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Junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are specialized membrane contacts ubiquitous in eukaryotic cells. Concentration of intracellular signaling machinery near ER-PM junctions allows these domains to serve critical roles in lipid and Ca2+ signaling and homeostasis. Subcellular compartmentalization of protein kinase A (PKA) signaling also regulates essential cellular functions, however, no specific association between PKA and ER-PM junctional domains is known. Here, we show that in brain neurons type I PKA is directed to Kv2.1 channel-dependent ER-PM junctional domains via SPHKAP, a type I PKA-specific anchoring protein. SPHKAP association with type I PKA regulatory subunit RI and ER-resident VAP proteins results in the concentration of type I PKA between stacked ER cisternae associated with ER-PM junctions. This ER-associated PKA signalosome enables reciprocal regulation between PKA and Ca2+ signaling machinery to support Ca2+ influx and excitation-transcription coupling. These data reveal that neuronal ER-PM junctions support a receptor-independent form of PKA signaling driven by membrane depolarization and intracellular Ca2+, allowing conversion of information encoded in electrical signals into biochemical changes universally recognized throughout the cell.

In history curriculum design in England, currently at least two loci of authority -- the history teachers' 'extended writing movement' and the national awarding body Pearson Edexcel -- present somewhat contrasting portrayals of the narrative mode for the purposes of historical causal explanation. Nonetheless, both loci suggest they are reappropriating academic knowledge for the purposes of secondary schooling in a fashion similar to what Basil Bernstein (1986) dubs 'recontextualisation'. As a practising history teacher, I provide a phenomenological critique of Pearson Edexcel's specifications for the national GCSE and A-level examinations from the perspective of the extended writing movement's realisation of the Bernsteinian model, with a specific focus on the narrative mode for the purposes of historical causal explanation. In order to characterise the status of historical narrative in the academic field of production, I draw on analytic philosophies of history, theories of history by practising historians and historical explanations from one historiography: the Salem witch trials. Finally, I make recommendations for future reforms in national history examinations in England: constant revaluation with reference to academic knowledge; the avoidance of specific yet unsustainable claims about the discipline of history generally; and the abandonment of a genre-led assessment in favour of an epistemology-led alternative.

Alarmed by his students' random use of causal language in their essays, James Edward Carroll resolved to help his students improve their understanding of causal processes. Carroll decided to introduce his students to the metaphors that historians use to describe causation in the historiography of the Salem witch trials. By modelling how historians use different types of metaphor to describe the conditions that allowed the witch trials to take place, Carroll showed his students how conditions of events differ from direct causes, and have a different causal role to play.

Lung cancer is the leading cause of cancer-related mortality worldwide. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapies, based on the evaluation of EGFR mutations, have shown dramatic clinical benefits. EGFR mutation assays are mainly performed on tumor biopsies, which carry risks, are not always successful and give results relevant to the timepoint of the assay. To detect secondary EGFR mutations, which cause resistance to 1st and 2nd generation TKIs and lead to the administration of a 3rd generation drug, effective and non-invasive monitoring of EGFR mutation status is needed. Liquid biopsy analytes, such as circulating tumor cells (CTCs) and circulating tumor DNA (cfDNA), allow such monitoring over the course of the therapy. The aim of this study was to develop and optimize a workflow for the evaluation of cfDNA and CTCs in NSCLC patients all from one blood sample. Using Vortex technology and EntroGen ctEGFR assay, EGFR mutations were identified at 0.5 ng of DNA (∼83 cells), with a sensitivity ranging from 0.1 to 2.0% for a total DNA varying from 25 ng (∼4 CTCs among 4000 white blood cells, WBCs) to 1 ng (∼4 CTCs among 200 WBCs). The processing of plasma-depleted-blood provided comparable capture recovery as whole blood, confirming the possibility of a multimodality liquid biopsy analysis (cfDNA and CTC DNA) from a single tube of blood. Different anticoagulants were evaluated and compared in terms of respective performance. Blood samples from 24 NSCLC patients and 6 age-matched healthy donors were analyzed with this combined workflow to minimize blood volume needed and sample-to-sample bias, and the EGFR mutation profile detected from CTCs and cfDNA was compared to matched tumor tissues. Despite the limited size of the patient cohort, results from this non-invasive EGFR mutation analysis are encouraging and this combined workflow represents a valuable means for informing therapy selection and for monitoring treatment of patients with NSCLC.

