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This study combines language assessment processes and interlanguage analysis techniques to determine rater agreement and disagreement in assessing English article acquisition. Employing native English speaking and non-native English speaking raters, picture sequence narratives that were written by English as a Foreign Language (EFL) learners (n=97) were coded and scored for suppliance-in-obligatory context (SOC) and target-like utterance (TLU). Although the kappa statistic revealed a fair agreement between raters (0.17 – 0.33), content analysis methods revealed much higher agreement (88.29% - 94.07%). Furthermore, language background effects between the raters could not be substantiated however the results demonstrated a discernable disagreement pattern between them. Thus, the study recommends the inclusion of a foreign language teaching background as a factor for rater selection to minimize language background effects on rating language assessments.

Exenatide, a glucagon-like peptide-1 receptor agonist, is the active pharmaceutical ingredient in Byetta® and Bydureon®, two type 2 diabetes drug products that have generics and multiple follow-up formulations currently in development. Even though exenatide is known to be chemically and physically unstable at pH 7.5, there lacks a systematic evaluation of the impact of pH and excipients on the peptide solution stability. In this study, we established analytical methods to measure the chemical and physical degradation of the peptide in solution. Exenatide remained relatively stable at pH 4.5 when incubated at 37 °C. At pH 5.5–6.5, degradation was driven by oxidation, while driven by deamidation at pH 7.5–8.5. Significant aggregation of exenatide at pH 7.5 and 8.5 was detected by size exclusion chromatography and dynamic light scattering. Each pH value greater than 4.5 exhibited unique profiles corresponding to a loss of α-helical content and an increase in unordered structures. The addition of sugars, including mannitol, sorbitol and sucrose, conferred small protective effects against peptide aggregation when incubating at pH 7.5 and 37 °C, as measured by size-exclusion chromatography and dynamic light scattering. The results of this study will be useful for investigators developing generic exenatide products, peptide analogs and novel exenatide drug delivery systems.

apoA-I, apoA-I mimetic peptides, and their lipid complexes or reconstituted high-density lipoprotein (HDL) have been studied as treatments for various pathologies. However, consensus is lacking about the best method for administration, by intravenous (IV) or intraperitoneal (IP) routes, and formulation, as an HDL particle or in a lipid-free form. The objective of this study was to systematically examine peptide plasma levels, cholesterol mobilization, and lipoprotein remodeling in vivo following administration of lipid-free apoA-I peptide (22A) or phospholipid reconstituted 22A-sHDL by IV and IP routes. The mean circulation half-life was longer for 22A-sHDL (T1/2 = 6.27 h) than for free 22A (T1/2 = 3.81 h). The percentage of 22A absorbed by the vascular compartment after the IP dosing was ∼50% for both 22A and 22A-sHDL. The strongest pharmacologic response came from IV injection of 22A-sHDL, specifically a 5.3-fold transient increase in plasma-free cholesterol (FC) level compared with 1.3- and 1.8-fold FC increases for 22A-IV and 22A-sHDL-IP groups. Addition of either 22A or 22A-sHDL to rat plasma caused lipoprotein remodeling and appearance of a lipid-poor apoA-I. Hence, both the route of administration and the formulation of apoA-I peptide significantly affect its pharmacokinetics and pharmacodynamics.

