Cognition after malignant media infarction and decompressive hemicraniectomy - a retrospective observational study

Background  

Decompressive hemicraniectomy is a life-saving procedure for patients with malignant middle cerebral artery infarctions. However, the neuropsychological sequelae in such patients have up to now received little attention. In this study we not only describe neuropsychological deficits but also the quality of life and the extent of depression and other psychiatric symptoms in patients after complete media infarction of the non-speech dominant hemisphere.     

Overview of FEED, the feeding experiments end-user database

The Feeding Experiments End-user Database (FEED) is a research tool developed by the Mammalian Feeding Working Group at the National Evolutionary Synthesis Center that permits synthetic, evolutionary analyses of the physiology of mammalian feeding. The tasks of the Working Group are to compile physiologic data sets into a uniform digital format stored at a central source, develop a standardized terminology for describing and organizing the data, and carry out a set of novel analyses using FEED. FEED contains raw physiologic data linked to extensive metadata. It serves as an archive for a large number of existing data sets and a repository for future data sets. The metadata are stored as text and images that describe experimental protocols, research subjects, and anatomical information. The metadata incorporate controlled vocabularies to allow consistent use of the terms used to describe and organize the physiologic data. The planned analyses address long-standing questions concerning the phylogenetic distribution of phenotypes involving muscle anatomy and feeding physiology among mammals, the presence and nature of motor pattern conservation in the mammalian feeding muscles, and the extent to which suckling constrains the evolution of feeding behavior in adult mammals. We expect FEED to be a growing digital archive that will facilitate new research into understanding the evolution of feeding anatomy.     

Identification and optimization of tetrahydro-2H-3-benzazepin-2-ones as squalene synthase inhibitors

Novel squalene synthase inhibitors are disclosed. SAR and pharmacological profile of selected compounds are discussed.     

Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function

Humans lacking sclerostin display progressive bone overgrowth due to increased bone formation. Although it is well established that sclerostin is an osteocyte-secreted bone formation inhibitor, the underlying molecular mechanisms are not fully elucidated. We identified in tandem affinity purification proteomics screens LRP4 (low density lipoprotein-related protein 4) as a sclerostin interaction partner. Biochemical assays with recombinant proteins confirmed that sclerostin LRP4 interaction is direct. Interestingly, in vitro overexpression and RNAi-mediated knockdown experiments revealed that LRP4 specifically facilitates the previously described inhibitory action of sclerostin on Wnt1/β-catenin signaling. We found the extracellular β-propeller structured domain of LRP4 to be required for this sclerostin facilitator activity. Immunohistochemistry demonstrated that LRP4 protein is present in human and rodent osteoblasts and osteocytes, both presumed target cells of sclerostin action. Silencing of LRP4 by lentivirus-mediated shRNA delivery blocked sclerostin inhibitory action on in vitro bone mineralization. Notably, we identified two mutations in LRP4 (R1170W and W1186S) in patients suffering from bone overgrowth. We found that these mutations impair LRP4 interaction with sclerostin and its concomitant sclerostin facilitator effect. Together these data indicate that the interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone.     

Quality control of Bacillus thuringiensis ssp. israelensis products based on toxin quantification with monoclonal antibodies

Quality control of Bacillus thuringiensis ssp. israelensis (Bti) products is currently based on international toxic units (ITUs). The potency of products is related to the activity of a standard (IPS-82, Institute Pasteur, Paris) assessed in bioassays using Aedes aegypti as a target host. The procedure is time consuming and costly, often producing variable results. The activity of Bti is based on four different insecticidal crystal proteins (ICPs): Cry4Aa, Cry4Ba, Cry11Aa and Cyt1Aa. Monoclonal antibodies were produced using IPS-82 for immunisation and an enzyme-linked immunosorbent assay (ELISA) was developed. Antibodies were selected with specificity against Cry11A and Cyt1A. Cry4 specific antibodies could not distinguish between Cry4A and Cry4B. Within five replicate assessments of the three ICPs (in µg mg^-1 ICP protein), an error between 3 and 8% was recorded, whereas a 14% error was obtained comparing seven samples of the same production batch for ITUs mg^-1. The toxicity against A. aegypti expressed in ITUs correlated well with the results of the ELISA (correlation coefficient r Cyt 1=0.79; Cry 11=0.87; Cry 4=0.91) also when related to the sum of all ICPs (r=0.87). The ELISA can reduce efforts to determine Bti quality compared with the labour-intensive and variable ITU bioassay.     

Novel heterocyclic thyromimetics. Part 2

Novel heterocyclic thyromimetics are presented carrying carboxy-substituted benzofurans or sulfur containing heterocycles, as replacements for the amino acid side chain of T3. Potent agonists were identified in both series. SAR trends are examined and found to be mostly consistent with previously published thyromimetics. The lack of isoform selectivity demonstrated with isoform-selective transient THR transfection assays has been confirmed by corresponding in vivo studies.