Effects of novel muscarinic M3 receptor ligand C1213 in pulmonary arterial hypertension models.

Pulmonary hypertension (PH) is a complex disease comprising a pathologic remodeling and thickening of the pulmonary vessels causing an after load on the right heart ventricle that can result in ventricular failure. Triggered by oxidative stress, episodes of hypoxia, and other undetermined causes, PH is associated with poor outcomes and a high rate of morbidity. In the neonate, this disease has a similar etiology but is further complicated by the transition to breathing after birth, which requires a reduction in vascular resistance. Persistent pulmonary hypertension of the newborn (PPHN) is one form of PH that is frequently unresponsive to current therapies including inhaled nitric oxide (due to lack of proper absorption and diffusion), and other therapeutics targeting signaling mediators in vascular endothelium and smooth muscle. The need for novel agents, which target distinct pathways in pulmonary hypertension, remains. Herein, we investigated the therapeutic effects of novel muscarinic receptor ligand C1213 in models of PH We demonstrated that via M3 muscarinic receptors, C1213 induced activating- eNOS phosphorylation (serine-1177), which is known to lead to nitric oxide (NO) production in endothelial cells. Using signaling pathway inhibitors, we discovered that AKT and calcium signaling contributed to eNOS phosphorylation induced by C1213. As expected for an eNOS-stimulating agent, in ex vivo and in vivo models, C1213 triggered pulmonary vasodilation and induced both pulmonary artery and systemic blood pressure reductions demonstrating its potential value in PH and PPHN In brief, this proof-of-concept study provides evidence that an M3 muscarinic receptor functionally selective ligand stimulates downstream pathways leading to antihypertensive effects using in vitro, ex vivo, and in vivo models of PH

The potential of elicited imitation for oral output practice in German L2

This paper reports on the potential of Oral Elicited Imitation (OEI) as a format for output practice, building on an analysis of picture-matching and spoken data collected from 36 university-level learners of German as a second language (L2) in a web-based assessment task inspired by Input Processing (VanPatten, 2004). The design and development of OEI for output practice faces two key challenges: learners must be engaged in meaningful language processing rather than in mere repetition of oral stimuli, and the task must eventually provide individualized and qualitative corrective feedback that helps learners to notice gaps between their interlanguage and the target language. Results show that learners attended to meaning and that a commercially available speech recognition tool was able to transcribe learner speech remarkably well.status: publishe

Production and processing asymmetries in the acquisition of tense morphology by sequential bilingual children

This study investigates the production and on-line processing of English tense morphemes by sequential bilingual (L2) Turkish-speaking children with more than three years of exposure to English. Thirty nine 6-9-year-old L2 children and 28 typically developing age-matched monolingual (L1) children were administered the production component for third person –s and past tense of the Test for Early Grammatical Impairment (Rice & Wexler, 1996) and participated in an on-line word-monitoring task involving grammatical and ungrammatical sentences with presence/omission of tense (third person –s, past tense -ed) and non-tense (progressive –ing, possessive ‘s) morphemes. The L2 children’s performance on the on-line task was compared to that of children with Specific Language Impairment (SLI) in Montgomery & Leonard (1998, 2006) to ascertain similarities and differences between the two populations. Results showed that the L2 children were sensitive to the ungrammaticality induced by the omission of tense morphemes, despite variable production. This reinforces the claim about intact underlying syntactic representations in child L2 acquisition despite non target-like production (Haznedar & Schwartz, 1997)

An analysis of formal errors in a corpus of l2 English produced by Chinese students

This paper describes the investigation of a small corpus of writing of English for academic purposes produced by L1 speakers of Mandarin. The investigation involved the development of a tagset for the identification of formal errors in the corpus, and the subsequent analysis of these errors with a view to creating remedial grammar materials for Chinese students studying in the medium of English. Some past approaches to error analysis are discussed, the process of developing the tagging system is described, and error types are identified, categorised, quantified, described and (as far as possible) explained

The generative approach to SLA and its place in modern second language studies

This article has two main goals. The first is to summarize and comment on the current state-of-affairs of generative approaches to SLA (GenSLA), thirty-five years into its history. This discussion brings the readership of SSLA up-to-date on the questions driving GenSLA agendas and clears up misconceptions about what GenSLA does and does not endeavor to explain. We engage key questions/debates/shifts within GenSLA such as focusing on the deterministic role of input in language acquisition, as well as expanding the inquiry to new populations and empirical methodologies and technologies used. The second goal is to highlight the place of GenSLA in the broader field of SLA. We argue that various theories of SLA are needed, showing that many existing SLA paradigms are much less mutually exclusive than commonly believed (cf. Rothman & VanPatten, 2013; Slabakova et al., 2014, 2015; VanPatten & Rothman, 2014) — especially in light of their different foci and research questions

