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The crystal structure of the tryptic core fragment of the lac repressor of Escherichia coli (LacR) complexed with the inducer isopropyl-β-D-thiogalactoside was determined at 2.6 $\\AA$ resolution. The quaternary structure consists of two dyad-symmetric dimers that are nearly parallel to each other. This structure places all four DNA binding domains of intact LacR on the same side of the tetramer, and results in a deep, V-shaped cleft between the two dimers. Each monomer contributes a carboxyl-terminal helix to an antiparallel four-helix bundle that functions as a tetramerization domain. Some of the side chains whose mutation reduce DNA binding form clusters on a surface near the amino terminus. Placing the structure of the DNA binding domain complexed with operator previously determined by nuclear magnetic resonance onto this surface results in two operators being adjacent and nearly parallel to each other. Structural considerations suggest that the two dimers of LacR may flexibly alter their relative orientation in order to bind to the known varied spacings between two operators.

New treatments for HCV (Hepatitis C virus) infections are likely to arise from inhibition of the essential, virally-encoded enzymes. These targets include the serine protease required for processing of the HCV polyprotein. The protease constitutes one functional domain of the bifunctional HCV NS3 (non-structural protein 3). Here, insights regarding the NS3 structure and recently synthesized NS3 inhibitors are reviewed. Interestingly, many NS3 protease inhibitors have taken advantage of an unusual product inhibition by Nterminal products of cleavage at the polyprotein processing sites.

Background Whether and how psychotherapies change brain structure and function is unknown. Its study is of great importance for contemporary psychotherapy, as it may lead to discovery of neurobiological mechanisms that predict and mediate lasting changes in psychotherapy, particularly in severely mentally ill patients, such as those with chronic depression. Previous studies have shown that psychoanalytic psychotherapies produce robust and enduring improvements in not only symptom severity but also personality organization in patients who have chronic depression and early life trauma, especially if therapy is delivered at a high weekly frequency. Methods/design Patients with chronic major depression and a history of early life trauma will be recruited, assessed, and treated across 3 international sites: Germany, Switzerland, and the United States. They will be randomized to one of two treatment arms: either (1) once weekly psychoanalytic psychotherapies, or (2) 3–4 times weekly psychoanalytic psychotherapies. They will have full clinical characterization as well as undergo MRI scanning at study baseline prior to randomization and again one year later. A group of matched healthy controls will undergo similar assessments and MRI scanning at the same time points to help discern whether study treatments induce brain changes toward or away from normal values. Primary study outcomes will include anatomical MRI, functional MRI, and Diffusion Tensor Imaging measures. Study hypotheses will be tested using the treatment-by-time interaction assessed in multiple general linear models with repeated measures analyses in an intent-to-treat analysis. Discussion MODE may allow the identification of brain-based biomarkers that may be more sensitive than traditional behavioral and clinical measures in discriminating, predicting, and mediating treatment response. These findings could help to personalize care for patients who have chronic depression patients and early life trauma , and they will provide new therapeutic targets for both psychological and biological treatments for major depressive illness.

The potential use of monoclonal antibodies in immunological, chemical and clinical applications has stimulated the protein engineering and expression of Fv fragments, which are heterodimers consisting of the light and heavy chain variable domains (VL and VH) of antibodies. Although Fv fragments exhibit antigen binding specificity and association constants similar to their parent antibodies or Fab moieties, similarity in their interactions with antigen at the level of three-dimensional structure has not been investigated. We have determined the high-resolution crystal structure of the genetically engineered FvD1.3 fragment of the anti-hen egg-white lysozyme (HEL) monoclonal antibody D1.3, and of its complex with HEL. On comparison with the crystallographically refined FabD1.3-HEL complex, we find that FvD1.3 and FabD1.3 make, with minor exceptions, very similar contacts with the antigen. Furthermore, a small but systematic rearrangement of the domains of FvD1.3 occurs on binding HEL, bringing the contacting residues closer to the antigen by a mean value of about 0.7 A for VH (aligning on VL) or of 0.5 A for VL (aligning on VH). This is indicative of an induced fit rather than a 'lock and key' fit to the antigen.

THE potential use of monoclonal antibodies in immunological, chemical and clinical applications has stimulated the protein engineering and expression of Fv fragments 1–8 , which are heterodimers consisting of the light and heavy chain variable domains (VL and VH) of antibodies. Although Fv fragments exhibit antigen binding specificity and association constants similar to their parent antibodies or Fab moieties, similarity in their interactions with antigen at the level of three-dimensional structure has not been investigated. We have determined the high-resolution crystal structure of the genetically engineered FvD1.3 fragment 1 of the anti-hen egg-white lysozyme (HEL) monoclonal antibody D1.3 (ref. 9), and of its complex with HEL. On comparison with the crystallographically refined FabD1.3-HEL complex, we find that FvD1.3 and FabD1.3 make, with minor exceptions, very similar contacts with the antigen. Furthermore, a small but systematic rearrangement of the domains of FvD1.3 occurs on binding HEL, bringing the contacting residues closer to the antigen by a mean value of about 0.7 Å for VH (aligning on VL) or of 0.5 Å for VL (aligning on VH). This is indicative of an induced fit rather than a 'lock and key' fit to the antigen.