CER-001 is a novel engineered HDL-mimetic comprised of recombinant human apoA-I and charged phospholipids that was designed to mimic the beneficial properties of nascent pre-ß HDL. In this study, we have evaluated the dose-dependent regulation of ABCA1 expression in vitro and in vivo in the presence of CER-001 and native HDL (HDL3).CER-001 induced cholesterol efflux from J774 macrophages in a dose-dependent manner similar to natural HDL. A strong down-regulation of the ATP-binding cassette A1 (ABCA1) transporter mRNA (- 50%) as well as the ABCA1 membrane protein expression (- 50%) was observed at higher doses of CER-001 and HDL3 compared to non-lipidated apoA-I. In vivo, in an apoE-/- mouse "flow cessation model," in which the left carotid artery was ligatured to induce local inflammation, the inhibition of atherosclerotic plaque burden progression in response to a dose-range of every-other-day CER-001 or HDL in the presence of a high-fat diet for two weeks was assessed. We observed a U-shaped dose-response curve: inhibition of the plaque total cholesterol content increased with increasing doses of CER-001 or HDL3 up to a maximum inhibition (- 51%) at 5 mg/kg; however, as the dose was increased above this threshold, a progressively less pronounced inhibition of progression was observed, reaching a complete absence of inhibition of progression at doses of 20 mg/kg and over. ABCA1 protein expression in the same atherosclerotic plaque was decreased by-45% and-68% at 50 mg/kg for CER-001 and HDL respectively. Conversely, a-12% and 0% decrease in ABCA1 protein expression was observed at the 5 mg/kg dose for CER-001 and HDL respectively.These data demonstrate that high doses of HDL and CER-001 are less effective at slowing progression of atherosclerotic plaque in apoE-/- mice compared to lower doses, following a U-shaped dose-response curve. A potential mechanism for this phenomenon is supported by the observation that high doses of HDL and CER-001 induce a rapid and strong down-regulation of ABCA1 both in vitro and in vivo. In conclusion, maximally efficient HDL- or CER-001-mediated cholesterol removal from atherosclerotic plaque is achieved by maximizing macrophage-mediated efflux from the plaque while minimizing dose-dependent down-regulation of ABCA1 expression. These observations may help define the optimal dose of HDL mimetics for testing in clinical trials of atherosclerotic burden regression.

Insects that evolved in mesic regions may have difficulty establishing in xeric regions. Rhagoletis pomonella (Walsh) (Diptera: Tephritidae) was introduced into drier western North America from mesic eastern North America while Rhagoletis indifferens Curran is native to western North America. Here, we predicted that R. indifferens survives water deprivation longer than R. pomonella, as R. indifferens is more abundant than R. pomonella in dry central Washington (WA) State, USA. Sweet and bitter cherry-origin R. indifferens and apple- and hawthorn-origin R. pomonella from xeric central or mesic western WA were provided water throughout or were water-deprived at 2-4 and 14-18 d old and held at 20°C or 30/31°C and daily survival recorded. At 20°C and 30°C, western WA apple-origin R. pomonella provided water survived longer than sweet cherry-origin R. indifferens. When water-deprived, however, 2-4 d old R. indifferens, although smaller, survived significantly longer than western WA apple-origin R. pomonella of the same age. This was also generally true for 14-18 d old flies, although differences were less often significant. Central WA large-thorn hawthorn-origin R. pomonella survived water deprivation significantly longer than western WA apple-origin R. pomonella, and as long as R. indifferens. Water-deprived flies of both species survived longer at 20°C than 30/31°C. Survival analyses suggest that low water availability rather than high temperature contributes to lower R. pomonella than R. indifferens abundances in central WA, with R. pomonella populations in that region differing from western WA R. pomonella with respect to tolerance of xeric climates., (Published by Oxford University Press on behalf of Entomological Society of America 2024.)

Anxiety about performing numerical calculations is becoming an increasingly important issue. Termed mathematics anxiety, this condition negatively impacts performance in numerical tasks which can affect education outcomes and future employment. The disruption account proposes poor performance is due to anxiety disrupting limited attentional and inhibitory resources leaving fewer cognitive resources for the current task. This study provides the first neural network model of math anxiety. The model simulates performance in two commonly-used tasks related to math anxiety: the numerical Stroop and symbolic number comparison. Different model modifications were used to simulate high and low math-anxious conditions by modifying attentional processes and learning; these model modifications address different theories of math anxiety. The model simulations suggest that math anxiety is associated with reduced attention to numerical stimuli. These results are consistent with the disruption account and the attentional control theory where anxiety decreases goal-directed attention and increases stimulus-driven attention., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Rose et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The British-born psychologist William McDougall (1871-1938) spent more than half of his academic career in the United States, holding successive positions after 1920 at Harvard and Duke universities. Scholarly studies uniformly characterize McDougall's relationship with his New World colleagues as contentious: in the standard view, McDougall's theory of innate drives clashed with the Americans' experimentation into learned habits. This essay argues instead that rising American curiosity about inborn appetites-an interest rooted in earlier pragmatic philosophy and empirically investigated by interwar scientists-explains McDougall's migration to the United States and his growing success there. A review of McDougall's intellectual and professional ties, evolving outside public controversy, highlights persistent American attention to natural agency and complicates arguments voiced by contemporaries in favor of nurture., (© 2016 Wiley Periodicals, Inc.)

