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1.  Sex Differences in Treatment Quality of Self-Managed Oral Anticoagulant Therapy: 6,900 Patient-Years of Follow-Up 
PLoS ONE  2014;9(11):e113627.
Patient-self-management (PSM) of oral anticoagulant therapy with vitamin K antagonists has demonstrated efficacy in randomized, controlled trials. However, the effectiveness and efficacy of PSM in clinical practice and whether outcomes are different for females and males has been sparsely investigated.The objective is to evaluate the sex-dependent effectiveness of PSM of oral anticoagulant therapy in everyday clinical practice.
All patients performing PSM affiliated to Aarhus University Hospital and Aalborg University Hospital, Denmark in the period 1996–2012 were included in a case-series study. The effectiveness was estimated using the following parameters: stroke, systemic embolism, major bleeding, intracranial bleeding, gastrointestinal bleeding, death and time spent in the therapeutic international normalized ratio (INR) target range. Prospectively registered patient data were obtained from two databases in the two hospitals. Cross-linkage between the databases and national registries provided detailed information on the incidence of death, bleeding and thromboembolism on an individual level.
A total of 2068 patients were included, representing 6,900 patient-years in total. Males achieved a significantly better therapeutic INR control than females; females spent 71.1% of the time within therapeutic INR target range, whereas males spent 76.4% (p<0.0001). Importantly, death, bleeding and thromboembolism were not significantly different between females and males.
Among patients treated with self-managed oral anticoagulant therapy, males achieve a higher effectiveness than females in terms of time spent in therapeutic INR range, but the incidence of major complications is low and similar in both sexes.
PMCID: PMC4240606  PMID: 25415603
2.  Adsorption of α-Synuclein to Supported Lipid Bilayers: Positioning and Role of Electrostatics 
ACS Chemical Neuroscience  2013;4(10):1339-1351.
An amyloid form of the protein α-synuclein is the major component of the intraneuronal inclusions called Lewy bodies, which are the neuropathological hallmark of Parkinson’s disease (PD). α-Synuclein is known to associate with anionic lipid membranes, and interactions between aggregating α-synuclein and cellular membranes are thought to be important for PD pathology. We have studied the molecular determinants for adsorption of monomeric α-synuclein to planar model lipid membranes composed of zwitterionic phosphatidylcholine alone or in a mixture with anionic phosphatidylserine (relevant for plasma membranes) or anionic cardiolipin (relevant for mitochondrial membranes). We studied the adsorption of the protein to supported bilayers, the position of the protein within and outside the bilayer, and structural changes in the model membranes using two complementary techniques—quartz crystal microbalance with dissipation monitoring, and neutron reflectometry. We found that the interaction and adsorbed conformation depend on membrane charge, protein charge, and electrostatic screening. The results imply that α-synuclein adsorbs in the headgroup region of anionic lipid bilayers with extensions into the bulk but does not penetrate deeply into or across the hydrophobic acyl chain region. The adsorption to anionic bilayers leads to a small perturbation of the acyl chain packing that is independent of anionic headgroup identity. We also explored the effect of changing the area per headgroup in the lipid bilayer by comparing model systems with different degrees of acyl chain saturation. An increase in area per lipid headgroup leads to an increase in the level of α-synuclein adsorption with a reduced water content in the acyl chain layer. In conclusion, the association of α-synuclein to membranes and its adsorbed conformation are of electrostatic origin, combined with van der Waals interactions, but with a very weak correlation to the molecular structure of the anionic lipid headgroup. The perturbation of the acyl chain packing upon monomeric protein adsorption favors association with unsaturated phospholipids preferentially found in the neuronal membrane.
PMCID: PMC3798988  PMID: 23823878
Parkinson; Lewy body; bilayer; α-synuclein; amyloidosis; neutron diffraction; perdeuterated protein
3.  Phylogenetic structure and evolution of regulatory genes and integrases of P2-like phages 
Bacteriophage  2011;1(4):207-218.
The phylogenetic relationships and structural similarities of the proteins encoded within the regulatory region (containing the integrase gene and the lytic–lysogenic transcriptional switch genes) of P2-like phages were analyzed, and compared with the phylogenetic relationship of P2-like phages inferred from four structural genes. P2-like phages are thought to be one of the most genetically homogenous phage groups but the regulatory region nevertheless varies extensively between different phage genomes.
The analyses showed that there are many types of regulatory regions, but two types can be clearly distinguished; regions similar either to the phage P2 or to the phage 186 regulatory regions. These regions were also found to be most frequent among the sequenced P2-like phage or prophage genomes, and common in phages using Escherichia coli as a host. Both the phylogenetic and the structural analyses showed that these two regions are related. The integrases as well as the cox/apl genes show a common monophyletic origin but the immunity repressor genes, the type P2 C gene and the type 186 cI gene, are likely of different origin. There was no indication of recombination between the P2–186 types of regulatory genes but the comparison of the phylogenies of the regulatory region with the phylogeny based on four structural genes revealed recombinational events between the regulatory region and the structural genes.
Less common regulatory regions were phylogenetically heterogeneous and typically contained a fusion of genes from distantly related or unknown phages and P2-like genes.
PMCID: PMC3448106  PMID: 23050214
gamma-proteobacteria; lytic-lysogenic transcriptional switch; P2-like bacteriophages; peduovirinae; phage integration; phylogenetic analysis
4.  Crystal structure of the P2 C-repressor: a binder of non-palindromic direct DNA repeats 
Nucleic Acids Research  2010;38(21):7778-7790.
As opposed to the vast majority of prokaryotic repressors, the immunity repressor of temperate Escherichia coli phage P2 (C) recognizes non-palindromic direct repeats of DNA rather than inverted repeats. We have determined the crystal structure of P2 C at 1.8 Å. This constitutes the first structure solved from the family of C proteins from P2-like bacteriophages. The structure reveals that the P2 C protein forms a symmetric dimer oriented to bind the major groove of two consecutive turns of the DNA. Surprisingly, P2 C has great similarities to binders of palindromic sequences. Nevertheless, the two identical DNA-binding helixes of the symmetric P2 C dimer have to bind different DNA sequences. Helix 3 is identified as the DNA-recognition motif in P2 C by alanine scanning and the importance for the individual residues in DNA recognition is defined. A truncation mutant shows that the disordered C-terminus is dispensable for repressor function. The short distance between the DNA-binding helices together with a possible interaction between two P2 C dimers are proposed to be responsible for extensive bending of the DNA. The structure provides insight into the mechanisms behind the mutants of P2 C causing dimer disruption, temperature sensitivity and insensitivity to the P4 antirepressor.
PMCID: PMC2995052  PMID: 20639540

Results 1-4 (4)