Effect of an advocacy intervention on mental health in Chinese women survivors of intimate partner violence: A randomized controlled trial

Context: Intimate partner violence (IPV) against women can have negative mental health consequences for survivors; however, the effect of interventions designed to improve survivors' depressive symptoms is unclear. Objective: To determine whether an advocacy intervention would improve the depressive symptoms of Chinese women survivors of IPV. Design, Setting, and Participants: Assessor-blinded randomized controlled trial of 200 Chinese women 18 years or older with a history of IPV, conducted from February 2007 to June 2009 in a community center in Hong Kong, China. Intervention: The intervention group (n=100) received a 12-week advocacy intervention comprising empowerment and telephone social support. The control group (n=100) received usual community services including child care, health care and promotion, and recreational programs. Main Outcome Measures: Primary outcome was change in depressive symptoms (Chinese version of the Beck Depression Inventory II) between baseline and 9 months. Secondary outcomes were changes in IPV (Chinese Revised Conflict Tactics Scales), health-related quality of life (12-Item Short Form Health Survey), and perceived social support (Interpersonal Support Evaluation List) between baseline and 9 months. Usefulness of the intervention and usual community services was evaluated at 9 months. Results: At 3 months, themeanchange in depressive symptom score was 11.6(95%CI, 9.5 to 13.7) in the control group and 14.9(95%CI, 12.4 to 17.5) in the intervention group; respective changes at 9 months were 19.6 (95% CI, 16.6 to 22.7) and 23.2 (95% CI, 20.4 to 26.0). Intervention effects at 3 and 9 months were not significantly different (P=.86). The intervention significantly reduced depressive symptoms by 2.66(95%CI, 0.26 to 5.06; P=.03) vs the control, less than the 5-unit minimal clinically important difference. Statistically significant improvement was found in partner psychological aggression (-1.87[95% CI, -3.34 to -0.40]; mean change at 3 months, 1.5 [95% CI, -1.0 to 3.9] in the control group and 0.3 [95% CI, -0.7 to 1.4] in the intervention group; mean change at 9 months, -6.4 [95% CI, -7.8 to -5.0] and -8.9 [95% CI, -10.6 to -7.2]) and perceived social support (2.18[95%CI, 0.48 to 3.89]; meanchange at 3 months, 6.4[95%CI, 4.9 to 7.8] and 9.2 [95% CI, 7.7 to 10.8]; mean change at 9 months, 12.4 [95% CI, 10.5 to 14.3] and 14.4 [95% CI, 12.7 to 16.1]) but not in physical assault, sexual coercion, or health-related quality of life. By end of study, more women in the intervention group found the advocacy intervention useful or extremely useful in improving intimate relationships vs those in the control group receiving usual community services (93.8%vs81.7%;difference,12.1% [95% CI, 2.1% to 22.0%]; P=.02) and in helping them to resolve conflicts with their intimate partners (97.5% vs 84.1%; difference,13.4%[95%CI,4.7%to 22.0%];P=.001). Conclusion: Among community-dwelling abused Chinese women, an advocacy intervention did not result in a clinically meaningful improvement in depressive symptoms. Trial Registration: clinicaltrials.gov Identifier: NCT01054898. ©2010 American Medical Association. All rights reserved.postprin

Ensemble-Based Computational Approach Discriminates Functional Activity of p53 Cancer and Rescue Mutants

The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (“cancer mutants”). Activity can be restored by second-site suppressor mutations (“rescue mutants”). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 µs of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r2 = 0.77) with reported values of experimentally measured ΔΔG protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants

RNA localization in neurite morphogenesis and synaptic regulation: current evidence and novel approaches

It is now generally accepted that RNA localization in the central nervous system conveys important roles both during development and in the adult brain. Of special interest is protein synthesis located at the synapse, as this potentially confers selective synaptic modification and has been implicated in the establishment of memories. However, the underlying molecular events are largely unknown. In this review, we will first discuss novel findings that highlight the role of RNA localization in neurons. We will focus on the role of RNA localization in neurotrophin signaling, axon outgrowth, dendrite and dendritic spine morphogenesis as well as in synaptic plasticity. Second, we will briefly present recent work on the role of microRNAs in translational control in dendrites and its implications for learning and memory. Finally, we discuss recent approaches to visualize RNAs in living cells and their employment for studying RNA trafficking in neurons

Encoding of Naturalistic Stimuli by Local Field Potential Spectra in Networks of Excitatory and Inhibitory Neurons

Recordings of local field potentials (LFPs) reveal that the sensory cortex displays rhythmic activity and fluctuations over a wide range of frequencies and amplitudes. Yet, the role of this kind of activity in encoding sensory information remains largely unknown. To understand the rules of translation between the structure of sensory stimuli and the fluctuations of cortical responses, we simulated a sparsely connected network of excitatory and inhibitory neurons modeling a local cortical population, and we determined how the LFPs generated by the network encode information about input stimuli. We first considered simple static and periodic stimuli and then naturalistic input stimuli based on electrophysiological recordings from the thalamus of anesthetized monkeys watching natural movie scenes. We found that the simulated network produced stimulus-related LFP changes that were in striking agreement with the LFPs obtained from the primary visual cortex. Moreover, our results demonstrate that the network encoded static input spike rates into gamma-range oscillations generated by inhibitory–excitatory neural interactions and encoded slow dynamic features of the input into slow LFP fluctuations mediated by stimulus–neural interactions. The model cortical network processed dynamic stimuli with naturalistic temporal structure by using low and high response frequencies as independent communication channels, again in agreement with recent reports from visual cortex responses to naturalistic movies. One potential function of this frequency decomposition into independent information channels operated by the cortical network may be that of enhancing the capacity of the cortical column to encode our complex sensory environment