Background: Phase 3 randomized trials have shown that maintenance rituximab (MR) therapy or radioimmunotherapy (RIT) consolidation following frontline therapy can improve progression-free survival for patients with follicular lymphoma (FL), but the cost-effectiveness of these approaches with respect to observation has not been examined using a common modeling framework., Objectives: To evaluate and compare the economic impact of MR and RIT consolidation versus observation, respectively, following the first-line induction therapy for patients with advanced-stage FL., Methods: We developed Markov models to estimate patients' lifetime costs, quality-adjusted life-years (QALYs), and life-years (LYs) after MR, RIT, and observation following frontline FL treatment from the US payer's perspective. Progression risks, adverse event probabilities, costs, and utilities were estimated from clinical data of Primary RItuximab and MAintenance (PRIMA) trial, Eastern Cooperative Oncology Group (ECOG) trial (for MR), and First-line Indolent Trial (for RIT) and the published literature. We evaluated the incremental cost-effectiveness ratio for direct comparisons between MR/RIT and observation. Model robustness was addressed by one-way and probabilistic sensitivity analyses., Results: Compared with observation, MR provided an additional 1.089 QALYs (1.099 LYs) and 1.399 QALYs (1.391 LYs) on the basis of the PRIMA trial and the ECOG trial, respectively, and RIT provided an additional 1.026 QALYs (1.034 LYs). The incremental cost per QALY gained was $40,335 (PRIMA) or $37,412 (ECOG) for MR and $40,851 for RIT. MR and RIT had comparable incremental QALYs before first progression, whereas RIT had higher incremental costs of adverse events due to higher incidences of cytopenias., Conclusions: MR and RIT following frontline FL therapy demonstrated favorable and similar cost-effectiveness profiles. The model results should be interpreted within the specific clinical settings of each trial. Selection of MR, RIT, or observation should be based on patient characteristics and expected trade-offs for these alternatives., (Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

The need to evaluate medicines for children is widely acknowledged due to pervasive unlicensed medicine use in the pediatric setting. The EU Paediatric Regulation was developed to address these considerations, which subsequently led to the establishment of the National Institute of Health Research (NIHR) Medicines for Children Research Network (MCRN) in England. MCRN supports public and industry studies, and facilitates feasibility, site setup, recruitment and other services. The MCRN and other networks are members of the European Network of Paediatric Research at the European Medicines Agency (Enpr-EMA). Enpr-EMA was established to foster and coordinate research, and develop collaborations across Europe. MCRN works with Enpr-EMA, industry and others to improve the conduct of research for the benefit of children's health.

Background: Follicular lymphoma (FL) is characterized by multiple relapses and progressively shorter response durations with subsequent therapies. Despite the development of numerous treatment strategies to reduce the risk of progression, optimal therapeutic strategies for patients with FL remain undefined. Radioimmunotherapy (RIT) with an anti-CD20 antibody linked to iodine-131 or to yttrium-90 has emerged as well-tolerated treatment after induction. We conducted a systematic literature review and meta-analyses to quantify the benefits of consolidative RIT., Methods: We searched the CENTRAL and MEDLINE libraries, and conference abstracts for reports on phase II/III clinical trials that assessed RIT consolidation for patients with untreated FL. Extracted data included pretreatment disease status, patient characteristics, treatment regimen, response rates, progression-free survival (PFS), and overall survival (OS). Pooled estimates of complete response (CR), overall response (OR), 2- and 5-year PFS and OS rates were computed by using random effects models., Results: Eight studies (n = 783) were included in the meta-analyses. CR rates after RIT ranged from 69.0% to 96.5%, 2-year PFS ranged from 64.8% to 86.1%, and 5-year PFS ranged from 47.0% to 67.3%. The pooled estimates of the CR rate and OR rate were 82.7% (95% CI, 67.4%-91.7%) and 96.2% (95% CI, 90.4%-98.6%), respectively. The pooled estimates for 5-year PFS and OS were 57.6% (95% CI, 47.8%-66.9%) and 90.1% (95% CI, 83.9%-94.1%), respectively., Conclusions: We believe that these aggregated data can further the discussion on RIT as a consolidation therapy and inform decisions on future study designs Additional studies are needed to compare the benefits of RIT consolidation to maintenance therapy with rituximab., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In nineteenth-century science, the emotions played a crucial role in explaining the social behavior of animals and human beings. Beginning in the 1890s, however, the first American psychologists, resolutely parsimonious in method, dismissed affective experience as intellectually imprecise. Yet in practice, feelings continued to influence at least one research setting: animal experiments. Laboratory reports, although focused on learning, became a repository of informal observations about the animals' temperaments and moods. When American psychologists began to reexamine the emotions between the world wars, they drew on this empirical legacy in animal studies. They also devised a conceptual approach to emotion consistent with their expectation of experimental precision., (© 2012 Wiley Periodicals, Inc.)

