Adult neuron addition to the zebra finch song motor pathway correlates with the rate and extent of recovery from botox-induced paralysis of the vocal muscles.

In adult songbirds, neurons are continually incorporated into the telencephalic nucleus HVC (used as a proper name), a premotor region necessary for the production of learned vocalizations. Previous studies have demonstrated that neuron addition to HVC is highest when song is most variable: in juveniles during song learning, in seasonally singing adults during peaks in plasticity that precede the production of new song components, or during seasonal reestablishment of a previously learned song. These findings suggest that neuron addition provides motor flexibility for the transition from a variable song to a target song. Here we test the association between the quality of song structure and HVC neuron addition by experimentally manipulating syringeal muscle control with Botox, which produces a transient partial paralysis. We show that the quality of song structure covaries with new neuron addition to HVC. Both the magnitude of song distortion and the rate of song recovery after syringeal Botox injections were correlated with the number of new neurons incorporated into HVC. We suggest that the quality of song structure is either a cause or consequence of the number of new neurons added to HVC. Birds with naturally high rates of neuron addition may have had the greatest success in recovering song. Alternatively, or in addition, new neuron survival in the song motor pathway may be regulated by the quality of song-generated feedback as song regains its original stereotyped structure. Present results are the first to show a relationship between peripheral muscle control and adult neuron addition to cortical premotor circuits.

Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival.

Although remission rates for metastatic melanoma are generally very poor, some patients can survive for prolonged periods following metastasis. We used gene expression profiling, mitotic index (MI), and quantification of tumor infiltrating leukocytes (TILs) and CD3+ cells in metastatic lesions to search for a molecular basis for this observation and to develop improved methods for predicting patient survival. We identified a group of 266 genes associated with postrecurrence survival. Genes positively associated with survival were predominantly immune response related (e.g., ICOS, CD3d, ZAP70, TRAT1, TARP, GZMK, LCK, CD2, CXCL13, CCL19, CCR7, VCAM1) while genes negatively associated with survival were cell proliferation related (e.g., PDE4D, CDK2, GREF1, NUSAP1, SPC24). Furthermore, any of the 4 parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of Tumor, Node, Metastasis (TNM) staging to predict postrecurrence survival; MI was the most significant contributor (HR = 2.13, P = 0.0008). An immune response gene expression signature and presence of TILs and CD3+ cells signify immune surveillance as a mechanism for prolonged survival in these patients and indicate improved patient subcategorization beyond current TNM staging.

Clinical relevance of neutral endopeptidase (NEP/CD10) in melanoma.

BACKGROUND: Overexpression of Neutral Endopeptidase (NEP) has been reported in metastatic carcinomas, implicating NEP in tumor progression and suggesting a role for NEP inhibitors in its treatment. We investigated the role of NEP expression in the clinical progression of cutaneous melanoma. METHODS: We screened 7 melanoma cell lines for NEP protein expression. NEP-specific siRNA was transfected into the lines to examine the role of gene transcription in NEP expression. Immunohistochemistry was done for 93 specimens and correlated with clinicopathologic parameters. Thirty-seven metastatic melanoma specimens were examined for NEP transcript expression using Affymetrix GeneChips. In a subset of 25 specimens for which both transcript and protein expression was available, expression ratios were used to identify genes that co-express with NEP in GeneChip analysis. RESULTS: NEP was overexpressed in 4/7 human melanoma cell lines, and siRNA knock-down of NEP transcripts led to downregulation of its protein expression. NEP protein overexpression was significantly more common in metastatic versus primary tumors (P = 0.002). Twelve of 37 (32%) metastatic tumors had increased NEP transcript expression, and an association was observed between NEP transcript upregulation and protein overexpression (P < 0.0001). Thirty-eight genes were found to significantly co-express with NEP (p < 0.005). Thirty-three genes positively correlated with NEP, including genes involved in the MAP kinase pathway, antigen processing and presentation, apoptosis, and WNT signaling pathway, and 5 genes negatively correlated with NEP, including genes of focal adhesion and the notch signaling pathways. CONCLUSION: NEP overexpression, which seems to be largely driven by increased transcription, is rare in primary melanoma and occurs late in melanoma progression. Functional studies are needed to better understand the mechanisms of NEP regulation in melanoma.

Can false memories spontaneously recover?

Can false memories that were suppressed at one time spontaneously recover at a later time? Fuzzy trace theory and activation-monitoring theory predict that false memories in the Deese, Roediger, and McDermott (DRM) procedure become substantially reduced as list learning progresses because participants employ a memory-editing process. It follows that if the editing process is rendered less effective, false memories should spontaneously recover. We found that after DRM lists were well learned and false recognition to critical words was substantially reduced by multiple study-test trials, those false memories spontaneously recovered when participants were either rushed or delayed on a retest. We attributed the reduction in false recognition over trials to a memory-editing process that suppresses false recognition as participants gradually learn which words were in the lists and which words, though similar, were not. Rushing or delaying the participants on a retest made it more difficult for them to edit their memory, and false memories spontaneously returned.