Responses were gathered from master's candidates in initial and advanced licensure teacher preparation programs. They were asked to discuss how completing a capstone research project contributed to their effectiveness as a teacher. Advanced candidates reported themes of improving practice, evaluating new school initiatives, and increasing collaboration with colleagues. Initial licensure candidates reported themes of using research to investigate specific topics, using research as part of assessment practices, and the importance of teachers as researchers. Conclusions suggested capstone research projects and the associated research experiences add value to teacher preparation programs and improve teacher self-efficacy.

PurposeSeveral biomarkers have been individually associated with response to PD-1 blockade, including PD-L1 and tumor mutational burden (TMB) in non-small cell lung cancer (NSCLC), and CD8 cells in melanoma. We sought to examine the relationship between these distinct variables with response to PD-1 blockade and long-term benefit.Experimental designWe assessed the association between baseline tumor characteristics (TMB, PD-L1, CD4, and CD8) and clinical features and outcome in 38 patients with advanced NSCLC treated with pembrolizumab (median follow-up of 4.5 years, range 3.8-5.5 years).ResultsPD-L1 expression and CD8 infiltration correlated with each other and each significantly associated with objective response rate (ORR) and progression-free survival (PFS). TMB was independent of PD-L1 and CD8 expression, and trended towards association with ORR and PFS. There was no association between CD4 infiltration and outcomes. Only PD-L1 expression was correlated with overall survival (OS). Among 5 patients with long-term survival >3 years with no additional systemic therapy, PD-L1 expression was the only discriminating feature. The increased predictive value for PFS and OS of composite biomarker inclusive of PD-L1, CD8, CD4, and TMB was limited.ConclusionsIn patients with NSCLC treated with PD-1 blockade with long-term follow up, TMB, PD-L1, and CD8 were each associated with benefit from PD-1 blockade. Pretreatment PD-L1 expression was correlated with T lymphocyte infiltration and OS, whereas models incorporating TMB and infiltrating CD4 and CD8 lymphocytes did not substantially add to the predictive value of PD-L1 alone for OS.

Imperfect information on future energy costs can lower the demand for more energy efficient technologies, with clear implications for energy supply, emissions and climate change. These hypotheses are explored using a randomised discrete choice experiment for property rental decisions. Results show that when energy consumption is expressed in physical units (as per the current EU labels) the willingness-to-pay for energy efficiency improvements is small and marginally significant. While bimonthly energy cost information displayed in monetary terms has no effect on the valuation of energy efficiency, annual monetary energy cost information led to a significant increase. This is the first paper to compare short and long-term point of sale energy cost information for household property decisions. There are clear implications for labelling policy for properties--framing energy consumption according to long-term monetary cost increases the demand for energy efficiency. Keywords: Energy Efficiency Labels, Cost Labels, Discrete Choice Experiment, Rental Properties, Framing Effect, Ireland, 1. INTRODUCTION While more energy efficient products generally cost more upfront, their lower running costs can make them better investments over their lifetime. Household failure to make this intertemporal trade-off [...]

Floating offshore wind (FOW) is a renewable energy source that is set to play an essential role in addressing climate change and the need for sustainable development. However, due to the increasing threat of climate emergency, more wind turbines are required to be deployed in deep water locations, further offshore. This presents heightened challenges for accessing the turbines and performing maintenance, leading to increased costs. Naturally, methods to reduce operational expenditure (OpEx) are highly desirable. One method that shows potential for reducing OpEx of FOW is LIDAR‐assisted pitch control. This approach uses wind velocity measurements from a nacelle‐mounted LIDAR to enable feedforward control of floating offshore wind turbines (FOWTs) and can result in reductions to the variations of structural loads. Results obtained from a previous study of combined feedforward collective and individual pitch control (FFCPC + FFIPC) are translated to OpEx reductions via reduced component failure rates for future FOW developments, namely, in locations awarded in the recent ScotWind leasing round. The results indicate that LIDAR‐assisted pitch control may allow for an up to 5% reduction in OpEx, increasing to up to 11% with workability constraints included. The results varied across the three ScotWind sites considered, with sites furthest from shore reaping the greatest benefit from LIDAR‐assisted control. This work highlights the potential savings and reduction in the overall levelised cost of energy for future offshore wind turbine projects deliverable through the implementation of LIDAR‐assisted pitch control. [ABSTRACT FROM AUTHOR]