Diffuse large B-cell lymphoma (DLBCL) is the most commonly occurring lymphoid malignancy. While a series of trials support R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone, plus rituximab)-21 as the standard of care for all patients, DLBCL has substantial biological and clinical heterogeneity, leading to marked differences in outcomes for disease subgroups. We examine clinical, biological, and functional imaging techniques for risk-stratifying patients, and we review approaches for dose intensification in the rituximab era that are aimed at improving outcomes for poor-risk patients. Together, the results achieved with these measures indicate no particular benefit for administering R-CHOP-14 vs R-CHOP-21 in older or younger patients with DLBCL, highlight opportunities for future studies of young patients with high-risk DLBCL, and suggest the promise of biologic risk stratification. Such approaches will provide key opportunities for further advances in the treatment of DLBCL, given that chemotherapy intensification appears to provide limited additional benefits over the current standard of care.

A sharp and personal polemical style characterized psychology as a new human science in American universities at the turn of the 20th century. When the experimental pursuit of truth about the mind produced quarreling rather than clarity, psychologists experienced a crisis of confidence. One solution was rhetorical: the use of a disclaimer that all current knowledge was rudimentary and a call for further research to end contention. The wording established a public tone of modesty and fostered collegiality. Scientific disagreements and underlying personal tensions remained, but conventional phrases promising future resolution of disputes contributed to a language of good manners and thereby facilitated debate. Nonetheless, the verbal formula of deferred hopes also made uncertainty seem normative. Confessions of tentativeness helped lay a historical foundation for routine investigation in psychology, but emphasis on incompleteness as an explanation of discord also made experimentation seem perpetual and truth elusive.

In the latter decades of the 19th century, European physicians debated a controversial practice that mixed placebos with suggestion therapy to treat children diagnosed with neurotic disorders and behavioral problems. Designed to optimize suggestibility in juvenile patients, this "moral orthopedics" offered parents and therapists the message that children could be saved from becoming victims of their own personalities, of familial neuroses, or even of public health problems. Case studies, published in medical journals and books, circulated accounts of innovative strategies to treat childhood hysteria and to change habits that were considered destructive. Moral orthopedics actualized the insight that suggestibility could be therapeutically productive for juvenile subjects. However, because its adherents sought to manipulate patients' behavior and health by influencing unconscious thought, moral orthopedics provoked questions of expertise and disciplinary propriety among domains of medicine, law, and philosophy. This article reconstructs the controversy surrounding moral orthopedics by examining case studies. I argue that adherents of moral orthopedics did overcome philosophical objections raised against the method, and that they did so through what physician Edgar B6rillon referred to as "education of the will."

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists.

Although the psychology of race in America has been the subject of significant research, psychological science in the principal region of racial interaction before Brown v. Board of Education-the South--has received little attention. This article argues that the introduction of psychological ideas about children by means of school reform in the South during the half-century before the Brown decision established a cultural foundation for both Black resistance to segregated schools and White determination to preserve them. In 1900, southern children and their schools were an afterthought in a culture more committed to tradition and racial stability than innovation and individual achievement. The advent of northern philanthropy, however, brought with it a new psychology of childhood. Although the reformers did not intend to subvert segregation, their premises downplayed natural endowment, including racial inheritance, and favored concepts highlighting nurture: that personality is developmental, childhood foundational, and adversity detrimental. Decades of discussion of children in their learning environment gave southern Blacks a rationale for protest and Whites a logical defense for conservative reaction.