Crystal structures of human endothelial nitric oxide synthase (eNOS) and human inducible NOS (iNOS) catalytic domains were solved in complex with the arginine substrate and an inhibitor S -ethylisothiourea (SEITU), respectively. The small molecules bind in a narrow cleft within the larger active-site cavity containing heme and tetrahydrobiopterin. Both are hydrogen-bonded to a conserved glutamate (eNOS E361, iNOS E377). The active-site residues of iNOS and eNOS are nearly identical. Nevertheless, structural comparisons provide a basis for design of isozyme-selective inhibitors. The high-resolution, refined structures of eNOS (2.4 Å resolution) and iNOS (2.25 Å resolution) reveal an unexpected structural zinc situated at the intermolecular interface and coordinated by four cysteines, two from each monomer.

Background While early programs to prevent aggression and violence are widely used, only a few controlled trials of effectiveness of psychoanalytically based prevention programs for preschoolers have been evaluated. This study compares ‘Faustlos’ (a violence prevention program) and ‘Early Steps’ (a psychoanalytically based, whole daycare center intervention to prevent violence) in daycare centers in socioeconomically deprived neighborhoods. Methods/Design Preschoolers in 14 daycare centers in Frankfurt, Germany, participate in a cluster randomized controlled trial (CRCT). The daycare centers were randomly chosen from a representative baseline survey of all Frankfurt’s daycare centers carried out in 2003 ( n = 5,300) with the following stratifying factors: children’s aggressiveness, hyperactivity, anxiety and socioeconomic status. Additionally, the geographic identification of socioeconomically deprived neighborhoods regarding low-income children was taken from the Frankfurt Municipality Statistics. Children’s attachment classification and children’s aggressiveness, hyperactivity, anxiety and social competence are measured as outcome criteria before and after 2 years of intervention. The programs in the study aim to reach a high-risk population. Therefore, the combination of a random sampling of daycare centers out of a representative baseline survey in all daycare centers in Frankfurt and the application of official data on the local distribution of low-income children are unique features offered by the EVA study design. Data on preschooler’s attachment representations are collected in socioeconomically deprived neighborhoods for the first time. Trial registration DRKS-ID: DRKS00003500

By using X-ray diffraction and immunochemical techniques, we have exploited the use of monoclonal antibodies raised against hen egg lysozyme (HEL) to study systematically those factors responsible for the high specificity of antigen-antibody interactions. HEL was chosen for our investigations because its three-dimensional structure and immunochemistry have been well characterized and because naturally occurring sequence variants from different avian species are readily available to test the fine specificity of the antibodies. The X-ray crystal structure of a complex formed between HEL and the Fab D1.3 shows a large complementary surface with close interatomic contacts between antigen and antibody. Thus single amino acid sequence changes in heterologous antigens give antigen-antibody association constants that are several orders of magnitude smaller than that of the homologous antigen. For example, a substitution of His for Glu at position 121 in the antigen is sufficient to diminish significantly the binding between D1.3 and the variant lysozyme. The conformation of HEL when complexed to D1.3 shows no significant difference from that seen in the free molecule, and immunobinding studies with other anti-HEL antibodies suggest that this observation may be generally true for the system of monoclonal antibodies that we have studied.

Book synopsis: This book looks at dreams from a twenty-first century perspective. It takes its inspiration from Freud’s insights, but pursues psychoanalytic interest into both neuroscience and the modern psychoanalytic consulting room. The book looks at laboratory research on dreaming alongside the modern clinical use of dreams and links together clinical and empirical research, integrating classical ideas with the plurality of psychoanalytic theoretical constructs available to modern researchers. Psychoanalysts writing about dreams have traditionally represented the cutting edge of clinical and theoretical development, and this book is no exception. Many of the contributions, as well as the epistemological position taken by the writers, represent a kind of radical openness to new ways of thinking about the clinical situation and about theory. In line with the ambition of the editors, this volume represents an integration of theories and disciplines, and a scientific context for modern psychoanalysis. The link between clinical research and extraclinical research via the royal road of dreaming is a theme that runs through all the contributions. These cover dreaming as it sheds light on clinical conditions such as depression and trauma, or dreams as they form a core aspect of clinical work; be that as a co-construction, or as shared play between therapist and patients. The book provides insight through dreams to understanding mental functions in all clinical situations and across all conditions.