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Adult anorexia nervosa (AN) often is persistent, significantly erodes quality of life for both the patient and loved ones, and carries high medical and psychiatric comorbidity. Whereas individual psychotherapy for adult AN leads to improvement in some patients, recent findings indicate that the magnitude of improvement is limited: Only a small percentage of individuals fully recover and dropout rates are high. Thus, it is important to build upon current interventions to improve treatment response. We present results from an open trial of a couple-based intervention for adult anorexia nervosa as an adjunct treatment to standard multidisciplinary care. Twenty couples received treatment over approximately 26 weeks, including a couple-based intervention, individual CBT sessions, psychiatry visits for medication management, and nutritional counseling sessions. The results indicate that patients improved at posttest and 3-month follow-up on a variety of AN-related measures, anxiety and depression, and relationship adjustment. Partners also improved on anxiety, depression, and relationship adjustment. In an exploratory analysis, the multicomponent couple treatment intervention was benchmarked to well-conducted randomized controlled trials of individual therapy for AN; the couple intervention seems to compare favorably on AN-related measures and was associated with a lower dropout rate. In spite of methodological limitations, the findings suggest that including partners in the treatment of adult AN holds potential for bolstering treatment outcomes.

This work investigates the mechanisms of binding of T cell receptors (TCRs) to Class I MHC-peptide complexes (pMHC). The structure of a TCR specific for the Melan-A tumour antigen bound to its cognate pMHC was solved to a resolution of 2.5 Å which gives insight into how this TCR could be mutated to optimize binding and subsequently used as a cancer vaccine. Detailed sequence and geometric analyses of all currently available structures of Class I TCR-pMHC complexes revealed that TCRs can bind to pMHC with a range of orientations, yet always focus on the central portion of the peptide and use a specific subset of six residues on the MHC helices for binding. The most striking finding was the use of aromatic residues in the TCR CDR loops to bind to residue Q155 on the MHC α2 helix. Attempts were also made to express and purify Toll-like receptors (TLRs) with the aim of solving one or more of these structures. However, despite testing of over 50 different constructs from 12 different TLRs or associated proteins, insufficient soluble protein expression was obtained for crystallization trials. Finally, a protein disorder prediction tool was developed to aid construct design for structural biology studies and improve the chances of obtaining protein crystals. This tool is based on a novel type of neural network and blind tests comparing it to 8 other disorder prediction tools showed it is one of the best in the field. It is freely available at www.strubi.ox.ac.uk/RONN. Analysis of large datasets revealed that the position of order/disorder transitions is quite precisely defined in amino-acid sequences and that transition regions have an amino acid composition distinct from that of bulk ordered and disordered sequences. There is a steady decrease in order-promoting residues on the ordered side of boundaries as well as a weak sequence signal, both of which signify the approaching disorder and may prove useful for improving existing disorder prediction tools.

Biological processes are commonly controlled by precise protein-protein interactions. These connections rely on specific amino acids at the binding interfaces. Here we predict the binding residues of such interprotein complexes. We have developed a suite of methods, i-Patch, which predict the interprotein contact sites by considering the two proteins as a network, with residues as nodes and contacts as edges. i-Patch starts with two proteins, A and B, which are assumed to interact, but for which the structure of the complex is not available. However, we assume that for each protein, we have a reference structure and a multiple sequence alignment of homologues. i-Patch then uses the propensities of patches of residues to interact, to predict interprotein contact sites. i-Patch outperforms several other tested algorithms for prediction of interprotein contact sites. It gives 59% precision with 20% recall on a blind test set of 31 protein pairs. Combining the i-Patch scores with an existing correlated mutation algorithm, McBASC, using a logistic model gave little improvement. Results from a case study, on bacterial chemotaxis protein complexes, demonstrate that our predictions can identify contact residues, as well as suggesting unknown interfaces in multiprotein complexes.

Bij grote organisaties komt het nogal eens voor dat de IT-afdeling langzaam losbreekt van het overkoepelende bouwwerk. De techneuten verschansen zich in hun bastion en verliezen het verband met de bedrijfsprocessen. Kunnen we bruggen bouwen om zo'n vervallen structuur weer te restaureren? Binnen en buiten het onderwijs zijn er verschillende ideeën over de bijdrage die architectuur kan leveren aan alignment.

The invention provides a method for the production of a flour-based food product comprising a tastant. The food product according to the invention has a tastant bulk weight percentage and an inhomogeneous tastant bulk distribution. The invention provides the use of an inhomogeneous tastant bulk distribution in a food product for providing a food product with a reduced tastant bulk weight percentage. Further, the invention provides the use of an inhomogeneous tastant bulk distribution in a food product for enhancing and/or improving the sensory perception of the tastant in a food product.

