NGF Causes TrkA to Specifically Attract Microtubules to Lipid Rafts

Membrane protein sorting is mediated by interactions between proteins and lipids. One mechanism that contributes to sorting involves patches of lipids, termed lipid rafts, which are different from their surroundings in lipid and protein composition. Although the nerve growth factor (NGF) receptors, TrkA and p75NTR collaborate with each other at the plasma membrane to bind NGF, these two receptors are endocytosed separately and activate different cellular responses. We hypothesized that receptor localization in membrane rafts may play a role in endocytic sorting. TrkA and p75NTR both reside in detergent-resistant membranes (DRMs), yet they responded differently to a variety of conditions. The ganglioside, GM1, caused increased association of NGF, TrkA, and microtubules with DRMs, but a decrease in p75NTR. When microtubules were induced to polymerize and attach to DRMs by in vitro reactions, TrkA, but not p75NTR, was bound to microtubules in DRMs and in a detergent-resistant endosomal fraction. NGF enhanced the interaction between TrkA and microtubules in DRMs, yet tyrosine phosphorylated TrkA was entirely absent in DRMs under conditions where activated TrkA was detected in detergent-sensitive membranes and endosomes. These data indicate that TrkA and p75NTR partition into membrane rafts by different mechanisms, and that the fraction of TrkA that associates with DRMs is internalized but does not directly form signaling endosomes. Rather, by attracting microtubules to lipid rafts, TrkA may mediate other processes such as axon guidance

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Size contrast and assimilation explained by the statistics of natural scene geometry

& The term ‘‘size contrast and assimilation’ ’ refers to a large class of geometrical illusions in which the apparent sizes of identical visual targets in various contexts are different. Here we have examined whether these intriguing discrepancies between physical and perceived size can be explained by a visual process in which percepts are determined by the probability distribution of the possible real-world sources of retinal stimuli. To test this idea, we acquired a range image database of natural scenes that specified the location of every image point in 3-D space. By sampling the possible physical sources of various size contrast or assimilation stimuli in the database, we determined the probability distributions of the size of the target in the images generated by these sources. For each of the various stimuli tested, these probability distributions of target size in different contexts accurately predicted the perceptual effects reported in psychophysical studies. We conclude that size contrast and assimilation effects are a further manifestation of a fundamentally probabilistic process of visual perception. &amp

Depression and ambivalence toward chronic opioid therapy for chronic noncancer pain.

ObjectivesChronic opioid therapy (COT) for chronic noncancer pain (CNCP) is characterized by both high rates of patient-initiated discontinuation and by perceived helpfulness among those who sustain opioid use. This study examines predictors of the desire to cut down or stop opioid therapy among patients receiving COT who report that opioids are helpful for relieving pain.MethodsWe conducted a cross-sectional survey of 1737 selected patients receiving COT for CNCP who perceived opioids to be helpful in relieving their pain. Ambivalence about opioid use was assessed by agreement/disagreement with a statement indicating that they would like to stop or cut down the use of prescribed opioid medications. Depression was measured with the 8-item Patient Health Questionnaire.ResultsA high percentage (43.3%) of survey respondents who found opioids helpful also reported the desire to stop or cut down opioids. Half of these patients reporting the desire to stop or cut down were clinically depressed, compared with a third of those not wanting to stop or cut down, a highly significant difference after controlling for covariates (P<0.0001). The group wanting to stop or cut down opioid use also reported significantly higher levels of opioid-related psychosocial problems and opioid control concerns.DiscussionThere are high rates of ambivalence about opioid use among COT recipients who consider opioids helpful for pain relief. Depressed patients are more likely to be ambivalent about use of prescribed opioids. Eliciting patient ambivalence may be helpful in patients who are not benefiting from long-term opioid use as an initial step toward consideration of discontinuation