Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure

Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent behavior follows from the binding of the bivalent ligands to dimeric receptors based on a TMH1-TMH2 interface. Moreover, in this arrangement, only the analogues with a well-defined spacer length (∼25 Å) precisely fit inside a channel-like passage between the two protomers of the dimer. The newly discovered oxytocin bivalent ligands represent a powerful tool for targeting dimeric OTR in neurodevelopmental and psychiatric disorders and, in general, provide a framework to untangle specific arrangements of G-protein coupled receptor dimers

Communication Biophysics

Contains reports on five research projects.National Institutes of Health (Grant 5 RO1 NB-05462-02)National Aeronautics and Space Administration (Grant NsG-496)National Science Foundation (Grant GP-2495)National Institutes of Health (Grant MH-04737-05

Cross-Frequency Integration for Consonant and Vowel Identification in Bimodal Hearing

Purpose: Improved speech recognition in binaurally combined acoustic–electric stimulation (otherwise known as bimodal hearing) could arise when listeners integrate speech cues from the acoustic and electric hearing. The aims of this study were (a) to identify speech cues extracted in electric hearing and residual acoustic hearing in the low-frequency region and (b) to investigate cochlear implant (CI) users' ability to integrate speech cues across frequencies. Method: Normal-hearing (NH) and CI subjects participated in consonant and vowel identification tasks. Each subject was tested in 3 listening conditions: CI alone (vocoder speech for NH), hearing aid (HA) alone (low-pass filtered speech for NH), and both. Integration ability for each subject was evaluated using a model of optimal integration—the PreLabeling integration model (Braida, 1991). Results: Only a few CI listeners demonstrated bimodal benefit for phoneme identification in quiet. Speech cues extracted from the CI and the HA were highly redundant for consonants but were complementary for vowels. CI listeners also exhibited reduced integration ability for both consonant and vowel identification compared with their NH counterparts. Conclusion: These findings suggest that reduced bimodal benefits in CI listeners are due to insufficient complementary speech cues across ears, a decrease in integration ability, or both.National Organization for Hearing ResearchNational Institute on Deafness and Other Communication Disorders (U.S.) (Grant R03 DC009684-01)National Institute on Deafness and Other Communication Disorders (U.S.) (Grant R01 DC007152-02

Padronização de métodos para análise granulométrica no Brasil.

bitstream/item/96926/1/ComTec-66-Analise-Granulometrica.pd

Communications Biophysics

Contains research objectives and summary of research.National Institutes of Health (Grant 5 PO1 GM14940-07)National Institutes of Health (Grant 1 RO1 NS11000-01)Clarence J. LeBel FundNational Institutes of Health (Grant 1 RO1 NS10737-01)National Aeronautics and Space Administration (Grant NGL 22-009-304)Boston City Hospital Purchase Order 1176-21335B-D Electrodyne Division, Becton Dickinson and Company (Grant)Chicago Musical Instrument Company (Grant

Late Holocene sedimentation in coastal areas of the northwestern Ross Sea (Antarctica).

Sediment cores and box cores collected in two coastal areas of the northwestern Ross Sea (Antarctica) highlight the possibility of studying the Late Holocene period in detail. In this work we propose a study on two box cores and two gravity cores collected in the Cape Hallett and Wood Bay areas during the 2005 PNRA oceanographic cruise. The two sites are feed by Eastern Antarctic Ice Shelf (EAIS) and previous studies have highlighted a complex postglacial sedimentary sequence, also influenced by local morphology. This study is performed within the framework of the PNRA-ESF PolarCLIMATE HOLOCLIP (Holocene climate variability at high-southern latitudes: an integrated perspective) Project. The data set includes: magnetic susceptibility, X-ray analyses, 210Pb, 14C dating, diatoms and foraminifera assemblages, organic carbon, and grain-size analyses. Furthermore XRF core scanner analyses, colour analysis from digital images, and major, minor and trace element concentration analyses (ICP-AES) are performed. Data show that the box core and upper core sediments represent a very recent sedimentation in which it is possible to observe the parameter variability probably linked to climate variability/changes: these variation will be compared with isotopic record form ice cores collected form the same Antarctic sector

