Local and Systemic Consequences of Reducing Notch Signaling in Skin Keratinocytes

Notch is a transmembrane receptor that mediates short-range signaling between neighboring cells. Notch signaling has been implicated in various cellular and developmental processes essential in the life of metazoans. Specifically, Notch signaling plays a critical role in mammalian skin. Removal of Notch alleles in skin keratinocytes has been associated with an array of phenotypes with varying severity based on the identity and number of remaining Notch receptors. Phenotypes include carcinogenesis: in the case of Notch1 loss), transformation of hair follicles to epidermal cysts and neonatal lethality, the latter seen in the absence of all Notch signaling. Although these phenotypes were previously described, the exact mechanisms underlying them have not been fully understood. This dissertation focuses on obtaining mechanistic insights into some of the observed phenotypes attained by analyses of the local and systemic changes downstream of Notch signaling loss in the skin. In order to examine the direct consequences of Notch loss in keratinocytes, we first focused on intrinsic changes detected at postnatal day 9 in Notch-deficient epidermis in vivo. Our findings helped establish that an additive function of Notch paralogs is required for proper epidermal differentiation and lipid biosynthesis in the epidermis, which in turn lead to formation of a competent skin-barrier. We showed that these functions were executed through both canonical: RBP-j-dependent) and non-canonical Notch signals. Accordingly, we discovered that the defective skin-barrier formed by Notch1-deficient keratinocytes created a sub-acute wound-like microenvironment that explained the tumor promotion seen in the absence of Notch1 in the skin. Therefore, skin carcinogenesis is a non-cell autonomous consequence of Notch deletion in keratinocytes, which represents the end result of a crosstalk between barrier-defective epidermis and its underlying stroma. Besides the intricate interaction between epidermis and its neighboring structures in the skin, we uncovered that defects in epidermal barrier sets off a systemic alarm by secreting thymic stromal lymphopoietin: TSLP), an epithelial-derived cytokine implicated in pathogenesis of asthma and atopic dermatitis. TSLP was highly expressed by Notch-deficient epidermis. Importantly, we were able to show that TSLP was both required and sufficient to cause a lethal systemic B-lymphoproliferative disorder in newborn or asthma in adult mice lacking Notch signaling in the skin. Overall, this body of work outlines the direct cellular effects of Notch loss, and describes the mechanisms connecting epidermal Notch deletion to its non-cell autonomous local and systemic consequences

Overexpression of the non-coding SOX2OT variants 4 and 7 in lung tumors suggests an oncogenic role in lung cancer

Despite the advances in cancer therapy, lung cancer still remains the most leading cause of cancer death worldwide. The long non-coding RNAs (lncRNAs) are recently introduced as novel regulators of human cancers. SOX2 overlapping transcript (SOX2OT) is a cancer-associated lncRNA gene that encodes different alternatively spliced transcripts. Here, we investigated the alterations in the preferential expression of different SOX2OTs in twenty non-small cell lung cancer (NSCLC) patients by real-time quantitative reverse transcription PCR (qRT-PCR) method. We observed preferential expression of SOX2OT4 and SOX2OT7 in lung tumor tissues. The quantitative gene expression analysis revealed that >30 % of NSCLC tumors express SOX2OT4 (mean = 7.6 times) and SOX2OT7 (mean = 5.9 times) more than normal tissues, with higher expression in squamous cell carcinoma. Further, we observed overexpression of pluripotency-associated transcription factor, SOX2 in 47 % of our samples concordant with SOX2OT (R = 0.62, P value <0.05). Overexpression of OCT4A gene was also observed in 36.8 % of tumor tissues. Then, we investigated the effects of SOX2OT suppression in lung adenocarcinoma cell line, by means of RNAi. Cell characteristics of colony formation, apoptosis, 2-D mobility, and cell cycle progression were measured in control and treated A549 cells. The SOX2OT knockdown significantly reduced the colony formation ability of cancer cells; however, no alterations in the rate of apoptosis were detected. On the other hand, SOX2OT-suppressed cells had elevated accumulation in G2/M phase of cell cycle and exhibited limited mobility. Altogether, our findings support a potential oncogenic role for SOX2OT in non-small cell lung cancer tumor genesis and SOX2OT seems a promising therapeutic candidate for NSCLC. © 2016, International Society of Oncology and BioMarkers (ISOBM)

Monotone and bounded interval equilibria in a coordination game with information aggregation

We analyze how private learning in a class of games with common stochastic payoffs affects the form of equilibria, and how properties such as player welfare and the extent of strategic miscoordination relate across monotone and non-monotone equilibria. Researchers typically focus on monotone equilibria. We provide conditions under which non-monotone equilibria also exist, where players attempt to coordinate to obtain the stochastic payoff whenever signals are in a bounded interval. In bounded interval equilibria (BIE), an endogenous fear of miscoordination discourages players from coordinating to obtain the stochastic payoff when their signals suggest coordination is most beneficial. In contrast to monotone equilibria, expected payoffs from successful coordination in BIE are lower than the ex-ante expected payoff from ignoring signals and always trying to coordinate to obtain the stochastic payoff. We show that BIE only exist when, absent private information, the game would be a coordination game

Reliability, agreement, and diagnostic accuracy of the modified lateral scapular slide test

The Lateral Scapular Slide Test is a static test used in clinical settings to assess medio-lateral inferior angle displacement and scapular asymmetry at three different degrees of shoulder abduction. However, there is no evidence in the literature about the reliability and diagnostic accuracy of a modified LSST (arm elevation in the scapular plane with loading) in a symptomatic populationinfo:eu-repo/semantics/publishedVersio