1. Chronic inflammation is a central feature of asthma. The inflammatory cytokine tumour necrosis factor alpha (TNFalpha) has been implicated in this disease, and is known to alter airway smooth muscle functionally. 2. The aim of this study was to investigate the influence of TNFalpha on tachykinin-induced airway relaxation. Mouse tracheae were cultured in the absence and presence of TNFalpha for 1 or 4 days. 3. In the absence of TNFalpha, substance P (SP) and neurokinin A (NKA) induced comparable levels of relaxation in fresh and cultured segments. Functional studies with selective antagonists/inhibitors indicated that the relaxation was mediated by the NK(1) receptor coupled to cyclooxygenase (COX)-2 activation and subsequent release of prostaglandin E(2) (PGE(2)). TNFalpha attenuated SP- and NKA-induced relaxation in a time- and concentration-dependent manner, decreasing the ability of PGE(2) to relax tissues. 4. Further studies indicated that TNFalpha elevated COX-2 activity and that concomitant inhibition of COX-2 reversed TNFalpha-attenuated PGE(2) relaxation. Culture with PGE(2) decreased SP- and PGE(2)-mediated relaxation, further implicating the activity of COX-2 in the attenuation of tachykinin signalling. 5. Gene expression analysis demonstrated that TNFalpha increased the expression of smooth muscle COX-2, PGE(2) synthase and EP(2) receptor mRNA, and decreased the expression of the EP(4) receptor. 6. Overall, these results show that NK(1) receptor-mediated relaxation induced by PGE(2) is attenuated by prolonged TNFalpha stimulation. Increased COX-2 activity induced by TNFalpha appears to be central to this process.

1. Asthma research is arguably limited by an absence of appropriate animal models to study the pharmacology of inflammatory mediators that affect airway hyperresponsiveness and remodelling. Here we assessed an assay based on mouse tracheal segments cultured for 1-32 days, and investigated contractile responses mediated by muscarinic and 5-hydroxytryptamine (5-HT) receptors following long-term exposure to tumour necrosis factor-alpha (TNFalpha). 2. Following culture, in the absence of TNFalpha, maximum contractile responses to KCl and carbachol were similar, with an increase in response up to day two and a decrease to a stable level after 8 days. Maximal relaxations to isoprenaline were not affected by the culture procedure. The potency of KCl and isoprenaline increased throughout the study. DNA microarray data revealed that global gene expression changes were greater when tissues were introduced to culture than when they were maintained in culture. The morphology of smooth muscle cells was maintained throughout the culture period. 3. 5-HT induced a weak contraction in both fresh and cultured (up to 8 days) segments. Culture with TNFalpha produced a time- and concentration-dependent increase in the maximal contraction to 5-HT, evidently mediated by 5-HT(2A) receptors, whereas, the potency for carbachol was reduced. 4. In conclusion, the phenotype of airway smooth muscle remained largely intact during the culture period, even though minor changes were obtained during the first days of culture. The time-dependent effect of TNFalpha indicates the importance of studying the long-term effect of cytokines on the smooth muscle cells in relation to airway hyperresponsiveness and remodelling.

Naked plasmid DNA and DNA/liposome complexes are currently being considered as gene therapy treatments for cystic fibrosis (CF) pulmonary disease. Current methods of gene delivery to the airways result only in transient correction of the CF ion transport defect, and disease treatment is likely to require repeated administrations of vector. However, it is unclear if repeat administration will be tolerated by CF individuals. Technologies including TaqMan (Applied Biosystems) real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) can be used to determine the efficacy of gene transfer formulations. TaqMan RT-PCR assays were designed and optimised to detect plasmid vector-derived and endogenous gene expression. Subsequently, these assays were used to quantify vector-derived mRNA after delivery of naked DNA and DNA/liposome formulations expressing human and murine cystic fibrosis transmembrane conductance regulator (CFTR) to the mouse airways. Vector-derived mRNA was detected in samples following the delivery of naked DNA or DNA/liposomes to the mouse airways, and no reduction in vector-derived mRNA was observed upon repeat administration, a finding that is consistent with the murine and human CFTR being tolerated by the mouse. Although it remains to be seen if CF patients can tolerate long-term expression of wild-type CFTR, these data demonstrate that TaqMan RT-PCR is an effective tool to accurately quantify transgene expression in the airways.