Communications Biophysics

Contains research objectives, summary of research and reports on two research project.National Institutes of Health (Grant 5 PO1 GM14940-03)National Institutes of Health (Grant 5 TO1 GM01555-03)National Aeronautics and Space Administration (Grant NGL 22-009-304

LSD1 modulates stress-evoked transcription of immediate early genes and emotional behavior

Behavioral changes in response to stressful stimuli can be controlled via adaptive epigenetic changes in neuronal gene expression. Here we indicate a role for the transcriptional corepressor Lysine-Specific Demethylase 1 (LSD1) and its dominant-negative splicing isoform neuroLSD1, in the modulation of emotional behavior. In mouse hippocampus, we show that LSD1 and neuroLSD1 can interact with transcription factor serum response factor (SRF) and set the chromatin state of SRF-targeted genes early growth response 1 (egr1) and c-fos. Deletion or reduction of neuroLSD1 in mutant mice translates into decreased levels of activating histone marks at egr1 and c-fos promoters, dampening their psychosocial stress-induced transcription and resulting in low anxiety-like behavior. Administration of suberoylanilide hydroxamine to neuroLSD1(KO) mice reactivates egr1 and c-fos transcription and restores the behavioral phenotype. These findings indicate that LSD1 is a molecular transducer of stressful stimuli as well as a stress-response modifier. Indeed, LSD1 expression itself is increased acutely at both the transcriptional and splicing levels by psychosocial stress, suggesting that LSD1 is involved in the adaptive response to stress

Violent behavior of patients living in psychiatric residential facilities: A comparison of male patients with different violence histories

People with severe mental disorders and a history of violence are often seen as a difficult-to-manage segment of the population. In addition, this group is usually characterized by a high risk of crime recidivism, and poor compliance with community and aftercare programs. To investigate a sample of male patients living in Residential Facilities (RFs) with a history of violent behavior against people and to compare their characteristics with those of never-violent residents; to analyze the associations between aggressive behaviors in the last two years and a history of previous violence; and, to assess the predictors of aggressive behaviors. This study is part of a prospective observational cohort study which involved 23 RFs in Northern Italy. A comprehensive set of sociodemographic, clinical, and treatment-related information was gathered, and standardized assessments were administered to each participant. Also a detailed assessment of aggressive behaviors in the past two years was carried out. The study involved 268 males: 81 violent and 187 never-violent. Compared to never-violent patients, violent patients were younger, with a higher proportion of personality disorders, and have displayed an increased number of aggressive behaviors in the last two years. The presence of a history of violent behavior in the past significantly increases the probability of committing aggressive acts in the future

The effect of service satisfaction and spiritual well-being on the quality of life of patients with schizophrenia.

Quality of life (QOL) has been considered an important outcome measure in psychiatric research and determinants of QOL have been widely investigated. We aimed at detecting predictors of QOL at baseline and at testing the longitudinal interrelations of the baseline predictors with QOL scores at a 1-year follow-up in a sample of patients living in Residential Facilities (RFs). Logistic regression models were adopted to evaluate the association between WHOQoL-Bref scores and potential determinants of QOL. In addition, all variables significantly associated with QOL domains in the final logistic regression model were included by using the Structural Equation Modeling (SEM). We included 139 patients with a diagnosis of schizophrenia spectrum. In the final logistic regression model level of activity, social support, age, service satisfaction, spiritual well-being and symptoms' severity were identified as predictors of QOL scores at baseline. Longitudinal analyses carried out by SEM showed that 40% of QOL follow-up variability was explained by QOL at baseline, and significant indirect effects toward QOL at follow-up were found for satisfaction with services and for social support. Rehabilitation plans for people with schizophrenia living in RFs should also consider mediators of change in subjective QOL such as satisfaction with mental health services