Examining the factors that affect structural repetition in question answering.

We present two experiments that examine structural priming in the single-trial phone-call paradigm introduced by Levelt and Kelter (Cognitive psychology, 14 (1), 78-106, 1982). Experimenters called businesses and asked either What time do you close? or At what time do you close? Participants were more likely to produce a prepositional response (At 7 o'clock vs. 7 o'clock) following a prepositional question than following a non-prepositional question. Experiments 1 and 2 attempted to strengthen the priming effect by having the experimenters engage in a brief interaction with the participant before asking the What time…? question. The interactions did not reliably affect the observed priming effect. An analysis across experiments demonstrated that the priming effect found in this paradigm is generally smaller than the average structural priming effect (as reported in Mahowald, James, Futrell, & Gibson, Journal of Memory and Language, 91, 5-27, 2016), but within the range of the effects that are observed in different structural priming paradigms.

Natural TCRs targeting KRASG12V display fine specificity and sensitivity to human solid tumors.

BACKGROUND: Neoantigens derived from KRASMUT have been described, but the fine antigen specificity of T cell responses directed against these epitopes are poorly understood. Here, we explore KRASMUT immunogenicity and the properties of 4 TCRs specific for KRASG12V restricted to HLA-A3 superfamily of class I alleles. METHODS: A phase I clinical vaccine trial targeting KRASMUT was conducted. TCRs targeting KRASG12V restricted to HLA-A*03:01 or HLA-A*11:01 were isolated from vaccinated patients or healthy individuals. A comprehensive analysis of TCR antigen specificity, affinity, cross-reactivity, and CD8 coreceptor dependence was performed. TCR lytic activity was evaluated, and target antigen density was determined by quantitative immunopeptidomics. RESULTS: Vaccination against KRASMUT resulted in the priming of CD8+ and CD4+ T cell responses. KRASG12V -specific natural (not affinity-enhanced) TCRs exhibited exquisite specificity to mutated protein with no discernable reactivity against KRASWT. TCR-recognition motifs were determined and used to identify and exclude cross-reactivity to non-cognate peptides derived from the human proteome. Both HLA-A*03:01 and HLA-A*11:01 restricted TCR-redirected CD8+ T cells exhibited potent lytic activity against KRASG12V cancers, while only HLA-A*11:01 restricted TCR-T CD4+ T cells exhibited anti-tumor effector functions consistent with partial co-receptor dependence. All KRASG12V-specific TCRs displayed high sensitivity for antigen as demonstrated by their ability to eliminate tumor cell lines expressing low levels of of peptide/HLA (4.4 to 242) complexes per cell. CONCLUSION: This study identifies KRASG12V-specific TCRs with high therapeutic potential for the development of TCR-T cell therapies. CLINICALTRIALS: gov NCT03592888. FUNDING: AACR SU2C / Lustgarten Foundation, Parker Institute for Cancer Immunotherapy, and NIH (R01 CA204261, P01 CA217805, P30 CA016520).

Randomized trial of Nordic walking in patients with moderate to severe heart failure.

BACKGROUND: Patients with heart failure are a growing population within cardiac rehabilitation. The purpose of this study was to compare, through a single-centre, parallel-group, randomized controlled trial, the effects of Nordic walking and standard cardiac rehabilitation care on functional capacity and other outcomes in patients with moderate to severe heart failure. METHODS: Between 2008 and 2009, 54 patients (aged 62.4 ± 11.4 years) with heart failure (mean ejection fraction = 26.9% ± 5.0%) were randomly assigned to standard cardiac rehabilitation care (n = 27) or Nordic walking (n = 27); both groups performed 200 to 400 minutes of exercise per week for 12 weeks. The primary outcome, measured after 12 weeks, was functional capacity assessed by a 6-minute walk test (6MWT). RESULTS: Compared with standard care, Nordic walking led to higher functional capacity (Δ 125.6 ± 59.4 m vs Δ 57.0 ± 71.3 m travelled during 6MWT; P = 0.001), greater self-reported physical activity (Δ 158.5 ± 118.5 minutes vs Δ 155.5 ± 125.6 minutes; P = 0.049), increased right grip strength (Δ 2.3 ± 3.5 kg vs Δ 0.3 ± 3.1 kg; P = 0.026), and fewer depressive symptoms (Hospital Anxiety and Depression Scale score = Δ -1.7 ± 2.4 vs Δ -0.8 ± 3.1; P = 0.014). No significant differences were found for peak aerobic capacity, left-hand grip strength, body weight, waist circumference, or symptoms of anxiety. CONCLUSIONS: Nordic walking was superior to standard cardiac rehabilitation care in improving functional capacity and other important outcomes in patients with heart failure. This exercise modality is a promising alternative for this population.