Forward Masking Estimated by Signal Detection Theory Analysis of Neuronal Responses in Primary Auditory Cortex

Psychophysical forward masking is an increase in threshold of detection of a sound (probe) when it is preceded by another sound (masker). This is reminiscent of the reduction in neuronal responses to a sound following prior stimulation. Studies in the auditory nerve and cochlear nucleus using signal detection theory techniques to derive neuronal thresholds showed that in centrally projecting neurons, increases in masked thresholds were significantly smaller than the changes measured psychophysically. Larger threshold shifts have been reported in the inferior colliculus of awake marmoset. The present study investigated the magnitude of forward masking in primary auditory cortical neurons of anaesthetised guinea-pigs. Responses of cortical neurons to unmasked and forward masked tones were measured and probe detection thresholds estimated using signal detection theory methods. Threshold shifts were larger than in the auditory nerve, cochlear nucleus and inferior colliculus. The larger threshold shifts suggest that central, and probably cortical, processes contribute to forward masking. However, although methodological differences make comparisons difficult, the threshold shifts in cortical neurons were, in contrast to subcortical nuclei, actually larger than those observed psychophysically. Masking was largely attributable to a reduction in the responses to the probe, rather than either a persistence of the masker responses or an increase in the variability of probe responses

Identification of tetrahydrocarbazoles as novel multifactorial drug candidates for treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most frequent cause of dementia. To date, there are only a few approved drugs for AD, which show little or no effect on disease progression. Impaired intracellular calcium homeostasis is believed to occur early in the cascade of events leading to AD. Here, we examined the possibility of normalizing the disrupted calcium homeostasis in the endoplasmic reticulum (ER) store as an innovative approach for AD drug discovery. High-throughput screening of a small-molecule compound library led to the identification of tetrahydrocarbazoles, a novel multifactorial class of compounds that can normalize the impaired ER calcium homeostasis. We found that the tetrahydrocarbazole lead structure, first, dampens the enhanced calcium release from ER in HEK293 cells expressing familial Alzheimer's disease (FAD)-linked presenilin 1 mutations. Second, the lead structure also improves mitochondrial function, measured by increased mitochondrial membrane potential. Third, the same lead structure also attenuates the production of amyloid-beta (A beta) peptides by decreasing the cleavage of amyloid precursor protein (APP) by beta-secretase, without notably affecting alpha- and gamma-secretase cleavage activities. Considering the beneficial effects of tetrahydrocarbazoles addressing three key pathological aspects of AD, these compounds hold promise for the development of potentially effective AD drug candidates

p53 Transactivation and the Impact of Mutations, Cofactors and Small Molecules Using a Simplified Yeast-Based Screening System

The p53 tumor suppressor, which is altered in most cancers, is a sequence-specific transcription factor that is able to modulate the expression of many target genes and influence a variety of cellular pathways. Inactivation of the p53 pathway in cancer frequently occurs through the expression of mutant p53 protein. In tumors that retain wild type p53, the pathway can be altered by upstream modulators, particularly the p53 negative regulators MDM2 and MDM4. promoter, ii) single copy, chromosomally located p53-responsive and control luminescence reporters, iii) enhanced chemical uptake using modified ABC-transporters, iv) small-volume formats for treatment and dual-luciferase assays, and v) opportunities to co-express p53 with other cofactor proteins. This robust system can distinguish different levels of expression of WT and mutant p53 as well as interactions with MDM2 or 53BP1.We found that the small molecules Nutlin and RITA could both relieve the MDM2-dependent inhibition of WT p53 transactivation function, while only RITA could impact p53/53BP1 functional interactions. PRIMA-1 was ineffective in modifying the transactivation capacity of WT p53 and missense p53 mutations. This dual-luciferase assay can, therefore, provide a high-throughput assessment tool for investigating a matrix of factors that can influence the p53 network, including the effectiveness of newly developed small molecules, on WT and tumor-associated p53 mutants as well as interacting proteins

Comparable Ages for the Independent Origins of Electrogenesis in African and South American Weakly Electric Fishes

One of the most remarkable examples of convergent evolution among vertebrates is illustrated by the independent origins of an active electric sense in South American and African weakly electric fishes, the Gymnotiformes and Mormyroidea, respectively. These groups independently evolved similar complex systems for object localization and communication via the generation and reception of weak electric fields. While good estimates of divergence times are critical to understanding the temporal context for the evolution and diversification of these two groups, their respective ages have been difficult to estimate due to the absence of an informative fossil record, use of strict molecular clock models in previous studies, and/or incomplete taxonomic sampling. Here, we examine the timing of the origins of the Gymnotiformes and the Mormyroidea using complete mitogenome sequences and a parametric Bayesian method for divergence time reconstruction. Under two different fossil-based calibration methods, we estimated similar ages for the independent origins of the Mormyroidea and Gymnotiformes. Our absolute estimates for the origins of these groups either slightly postdate, or just predate, the final separation of Africa and South America by continental drift. The most recent common ancestor of the Mormyroidea and Gymnotiformes was found to be a non-electrogenic basal teleost living more than 85 millions years earlier. For both electric fish lineages, we also estimated similar intervals (16–19 or 22–26 million years, depending on calibration method) between the appearance of electroreception and the origin of myogenic electric organs, providing rough upper estimates for the time periods during which these complex electric organs evolved de novo from skeletal muscle precursors. The fact that the Gymnotiformes and Mormyroidea are of similar age enhances the comparative value of the weakly electric fish system for investigating pathways to evolutionary novelty, as well as the influences of key innovations in communication on the process of species radiation