An apicobasal gradient of Rac activity determines protrusion form and position

Each cell within a polarised epithelial sheet must align and correctly position a wide range of subcellular structures, including actin-based dynamic protrusions. Using in vivo inducible transgenes that can sense or modify Rac activity, we demonstrate an apicobasal gradient of Rac activity that is required to correctly form and position distinct classes of dynamic protrusion along the apicobasal axis of the cell. We show that we can modify the Rac activity gradient in genetic mutants for specific polarity proteins, with consequent changes in protrusion form and position and additionally show, using photoactivatable Rac transgenes, that it is the level of Rac activity that determines protrusion form. Thus, we demonstrate a mechanism by which polarity proteins can spatially regulate Rac activity and the actin cytoskeleton to ensure correct epithelial cell shape and prevent epithelial-to-mesenchymal transitions

Information content and reward processing in the human striatum during performance of a declarative memory task

Negative feedback can signal poor performance, but it also provides information that can help learners reach the goal of task mastery. The primary aim of this study was to test the hypothesis that the amount of information provided by negative feedback during a paired-associate learning task influences feedback-related processing in the caudate nucleus. To do this, we manipulated the number of response options: With two options, positive and negative feedback provide equal amounts of information, whereas with four options, positive feedback provides more information than does negative feedback. We found that positive and negative feedback activated the caudate similarly when there were two response options. With four options, the caudate’s response to negative feedback was reduced. A secondary goal was to investigate the link between brain-based measures of feedback-related processing and behavioral indices of learning. Analysis of the posttest measures showed that trials with positive feedback were associated with higher posttest confidence ratings. Additionally, when positive feedback was delivered, caudate activity was greater for trials with high than with low posttest confidence. This experiment demonstrated the context sensitivity of feedback processing and provided evidence that feedback processing in the striatum can contribute to the strengthening of the representations available within declarative memory

CMB-S4: Forecasting Constraints on Primordial Gravitational Waves

CMB-S4---the next-generation ground-based cosmic microwave background (CMB) experiment---is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the Universe, from the highest energies at the dawn of time through the growth of structure to the present day. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semi-analytic projection tool, targeted explicitly towards optimizing constraints on the tensor-to-scalar ratio, $r$, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2--3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments given a desired scientific goal. To form a closed-loop process, we couple this semi-analytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for $r > 0.003$ at greater than $5\sigma$, or, in the absence of a detection, of reaching an upper limit of $r < 0.001$ at $95\%$ CL.Comment: 24 pages, 8 figures, 9 tables, submitted to ApJ. arXiv admin note: text overlap with arXiv:1907.0447

CMB-S4

We describe the stage 4 cosmic microwave background ground-based experiment CMB-S4

CMB-S4: Forecasting Constraints on Primordial Gravitational Waves

Abstract: CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Functional Forms-Formal Functions: An Account of Coeur d'Alene Clause Structure

Coeur d'Alene, also known as Snchitsu'umshtsn, is a Southern Interior Salishan language no longer learned by children. Descriptive work on the language has been carried out since the early nineteenth-century (Tiet 1904 through 1909 in Boaz and Tiet 1930; Reichard 1927-29, 1938, 1939; Doak 1997); however, a formal account of the basic clause structure of this polysynthetic language has until now not been proposed. This thesis presents such a formal analysis within the Minimalist Program (Chomsky 1995, 1998, 2000, 2001a, 2001b; Lasnik 1999a, 1999b, 2000; among others), employing the tenets of Distributed Morphology (Halle and Marantz 1993; Harley and Noyer 1999; among others). Demonstrating that an analysis of person marking morphemes as bound pronouns (Jelinek 1984) is more "economical" in terms of Chomsky's (1995:367)Elementary Principles of Economy, the thesis goes on to account for the phenomena of lexical affixation (Carlson 1990; Kinkade 1998; Gerdts 2003; among others), in Coeur d'Alene as incorporation. Appealing to Hale and Keyser's (2002) theory of conflation as Head-movement (Harley 2004), an approach to incorporation is proposed which captures Chomsky's (1995) claim that head-movement is phonological while at the same time illustrating that lexical affixes in Coeur d'Alene serve as incorporated arguments. The thesis concludes with an articulation of the left periphery (material above vP here), based on the strict ordering of a series of mood, adverbial, model, and aspectual particles. It is shown that this articulation in Coeur d'Alene patterns with Cinque's (1999) proposed universal hierarchy of functional and adverbial heads. In this way, the basic clause structure of Coeur d'Alene is formally presente

A simple formalism for capturing order and co-occurrence in computational morphology

Tradicionalmente, modelos computacionales de morfología y fonología han venido asumiendo, como punto de partida, un modelo morfotáctico donde los morfemas se extraen de subléxicos y se van concatenando de izquierda a derecha. El modelo de "clase de continuación" se ha venido utilizando como el sistema estándar de facto en la creación de diferentes cajas de herramientas de software. Tras estudiar lenguas de tipología diversa, proponemos aqu´ı un modelo de rasgos ampliado. Nuestro modelo consta de varias operaciones dise˜nadas con el fin de que un buen número de restrictiones de co-ocurrencia local y global puedan ser descritas de manera concisa. Aparte también sugerimos ciertas formas de implementar estos operadores en modelos de morfología basados en transductores de estado finito.Computational models of morphology and phonology have traditionally assumed as a starting point a morphotactic model where morpehemes are drawn from sublexicons and concatenated left-to-right. In defining the lexicon-morphotactic level of a system, this ‘continuation-class’ model has been the de facto standard im- plementation in various software toolkits. From surveying of a number of typologically different languages, we propose a more comprehensive feature-driven model of morphotactics that provides the linguist with various operations that are designed to concisely define a variety of local and global co-occurrence restrictions. We also sketch ways to implement these operators in finite-state-transducer-based models of morphology

An experiment in computational parsing of the Navajo verb

Coyote Papers, Vol. 16 features a combined bibliography for all articles in the issue. This bibliography is available at https://repository.arizona.edu/handle/10150/125965.This paper presents preliminary research on a computational parser for core Navajo morphology where any inflected verb is automatically decomposed, together with the inflectional and derivational structure of the verb. The grammatical implementation largely follows Faltz (1998) and Young and Morgan (1987); Young et al. (1992). We also report some proposals for reducing the amount of allomorphy and phonological rules in the description of Navajo verbal morphology, and potential uses of such a parser.The Coyote Papers are made available by the Arizona Linguistics Circle at the University of Arizona and the University of Arizona Libraries. Contact [email protected] with questions about these materials