IntroductionInternalized lung cancer stigma (i.e., feelings of regret, shame, and self-blame about one's lung cancer) is related to poorer psychological outcomes. Less is known about how internalized stigma relates to physical and functional outcomes or how constrained disclosure (i.e., avoidance of or discomfort about disclosing one's lung cancer status to others) relates to well-being. Furthermore, no study has examined whether internalized stigma and constrained disclosure predict changes in well-being for lung cancer patients. This longitudinal study characterized relationships of internalized stigma and constrained disclosure with emotional and physical/functional outcomes.MethodsParticipants (N = 101, 52.4% male, 63.4% currently/formerly smoked) were lung cancer patients on active medical treatment who completed questionnaires on stigma and well-being at study entry and at 6- and 12-week follow-up. Multivariable linear regressions characterized relationships of internalized stigma and constrained disclosure with emotional and physical/functional well-being at study entry and across time.ResultsParticipants who currently or formerly smoked reported higher levels of internalized stigma (but not constrained disclosure), compared to never smokers (p < 0.001). Higher internalized stigma and constrained disclosure were uniquely associated with poorer emotional and physical/functional well-being at study entry (all p < 0.05), beyond sociodemographic characteristics, time elapsed since diagnosis, and smoking status. Higher internalized stigma predicted significant declines in emotional well-being across 6 and 12 weeks (all p < 0.01) and declines in physical/functional well-being across 6 weeks (p < 0.05).ConclusionsInternalized lung cancer stigma and constrained disclosure relate to emotional and physical/functional maladjustment. Findings carry implications for provider- and patient-focused interventions to reduce internalized stigma and promote well-being.

We retrospectively analyzed non-small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to Common Terminology Criteria for Adverse Events v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated. Ninety-seven NSCLC patients treated on KEYNOTE-001 at the University of California, Los Angeles were evaluated. Ten percent (85/826) of AEs were trAEs, occurring in 40% (39/97) of patients. The most frequent trAEs were rash (21% patients), fatigue (6% patients), and hypothyroidism (6% patients). The 39 patients that experienced a trAE had increased objective response rate (ORR, 38.5%), progression-free survival (PFS: median, 248 days), and overall survival (OS: median, 493 days), compared with the 58 patients that did not (ORR: 8.9%, PFS: median 60 days, OS: median 144.5 days). The observed association between trAEs and improved clinical outcome persisted when using Cox proportional hazards regression models to assess the confounding effect of covariates and mitigate guarantee-time bias. The association also remained when data were substratified by grade, degree of association, and treatment-related select AE designation. This single-center analysis revealed that trAEs predicted for improved clinical outcome with pembrolizumab, and when controlling for guarantee-time bias and plausible confounders, this association remained. This observed relationship adds to our understanding of anti-PD-1 therapy and could aid clinicians in identifying patients most likely to benefit from therapy. Cancer Immunol Res; 6(3); 288-94. ©2018 AACR.

The purpose of this study was to examine the impact on program improvement of systematically gathering P-12 student learning data over a 5-year period. This study was completed over 5 academic years (2008-2009 to 2012-2013) in a teacher preparation program in northwest Oregon. Data were gathered from two student teaching experiences of teacher candidates during the fall and spring semesters of their practicum experience. The candidates were completing either a 10-month master of arts in teaching (MAT) program or a 4-year, undergraduate licensure program. To these ends, the most gratifying finding is that candidates can demonstrate a positive impact on student learning that is generally equivalent for P-12 students of all ethnicities and learning needs.