A fundamental issue in neural coding is the role of spike timing variation in information transmission of sensory stimuli. Vestibular afferents are particularly well suited to study this issue because they are classified as either regular or irregular based on resting discharge variability as well as morphology. Here, we compared the responses of each afferent class to sinusoidal and random head rotations using both information theoretic and gain measures. Information theoretic measures demonstrated that regular afferents transmitted, on average, two times more information than irregular afferents, despite having significantly lower gains. Moreover, consistent with information theoretic measures, regular afferents had angular velocity detection thresholds that were 50% lower than those of irregular afferents (ϳ4 vs 8°/s). Finally, to quantify the information carried by spike times, we added spike-timing jitter to the spike trains of both regular and irregular afferents. Our results showed that this significantly reduced information transmitted by regular afferents whereas it had little effect on irregular afferents. Thus, information is carried in the spike times of regular but not irregular afferents. Using a simple leaky integrate and fire model with a dynamic threshold, we show that differential levels of intrinsic noise can explain differences in the resting discharge, the responses to sensory stimuli, as well as the information carried by action potential timings of each afferent class. Our experimental and modeling results provide new insights as to how neural variability influences the strategy used by two different classes of sensory neurons to encode behaviorally relevant stimuli.

Background BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome.DesignTo characterize BAP1's contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds.ResultsGermline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition.ConclusionGermline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive BAP1 inactivation.

BRAF(V600E) is the most common oncogenic lesion in melanoma and results in constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth and improve patient outcome. Although several mechanisms of vemurafenib resistance have been described, directed solutions to overcome these resistance lesions are still lacking. Herein, we found that vemurafenib resistance can be (i) mediated by EphA2- a member of the largest receptor tyrosine kinases (RTK) subfamily erythropoietin-producing hepatocellular (Eph) receptors and (ii) associated with a greater phenotypic dependence on EphA2. Furthermore, we developed a series of first-in-class EphA2 inhibitors and show that these new compounds potently induce apoptosis, suppress viability and abrogate tumorigenic growth of melanoma cells, including those that are resistant to vemurafenib. These results provide proof-of-concept that RTK-guided growth, and therapeutic resistance, can be prospectively defined and selectively targeted.

Response to targeted therapies varies significantly despite shared oncogenic mutations. Nowhere is this more apparent than in BRAF(V600E)-mutated melanomas where initial drug response can be striking and yet relapse is commonplace. Resistance to BRAF inhibitors have been attributed to the activation of various receptor tyrosine kinases (RTKs) though the underlying mechanisms have been largely uncharacterized. Here, we found that EGFR induced vemurafenib resistance is ligand dependent. We then employed whole-genome expression analysis and discovererd that vemurafenib resistance correlated with the loss of MITF, along with its melanocyte lineage program, and with the activation of EGFR signaling. An inverse relationship between MITF, vemurafenib resistance and EGFR was then observed in patient samples of recurrent melanoma and was conserved across melanoma cell lines and patients’ tumor specimens. Functional studies revealed that MITF depletion activated EGFR signaling and consequently recapitulated the resistance phenotype. In contrast, forced expression of MITF in melanoma and colon cancer cells inhibited EGFR and conferred sensitivity to BRAF/MEK inhibitors. These findings indicate that an “autocrine drug resistance loop” is suppressed by melanocyte lineage signal(s), such as MITF. This resistance loop modulates drug response and could explain the unique sensitivity of melanomas to BRAF inhibition.

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Introduction: Children with developmental coordination disorder are frequently referred to an occupational therapist. However, while there is a growing body of research about developmental coordination disorder, there is a paucity of research from the perspective of adolescents living with the condition. Purpose: The purpose of this study was to investigate the experience of teenagers living with developmental coordination disorder from their own perspective. This article presents findings from interviews with teenagers aged 13 years. Method: The research adopted an interpretive phenomenological approach. Semi-structured interviews were carried out to examine the personal experiences of six individuals diagnosed with developmental coordination disorder. Interviews were audio-recorded, transcribed and analysed using in-depth ideographic, inductive and interrogative techniques. Findings: All participants felt that the visible and hidden effects of their condition had an impact on their relationships with peers and family members. Three sub-themes emerged: (1) relationships with peers; (2) relationships with parents and (3) relationships with siblings. Conclusion: Participants described how their personal attributes, shared interests and the attitudes of others affected their relationships and social participation at home, at school and in the community. Understanding the issues that matter to teenagers with developmental coordination disorder will help occupational therapists to offer advice and meaningful interventions that increase teenagers' social confidence and participation.

Oncogenesis reflects an orchestrated interaction between misguided growth signals. Although much effort has been launched to pharmacologically disable activated oncogenes, one sidelined approach is the restoration of tumor suppressive signals. As TP53 is often structurally preserved, but functionally crippled, by CDKN2A/ARF loss in melanoma, rescue of p53 function represents an attractive point of vulnerability in melanoma. In this study, we showed that both p53 protein and activity levels in melanoma cells were strongly induced by nutlin-3, a canonical HDM2 antagonist. Among a test panel of 51 cell lines, there was a marked reduction in melanoma viability that was directly linked to TP53 status. Moreover, we also found that the melanoma growth suppression mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase inhibition was potentiated by HDM2 antagonism. These results provide fundamental insights into the intact p53 circuitry, which can be restored through small molecule inhibitors and potentially deployed for therapeutic gain.

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