127 research outputs found

    Targeted proteomic quantitation of NRF2 signaling and predictive biomarkers in HNSCC

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    The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min

    Evaluation of a multifaceted "Resident-as-Teacher" educational intervention to improve morning report

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    BACKGROUND: Resident-led morning report is an integral part of most residency programs and is ranked among the most valuable of educational experiences. The objectives of this study were to evaluate the effect of a resident-as-teacher educational intervention on the educational and teaching experience of morning report. METHODS: All senior internal medicine residents were invited to participate in this study as teaching participants. All internal medicine residents and clerks were invited to participate as audience participants. The educational intervention included reading material, a small group session and feedback after teaching sessions. The educational and teaching experiences were rated prior to and three months after the intervention using questionnaires. RESULTS: Forty-six audience participants and 18 teaching participants completed the questionnaires. The degree to which morning report met the educational needs of the audience was higher after the educational intervention (effect size, d = 0.26, p = 0.01). The perceptions of the audience were that delivery had improved and that the sessions were less intimidating and more interactive. The perception of the teaching participants was that delivery was less stressful, but this group now reported greater difficulty in engaging the audience and less confidence in their medical knowledge. CONCLUSION: Following the educational intervention the audience's perception was that the educational experience had improved although there were mixed results for the teaching experience. When evaluating such interventions it is important to evaluate the impact on both the educational and teaching experiences as results may differ

    Is American Public Administration Detached From Historical Context?: On the Nature of Time and the Need to Understand It in Government and Its Study

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    The study of public administration pays little attention to history. Most publications are focused on current problems (the present) and desired solutions (the future) and are concerned mainly with organizational structure (a substantive issue) and output targets (an aggregative issue that involves measures of both individual performance and organizational productivity/services). There is much less consideration of how public administration (i.e., organization, policy, the study, etc.) unfolds over time. History, and so administrative history, is regarded as a “past” that can be recorded for its own sake but has little relevance to contemporary challenges. This view of history is the product of a diminished and anemic sense of time, resulting from organizing the past as a series of events that inexorably lead up to the present in a linear fashion. To improve the understanding of government’s role and position in society, public administration scholarship needs to reacquaint itself with the nature of time.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

    Optimization of interneuron function by direct coupling of cell migration and axonal targeting

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    Neural circuit assembly relies on the precise synchronization of developmental processes, such as cell migration and axon targeting, but the cell-autonomous mechanisms coordinating these events remain largely unknown. Here we found that different classes of interneurons use distinct routes of migration to reach the embryonic cerebral cortex. Somatostatin-expressing interneurons that migrate through the marginal zone develop into Martinotti cells, one of the most distinctive classes of cortical interneurons. For these cells, migration through the marginal zone is linked to the development of their characteristic layer 1 axonal arborization. Altering the normal migratory route of Martinotti cells by conditional deletion of Mafb—a gene that is preferentially expressed by these cells—cell-autonomously disrupts axonal development and impairs the function of these cells in vivo. Our results suggest that migration and axon targeting programs are coupled to optimize the assembly of inhibitory circuits in the cerebral cortex

    Sleep’s Role in Schema Learning and Creative Insights

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    Purpose of Review A recent resurgence of interest in schema theory has influenced research on sleep-dependent memory consolidation and led to a new understanding of how schemata might be activated during sleep and play a role in the reorganisation of memories. This review aims to synthesise recent findings into a coherent narrative and draw overall conclusions. Recent Findings Rapid consolidation of schematic memories has been shown to benefit from an interval containing sleep. These memories have shown reduced reliance on the hippocampus following consolidation in both humans and rodents. Using a variety of methodologies, notably including the DRM paradigm, it has been shown that activation of a schema can increase the rate of false memory as a result of activation of semantic associates during slow wave sleep (SWS). Memories making use of a schema have shown increased activity in the medial prefrontal cortex, which may reflect both the schematic activation itself and a cognitive control component selecting an appropriate schema to use. SWS seems to be involved in assimilation of new memories within existing semantic frameworks and in making memories more explicit, while REM sleep may be more associated with creating entirely novel associations while keeping memories implicit. Summary Sleep plays an important role in schematic memory consolidation, with more rapid consolidation, reduced hippocampal involvement and increased prefrontal involvement as the key characteristics. Both SWS and REM sleep may have a role to play

    Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

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    It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations

    Hygienic pelleting can decrease Hubbard × Ross 708 apparent ileal amino acid digestibility, broiler performance, and increase digestible amino acid requirement

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    SUMMARY: To reduce pathogenic bacteria such as Salmonella in feed and ensure a high-quality pellet, diets for broilers, turkeys, and breeders may be pelleted using high conditioning temperatures and extended times. However, increased conditioning temperature and time may alter amino acid conformation regarding secondary and tertiary structure, decrease digestibility and subsequent bird performance, and necessitate increased amino acid formulation density. The objective of this study was to evaluate increased conditioning temperature and exposure time within the pelleting process using a hygienizer (hygienic pelleting) in diets that vary in digestible lysine and corresponding amino acid ratio on Hubbard × Ross 708 starter broiler performance, apparent ileal amino acid digestibility (AIAAD), and requirement. A 5 × 2 factorial arrangement of treatments with 5 levels of digestible lysine (−20, −10%, 2019 Ross Broiler Starter Nutrition recommendation, +10, and +20%) and 2 techniques of pelleting (standard and hygienic) was utilized in a randomized complete block design. Standard pelleting utilized 77°C conditioning for 30 s and hygienic pelleting utilized 88°C conditioning for 60 s and 6-min retention time in a hygienizer. Each treatment was fed to 12 replicate pens of 10 male broiler Hubbard × Ross 708 chicks for a 21-day period. Standard pelleting and hygienic pelleting demonstrated a 1.19 and 1.37% digestible Lys requirement, respectively, using the 2 straight line, 1-breakpoint broken-line regression model. Performance data, AIAAD, and the broken-line regression model suggest an approximate 10% increase in digestible Lys and corresponding amino acid ratio relative to 2019 Ross Broiler Starter Nutrition Specifications for Hygienic Pelleting. Nutritionists should be cognizant that nutritional detriment may accompany procedures used to create hygienic pelleted feed
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