Identification of new SOX2OT transcript variants highly expressed in human cancer cell lines and down regulated in stem cell differentiation

Long non-coding RNAs are manifested as a new paradigm of molecular effectors in a wide range of human diseases. Human SOX2 overlapping transcript (SOX2OT) gene can generate six lncRNA transcript variants which are functionally assumed to be correlated with cellular differentiation and carcinogenesis. However, the circumstances determining expressional and functional differences between SOX2OT transcript variants remain to be explored. Here, we studied the expression of all SOX2OT transcript variants specifically in five human cancer cell lines by real-time RT-PCR. Changes of the new SOX2OT transcript variants expression were measured during the NT2 teratocarcinoma cell line neuronal-like differentiation and were compared to pluripotency regulators, SOX2 and OCT4A gene expressions. Surprisingly, we identified two new SOX2OT transcripts, named SOX2OT-7, SOX2OT-8 which lack exon 8. We discovered that beside active proximal and distal SOX2OT promoters, different cancer cell lines express high levels of some SOX2OT transcript variants differentially by alternative splicing. Significantly, both SOX2OT-7 and SOX2OT-8 are highly expressed in human cancer cell lines coinciding with SOX2, one of the pluripotency regulators. Our results revealed that SOX2OT-7 is almost the most abundant form of SOX2OT transcript variants in the examined cancer cell lines particularly in NT2 teratocarcinoma cell line where its expression falls upon neuronal-like differentiation similar to SOX2 and OCT4A. We suggest that at least some of SOX2OT transcripts are significantly associated with cancer and stem cell related pathways. © 2015, Springer Science+Business Media Dordrecht

State censorship

We characterize a ruler's decision of whether to censor media reports that convey information to citizens who decide whether to revolt. We find: (i) a ruler gains (his ex ante expected payoff increases) by committing to censoring slightly less than he does in equilibrium: his equilibrium calculations ignore that censoring less causes citizens to update more positively following no news; (ii) a ruler gains from higher censorship costs if and only if censorship costs exceed a critical threshold; (iii) a bad ruler prefers a very strong media to a very weak one, but a good ruler prefers the opposite

Learning from Sensory and Reward Prediction Errors during Motor Adaptation

Voluntary motor commands produce two kinds of consequences. Initially, a sensory consequence is observed in terms of activity in our primary sensory organs (e.g., vision, proprioception). Subsequently, the brain evaluates the sensory feedback and produces a subjective measure of utility or usefulness of the motor commands (e.g., reward). As a result, comparisons between predicted and observed consequences of motor commands produce two forms of prediction error. How do these errors contribute to changes in motor commands? Here, we considered a reach adaptation protocol and found that when high quality sensory feedback was available, adaptation of motor commands was driven almost exclusively by sensory prediction errors. This form of learning had a distinct signature: as motor commands adapted, the subjects altered their predictions regarding sensory consequences of motor commands, and generalized this learning broadly to neighboring motor commands. In contrast, as the quality of the sensory feedback degraded, adaptation of motor commands became more dependent on reward prediction errors. Reward prediction errors produced comparable changes in the motor commands, but produced no change in the predicted sensory consequences of motor commands, and generalized only locally. Because we found that there was a within subject correlation between generalization patterns and sensory remapping, it is plausible that during adaptation an individual's relative reliance on sensory vs. reward prediction errors could be inferred. We suggest that while motor commands change because of sensory and reward prediction errors, only sensory prediction errors produce a change in the neural system that predicts sensory consequences of motor commands

When can citizen communication hinder successful revolution

We show that when citizens are uncertain about whether a successful revolution will turn out better than the status quo, communication between citizens reduces the likelihood of successful revolution when the status quo is sufficiently bad. A bad regime faces a tradeoff: communication helps citizens to coordinate, facilitating revolution; but it also facilitates the dissemination of any negative information about the alternative to the status quo, forestalling revolution. When the regime is sufficiently bad, this latter effect dominates. This result contrasts with the literature that assumes that each citizen knows that he wants to change the regime, but he is uncertain about whether enough citizens will revolt. In such settings, communication always raises the likelihood of successful revolution

Vanguards in revolution

Revolutionary vanguards, their radicalism and coercive actions, and their interactions with ordinary citizens and the state are common threads in narratives of revolutionary movements. But what are the defining features of revolutionary vanguards? The literature is replete with terms that allude to some notion of a revolutionary vanguard (e.g., revolutionary entrepreneurs, entrepreneurs of violence, early-risers), but the essence of these conceptions and their implications for revolutionary process remain obscure. We identify and differentiate the two main notions of vanguards, the Leninist and “early-riser” notions, and develop a formal framework that captures their distinguishing features, deriving their implications for the likelihood of revolution. We then use this framework to study three related and overlooked topics: (a) state strategies in mitigating the vanguard's influence on citizens; (b) citizens' preferences for the degree of vanguard radicalism; and (c) the vanguards' use of coercion against citizens

Geometric Structure of the Adaptive Controller of the Human Arm

The objects with which the hand interacts with may significantly change the dynamics of the arm. How does the brain adapt control of arm movements to this new dynamic? We show that adaptation is via composition of a model of the task's dynamics. By exploring generalization capabilities of this adaptation we infer some of the properties of the computational elements with which the brain formed this model: the elements have broad receptive fields and encode the learned dynamics as a map structured in an intrinsic coordinate system closely related to the geometry of the skeletomusculature. The low--level nature of these elements suggests that they may represent asset of primitives with which a movement is represented in the CNS