Neural cell adhesion molecule (NCAM) is a membrane-bound cell recognition molecule that exerts important functions in normal neurodevelopment including cell migration, neurite outgrowth, axon fasciculation, and synaptic plasticity. Alternative splicing of NCAM mRNA generates three main protein isoforms: NCAM-180, -140, and -120. Ectodomain shedding of NCAM isoforms can produce an extracellular 105–115 kDa soluble NCAM fragment (NCAM-EC) and a smaller intracellular cytoplasmic fragment (NCAM-IC). NCAM also undergoes a unique post-translational modification in brain by the addition of polysialic acid (PSA)-NCAM. Interestingly, both PSA-NCAM and NCAM-EC have been implicated in the pathophysiology of schizophrenia. The developmental expression patterns of the main NCAM isoforms and PSA-NCAM have been described in rodent brain, but no studies have examined NCAM expression across human cortical development. Western blotting was used to quantify NCAM in human postmortem prefrontal cortex in 42 individuals ranging in age from mid-gestation to early adulthood. Each NCAM isoform (NCAM-180, -140, and -120), post-translational modification (PSA-NCAM) and cleavage fragment (NCAM-EC and NCAM-IC) demonstrated developmental regulation in frontal cortex. NCAM-180, -140, and -120, as well as PSA-NCAM, and NCAM-IC all showed strong developmental regulation during fetal and early postnatal ages, consistent with their identified roles in axon growth and plasticity. NCAM-EC demonstrated a more gradual increase from the early postnatal period to reach a plateau by early adolescence, potentially implicating involvement in later developmental processes. In summary, this study implicates the major NCAM isoforms, PSA- NCAM and proteolytically cleaved NCAM in pre- and postnatal development of the human prefrontal cortex. These data provide new insights on human cortical development and also provide a basis for how altered NCAM signaling during specific developmental intervals could affect synaptic connectivity and circuit formation, and thereby contribute to neurodevelopmental disorders.

Previous studies of postnatal synaptic development in human frontal cortex have shown that synaptic density rises after birth, reaches a plateau in childhood and then decreases to adult levels by late adolescence. A similar pattern has been seen in nonhuman primate cortex. These earlier studies in human cortex are limited, however, by significant age gaps in study subjects at critical inflection points of the developmental curve. Additionally, it is unclear if synaptic development occurs in different patterns in different cortical layers in prefrontal cortex (PFC). The purpose of this study was to examine synaptic density in human PFC across development by measuring two synaptic marker proteins: synaptophysin (presynaptic), and postsynaptic density-95 (PSD-95; postsynaptic). Western blotting was used to assess the relative levels of synaptophysin and PSD-95 in dorsolateral PFC of 42 subjects, distributed in age from 18 weeks gestation to 25 years. In addition, synaptophysin immunoreactivity was examined in each layer of areas 9 and 46 of PFC in 24 subjects, ranging in age from 0.1 to 25 years. Synaptophysin levels slowly increased from birth until age 5 and then increased more rapidly to peak in late childhood around age 10. Synaptophysin subsequently decreased until the adult level was reached by mid-adolescence, around age 16. PSD-95 levels increased postnatally to reach a stable plateau by early childhood with a slight reduction in late adolescence and early adulthood. The pattern of synaptophysin immunoreactivity seen with immunohistochemistry was similar to the Western experiments but the changes across age were more subtle, with little change by layer within and across age. The developmental patterns exhibited by these synaptic marker proteins expand upon previous studies of developmental synaptic changes in human frontal cortex; synaptic density increases steadily from birth to late childhood, then decreases in early adolescence to reach adult levels by late adolescence.

Although there has been recent interest in the study of childhood and adolescent brain development, very little is known about normal brain development in the first few months of life. In older children, there are regional differences in cortical gray matter development, whereas cortical gray and white matter growth after birth has not been studied to a great extent. The adult human brain is also characterized by cerebral asymmetries and sexual dimorphisms, although very little is known about how these asymmetries and dimorphisms develop. We used magnetic resonance imaging and an automatic segmentation methodology to study brain structure in 74 neonates in the first few weeks after birth. We found robust cortical gray matter growth compared with white matter growth, with occipital regions growing much faster than prefrontal regions. Sexual dimorphism is present at birth, with males having larger total brain cortical gray and white matter volumes than females. In contrast to adults and older children, the left hemisphere is larger than the right hemisphere, and the normal pattern of fronto-occipital asymmetry described in older children and adults is not present. Regional differences in cortical gray matter growth are likely related to differential maturation of sensory and motor systems compared with prefrontal executive function after birth. These findings also indicate that whereas some adult patterns of sexual dimorphism and cerebral asymmetries are present at birth, others develop after birth.

The structure of the central repetitive domain of high molecular weight HMW) wheat gluten proteins was characterized in solution and in the dry state using HMW proteins Bx6 and Bx7 and a subcloned, bacterially expressed part of the repetitive domain of HMW Dx5. Model studies of the HMW consensus peptides PGQGQQ and GYYPTSPQQ formed the basis for the data analysis (van Dijk AA et al., 1997, Protein Sci 6:637-648). In solution, the repetitive domain contained a continuous nonoverlapping series of both type I and type II II beta-turns at positions predicted from the model studies; type II beta-turns occurred at QPGQ and QQGY sequences and type I beta-turns at YPTS and SPQQ. The subcloned part of the HMW Dx5 repetitive domain sometimes migrated as two bands on SDS-PAGE; we present evidence that this may be caused by a single amino acid insertion that disturbs the regular structure of beta-turns. The type I beta-turns are lost when the protein is dried on a solid surface, probably by conversion to type II beta-turns. The homogeneous type II beta-turn distribution is compatible with the formation of a beta-spiral structure, which provides the protein with elastic properties. The beta-turns and thus the beta-spiral are stabilized by hydrogen bonds within and between turns. Reformation of this hydrogen bonding network after, e.g., mechanical disruption may be important for the elastic properties of gluten proteins.