Online and offline effects of L1 practice in L2 grammar learning : a partial replication

This study partially replicates McManus and Marsden (2016), who found that providing L1 explicit information (EI) plus task-essential practice led L2 learners to make more accurate and faster interpretations of French morphosyntax. The current study removed the original study’s L1 EI component to examine the extent and nature of its role and that of the remaining L1 practice. This design tested whether providing L1 task-essential practice only (alongside a core treatment of L2 EI plus practice) resulted in similar online and offline learning gains compared to the original study’s L1 EI plus L1 practice. We used the same online and offline tests, with a similar population of English-speaking learners of L2 French (n=19). Compared to L2 EI plus L2 practice, the findings suggest that L1 practice did not generally benefit accurate interpretation or speed of online processing, indicating that the original study’s L1 EI contribute

Perform a gyro test of general relativity in a satellite and develop associated control technology

The progress accomplished in the Stanford Gyro Relativity program during the period November 1974 to October 1975 was described. Gyro developments were continued in the main laboratory dewar, concentrating on the operation of a three axis gyro readout and on improvements to the methods of canceling trapped fields in the rotor; these efforts culminated in the first successful observation of the London moment in the spinning gyro rotor in March 1975. Following a review meeting at that time, a new goal was formulated for the next 12 to 18 months, namely to operate a gyroscope in the new ultra-low field facility with readout resolution approaching 1 arc-second. The following other tasks were also completed: (1) sputtering work, (2) magnetometry, (3) construction and installation of the North Star simulator, (4) analysis of torques on the gyro, especially in inclined orbits, (5) equivalence principle accelerometer, and (6) analysis of a twin-satellite test of relativity

How input processing factors into lexical semantics: Motion events with double particles in L3 German

Motion events are almost absent in the course syllabus of L2 German as a formally addressed structure in the classroom. Learners have merely receptive contact with this type of structure in reading texts or in aural activities. The occurrence of motion events with the so-called “double particles” is even less frequent. These are composed of the deictic morphemes hin- and her- denoting the speaker’s perspective and Path morphemes (-ein-, -aus-, -auf-, etc.). The main goal of the present study is to test a group of Portuguese L3 learners of German regarding their knowledge of double particles, and to apply VanPatten’s Processing Instruction (PI) model (VanPatten 2004; VanPatten and Williams 2015), which rests on an input-based focus-on-form approach for teaching grammar. The theoretical framework is based on Talmy’s typology of motion events (Talmy 2000a, 2000b). The empirical component of this study was divided into three parts: first, I tested the participants by means of a pretest; then, I conducted a pedagogical intervention based on the PI model; finally, a posttest determined the successful effects of PI in the participants’ knowledge of the target forms, both in interpretative and productive contexts.I would like to thank Cristina Flores for her diligent coordination during the realization ofthis study and for her insightful and constructive comments on earlier versions of this pap

Spin Dynamics of the LAGEOS Satellite in Support of a Measurement of the Earth's Gravitomagnetism

LAGEOS is an accurately-tracked, dense spherical satellite covered with 426 retroreflectors. The tracking accuracy is such as to yield a medium term (years to decades) inertial reference frame determined via relatively inexpensive observations. This frame is used as an adjunct to the more difficult and data intensive VLBI absolute frame measurements. There is a substantial secular precession of the satellite's line of nodes consistent with the classical, Newtonian precession due to the non-sphericity of the earth. Ciufolini has suggested the launch of an identical satellite (LAGEOS-3) into an orbit supplementary to that of LAGEOS-1: LAGEOS-3 would then experience an equal and opposite classical precession to that of LAGEOS-1. Besides providing a more accurate real-time measurement of the earth's length of day and polar wobble, this paired-satellite experiment would provide the first direct measurement of the general relativistic frame-dragging effect. Of the five dominant error sources in this experiment, the largest one involves surface forces on the satellite, and their consequent impact on the orbital nodal precession. The surface forces are a function of the spin dynamics of the satellite. Consequently, we undertake here a theoretical effort to model the spin ndynamics of LAGEOS. In this paper we present our preliminary results.Comment: 16 pages, RevTeX, LA-UR-94-1289. (Part I of II, postscript figures in Part II