Control of translation is a fundamental source of regulation in gene expression. The induction of protein synthesis by brain-derived neurotrophic factor (BDNF) critically contributes to enduring ...modifications of synaptic function, but how BDNF selectively affects only a minority of expressed mRNAs is poorly understood. We report that BDNF rapidly elevates Dicer, increasing mature miRNA levels and inducing RNA processing bodies in neurons. BDNF also rapidly induces Lin28, causing selective loss of Lin28-regulated miRNAs and a corresponding upregulation in translation of their target mRNAs. Binding sites for Lin28-regulated miRNAs are necessary and sufficient to confer BDNF responsiveness to a transcript. Lin28 deficiency, or expression of a Lin28-resistant Let-7 precursor miRNA, inhibits BDNF translation specificity and BDNF-dependent dendrite arborization. Our data establish that specificity in BDNF-regulated translation depends upon a two-part posttranscriptional control of miRNA biogenesis that generally enhances mRNA repression in association with GW182 while selectively derepressing and increasing translation of specific mRNAs.
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► Brain-derived neurotrophic factor (BDNF) increases levels of Dicer and mature miRNAs ► BDNF also induces Lin28 and selective miRNA loss in terminally differentiated neurons ► BDNF-induced dendrite growth requires Lin28-mediated degradation of pre-Let-7 miRNAs ► Regulation of miRNA biogenesis underlies BDNF's target selection in protein synthesis
Brain-derived neurotrophic factor selectively increases the translation of a subset of expressed mRNAs by regulating levels of both Dicer and Lin28 and, in this way, dictating the profile of neuronal miRNAs.
Background and Objectives
Many individuals receiving methadone maintenance treatment (MMT) for opioid addiction also require treatment for acute or chronic pain, and the presence of pain is known to ...have a negative impact on patient health and function. However, effective pain management in this population is complicated by many factors, including heightened pain sensitivity, high opioid tolerance, illicit substance use, and variable cross‐tolerance to opioid pain medications. This article reviews the recent literature on acute and chronic pain among, and pain treatment of, patients receiving MMT for opioid addiction and discusses the implications for effective pain management. Acute pain management among women maintained on methadone during and after labor and delivery is also discussed, as well as common concerns held by patients and providers about appropriate pain management strategies in the context of methadone maintenance and addiction treatment.
Methods
One hundred nine articles were identified in a PubMed/MEDLINE electronic database search using the following search terms: methadone, methadone maintenance, methadone addiction, pain, pain management, chronic pain, and acute pain. s were reviewed for relevance, and additional studies were extracted from the reference lists of articles identified in the original search.
Results
The pain sensitivity and pain responses of MMT patients differ significantly from those of patients not maintained on opioids, and few data are available to guide patient care.
Conclusions and Scientific Significance
Rigorous studies are needed to identify and evaluate effective pain management approaches for this unique patient population and to improve patient treatment outcomes. (Am J Addict 2012;XX:000–000) (Am J Addict 2013;22:75‐83)
In Saccharomyces cerevisiae, the Ku heterodimer contributes to telomere maintenance as a component of telomeric chromatin and as an accessory subunit of telomerase. How Ku binding to double-stranded ...DNA (dsDNA) and to telomerase RNA (TLC1) promotes Ku's telomeric functions is incompletely understood. We demonstrate that deletions designed to constrict the DNA-binding ring of Ku80 disrupt nonhomologous end-joining (NHEJ), telomeric gene silencing, and telomere length maintenance, suggesting that these functions require Ku's DNA end-binding activity. Contrary to the current model, a mutant Ku with low affinity for dsDNA also loses affinity for TLC1 both in vitro and in vivo. Competition experiments reveal that wild-type Ku binds dsDNA and TLC1 mutually exclusively. Cells expressing the mutant Ku are deficient in nuclear accumulation of TLC1, as expected from the RNA-binding defect. These findings force reconsideration of the mechanisms by which Ku assists in recruiting telomerase to natural telomeres and broken chromosome ends.
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► Yeast Ku's telomeric functions require its DNA-binding ring ► Ku mutation that inhibits DNA binding unexpectedly inhibits telomerase RNA binding ► Competition experiments show mutually exclusive binding of DNA and RNA to Ku ► Supports revision of the current model for recruitment of telomerase to telomeres by Ku
The DNA-repair protein Ku binds to the telomerase RNA and helps recruit telomerase to chromosome ends; however, Ku cannot bind DNA and telomerase RNA simultaneously. DNA displaces Ku from telomerase, suggesting a reconsideration of the current model for Ku recruitment of telomerase.
Self‐esteem and well‐being are important for successful aging, and some evidence suggests that self‐esteem and well‐being are associated with hippocampal volume, cognition and stress responsivity. ...Whereas most of this evidence is based on studies on older adults, we investigated self‐esteem, well‐being and hippocampal volume in 474 male middle‐aged twins. Self‐esteem was significantly positively correlated with hippocampal volume (0.09, P = 0.03 for left hippocampus, 0.10, P = 0.04 for right). Correlations for well‐being were not significant (Ps > 0.05). There were strong phenotypic correlations between self‐esteem and well‐being (0.72, P < 0.001) and between left and right hippocampal volume (0.72, P < 0.001). In multivariate genetic analyses, a two‐factor additive genetic and unique environmental (AE) model with well‐being and self‐esteem on one factor and left and right hippocampal volumes on the other factor fits the data better than Cholesky, independent pathway or common pathway models. The correlation between the two genetic factors was 0.12 (P = 0.03); the correlation between the environmental factors was 0.09 (P > 0.05). Our results indicate that largely different genetic and environmental factors underlie self‐esteem and well‐being on one hand and hippocampal volume on the other.
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