fashion. To examine the relationship of autoinactivation to physical separation of stargazin from the AMPA receptor, we analyzed a GluA4-stargazin fusion protein. Notably, the covalently linked complex and separately expressed proteins expressed a similar level of autoinactivation. We conclude that autoinactivation is a subunit and splice form dependent property of AMPA receptor-stargazin complexes, which involves structural rearrangements within the complex rather than any physical dissociation.Peer reviewe

Importance of GluA1 Subunit-Containing AMPA Glutamate Receptors for Morphine State-Dependency

Peer reviewe

Acute Ethanol Inhibition of γ Oscillations Is Mediated by Akt and GSK3β

Hippocampal network oscillations at gamma band frequency (γ, 30–80 Hz) are closely associated with higher brain functions such as learning and memory. Acute ethanol exposure at intoxicating concentrations (≥50 mM) impairs cognitive function. This study aimed to determine the effects and the mechanisms of acute ethanol exposure on γ oscillations in an in vitro model. Ethanol (25–100 mM) suppressed kainate-induced γ oscillations in CA3 area of the rat hippocampal slices, in a concentration-dependent, reversible manner. The ethanol-induced suppression was reduced by the D1R antagonist SCH23390 or the PKA inhibitor H89, was prevented by the Akt inhibitor triciribine or the GSk3β inhibitor SB415286, was enhanced by the NMDA receptor antagonist D-AP5, but was not affected by the MAPK inhibitor U0126 or PI3K inhibitor wortmanin. Our results indicate that the intracellular kinases Akt and GSk3β play a critical role in the ethanol-induced suppression of γ oscillations and reveal new cellular pathways involved in the ethanol-induced cognitive impairment

InDEx – Industrial Data Excellence

InDEx, the Industrial Data Excellence program, was created to investigate what industrial data can be collected, shared, and utilized for new intelligent services in high-performing, reliable and secure ways, and how to accomplish that in practice in the Finnish manufacturing industry.InDEx produced several insights into data in an industrial environment, collecting data, sharing data in the value chain and in the factory environment, and utilizing and manipulating data with artificial intelligence. Data has an important role in the future in an industrial context, but data sources and utilization mechanisms are more diverse than in cases related to consumer data. Experiences in the InDEx cases showed that there is great potential in data utili zation.Currently, successful business cases built on data sharing are either company-internal or utilize an existing value chain. The data market has not yet matured, and third-party offerings based on public and private data sources are rare. In this program, we tried out a framework that aimed to securely and in a controlled manner share data between organizations. We also worked to improve the contractual framework needed to support new business based on shared data, and we conducted a study of applicable business models. Based on this, we searched for new data-based opportunities within the project consortium. The vision of data as a tradeable good or of sharing with external partners is still to come true, but we believe that we have taken steps in the right direction.The program started in fall 2019 and ended in April 2022. The program faced restrictions caused by COVID-19, which had an effect on the intensity of the work during 2020 and 2021, and the program was extended by one year. Because of meeting restrictions, InDEx collaboration was realized through online meetings. We learned to work and collaborate using digital tools and environments. Despite the mentioned hindrances, and thanks to Business Finland’s flexibility, the extension time made it possible for most of the planned goals to be achieved.This report gives insights in the outcomes of the companies’ work within the InDEx program. DIMECC InDEx is the first finalized program by the members of the Finnish Advanced Manufacturing Network (FAMN, www.famn.fi).</p