Asymmetric Cerebral Blood Flow in Patients with Mild Cognitive Impairment: Possible Relationship to Further Cognitive Deterioration

To explore patterns of cerebral blood flow in patients with mild cognitive impairment (MCI), who (1) eventually deteriorate into overt dementia, with no particular focus on the type of dementia, or (2) do not appear to further deteriorate in their cognitive functions

Ligand binding mechanism in steroid receptors; from conserved plasticity to differential evolutionary constraints

Steroid receptor drugs have been available for more than half a century, but details 24 of the ligand binding mechanism has remained elusive. We solved X-ray structures of 25 the glucocorticoid and mineralocorticoid receptors to identify a conserved plasticity at 26 helix 6-7 region that extend the ligand binding pocket towards the receptor surface. 27 Since none of the endogenous ligands exploit this region, we hypothesized that it 28 constitutes an integral part of the binding event. Extensive all atom unbiased ligand 29 exit and entrance simulations corroborate a ligand binding pathway that gives the 30 observed structural plasticity a key functional role. Kinetic measurements reveal that 31 the receptor residence time correlate with structural rearrangements observed in both 32 structures and simulations. Ultimately, our findings reveal why nature has conserved 33 the capacity to open up this region and highlight how differences in the details of the 34 ligand entry process result in differential evolutionary constraints across the steroid 35 receptors.This study was supported by The European Research Council (2009-Adg25027-535 PELE) to V.G and by the SEV-2011-00067 grant of the Severo Ochoa Program. We 536 would like to acknowledge our AstraZeneca colleagues J. Hartleib, R.Unwin and 537 R.Knöll for helpful discussions. We also thank N. Blomberg (ELIXIR) and R. Neutze 538 (University of Gothenburg) for careful reading of the manuscript.Peer ReviewedPostprint (author's final draft

Screening for New Biomarkers for Subcortical Vascular Dementia and Alzheimer's Disease

BACKGROUND: Novel biomarkers are important for identifying as well as differentiating subcortical vascular dementia (SVD) and Alzheimer's disease (AD) at an early stage in the disease process. METHODS: In two independent cohorts, a multiplex immunoassay was utilized to analyze 90 proteins in cerebrospinal fluid (CSF) samples from dementia patients and patients at risk of developing dementia (mild cognitive impairment). RESULTS: The levels of several CSF proteins were increased in SVD and its incipient state, and in moderate-to-severe AD compared with the control group. In contrast, some CSF proteins were altered in AD, but not in SVD. The levels of heart-type fatty acid binding protein (H-FABP) were consistently increased in all groups with dementia but only in some of their incipient states. CONCLUSIONS: In summary, these results support the notion that SVD and AD are driven by different pathophysiological mechanisms reflected in the CSF protein profile and that H-FABP in CSF is a general marker of neurodegeneration

Glucocorticoid receptor Thr524 phosphorylation by MINK1 induces interactions with 14-3-3 protein regulators

The glucocorticoid receptor (GR) is a ligand-dependent transcription factor that plays a central role in inflammation. The GR activity is also modulated via protein-protein interactions, including binding of 14-3-3 proteins induced by GR phosphorylation. However, the specific phosphorylation sites on the GR that trigger these interactions and their functional consequences are less clear. Hence, we sought to examine this system in more detail. We used phosphorylated GR peptides, biophysical studies, and X-ray crystallography to identify key residues within the ligand-binding domain of the GR, T524 and S617, whose phosphorylation results in binding of the representative 14-3-3 protein 14-3-3ζ. A kinase screen identified misshapen-like kinase 1 (MINK1) as responsible for phosphorylating T524 and Rho-associated protein kinase 1 for phosphorylating S617; cell-based approaches confirmed the importance of both GR phosphosites and MINK1 but not Rhoassociated protein kinase 1 alone in inducing GR-14-3-3 binding. Together our results provide molecular-level insight into 14-3-3-mediated regulation of the GR and highlight both MINK1 and the GR-14-3-3 axis as potential targets for future therapeutic intervention

Assessment of eutrophication abatement scenarios for the Baltic Sea by multi-model ensemble simulations

Peer reviewe

Assessment of Uncertainties in Scenario Simulations of Biogeochemical Cycles in the Baltic Sea

Following earlier regional assessment studies, such as the Assessment of Climate Change for the Baltic Sea Basin and the North Sea Region Climate Change Assessment, knowledge acquired from available literature about future scenario simulations of biogeochemical cycles in the Baltic Sea and their uncertainties is assessed. The identification and reduction of uncertainties of scenario simulations are issues for marine management. For instance, it is important to know whether nutrient load abatement will meet its objectives of restored water quality status in future climate or whether additional measures are required. However, uncertainties are large and their sources need to be understood to draw conclusions about the effectiveness of measures. The assessment of sources of uncertainties in projections of biogeochemical cycles based on authors' own expert judgment suggests that the biggest uncertainties are caused by (1) unknown current and future bioavailable nutrient loads from land and atmosphere, (2) the experimental setup (including the spin up strategy), (3) differences between the projections of global and regional climate models, in particular, with respect to the global mean sea level rise and regional water cycle, (4) differing model-specific responses of the simulated biogeochemical cycles to long-term changes in external nutrient loads and climate of the Baltic Sea region, and (5) unknown future greenhouse gas emissions. Regular assessments of the models' skill (or quality compared to observations) for the Baltic Sea region and the spread in scenario simulations (differences among projected changes) as well as improvement of dynamical downscaling methods are recommended.Peer reviewe