Search

Full documentation for the GROMACS 2023.1 release version.

Formålet med denne undersøkelsen var å kartlegge generelt samarbeid på individ- og systemnivå mellom helsestasjon og barnehage og mellom skolehelsetjeneste og skole. I tillegg undersøkes samarbeidet om kosthold og måltidsvaner og fysisk aktivitet. Helsesykepleiere som arbeidet i helsestasjons- eller skolehelsetjenesten, og som var medlem i Landsgruppen av helsesykepleiere, fikk tilsendt lenke til et elektronisk spørreskjema. Spørreskjemaet var utarbeidet av Nasjonalt senter for mat, helse og fysisk aktivitet og Fagseksjon for master i jordmorfag og helsesykepleie ved Høgskulen på Vestlandet. Både helsesykepleiere i helsestasjon og i skolehelsetjenesten rapporterte om mer samarbeid på individnivå enn på systemnivå. Helsesykepleierne opplevde at det var for lite tid og ressurser til å arbeide på systemnivå, og ulikt lovverk og sentrale føringer for de ulike aktørene, ble trukket frem som barrierer for samarbeid. I skolen var systemrettet samarbeid om psykisk og seksuell helse, og psykososialt miljø mer etablert enn samarbeid om mat og måltid og fysisk aktivitet. I barnehagen var systemrettet samarbeid i mindre grad etablert. Samarbeid om kosthold ble oppgitt som et av de vanligste temaene i samarbeidet med barnehagene. Gjennom å nytte den samlete kompetansen kan videreutvikling av systemrettet samarbeid mellom helsestasjon og barnehage og skolehelsetjenesten og skolen bidra til et enda bedre tilbud til barn og unge. Selv om begrenset tid og ressurser og ulikt lovverk oppleves som barrierer for samarbeid, kan det synes å være et uutnyttet mulighetsrom i hva det systemrettede samarbeidet kan innebære.

Contains fulltext : 292088.pdf (Publisher’s version ) (Closed access)

Ligand-gated ion channels transduce electrochemical signals in neurons and other excitable cells. Aside from canonical ligands, phospholipids are thought to bind specifically to the transmembrane domain of several ion channels. However, structural details of such lipid contacts remain elusive, partly due to limited resolution of these regions in experimental structures. Here, we discovered multiple lipid interactions in the channel GLIC by integrating cryo-electron microscopy and large-scale molecular simulations. We identified 25 bound lipids in the GLIC closed state, a conformation where none, to our knowledge, were previously known. Three lipids were associated with each subunit in the inner leaflet, including a buried interaction disrupted in mutant simulations. In the outer leaflet, two intrasubunit sites were evident in both closed and open states, while a putative intersubunit site was preferred in open-state simulations. This work offers molecular details of GLIC-lipid contacts particularly in the ill-characterized closed state, testable hypotheses for state-dependent binding, and a multidisciplinary strategy for modeling protein-lipid interactions.

The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unfortunately, unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of ~30,000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing ~200 virtual screenings of compound libraries on selected protein structures, we redefine the protein’s druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by in vitro assays performed here and by a newly solved X-ray crystal structure. These results provide a strong basis for effective rational drug design campaigns against SARS-CoV-2 Mpro and a new computational approach to screen protein targets with malleable binding sites.

Summary Understanding how proteins transition between different conformers, and how conformers relate to each other in terms of structure and function, is not trivial. Here, we present an online tool for transition pathway generation between two protein conformations using Elastic Network Driven Brownian Dynamics Importance Sampling, a coarse-grained simulation algorithm, which spontaneously predicts transition intermediates trapped experimentally. In addition to path-generation, the server provides an interactive 2D-motion landscape graphical representation of the transitions or any additional conformers to explore their structural relationships. Availability and implementation eBDIMS is available online: http://ebdims.biophysics.se/ or as standalone software: https://github.com/laura-orellana/eBDIMS, https://github.com/cabergh/eBDIMS. Supplementary information Supplementary data are available at Bioinformatics online.

Allosteric Modulation via Transmembrane Interfaces in a Pentameric Ligand-Gated Ion Channel

Mapping pH-Dependent State Transitions of a Pentameric Ligand-gated Ion Channel through Markov State Modeling

Allosteric Gating Determinants in the Transmembrane Domain of Pentameric Ligand-Gated Ion Channels