Learning Effects on Pain Generalize to Perceptually and Conceptually Similar Cues and Modify Pain Perception

Prior learning about pain can drive a placebo or nocebo effect in later settings and influence pain more broadly. This up- or down-modulation of pain is influenced by expectations and learning during conditioning. After conditioning, it has been shown that the association between the original conditioned stimulus (CS) and the unconditioned stimulus (UCS) can generalize to novel, but similar stimuli. This is known as generalization, which is seen across humans and non-human animals. The present studies tested the hypothesis that conditioning effects on pain will generalize to similar, but novel stimuli; meaning that pain will be modulated in new situations based on perceptual or conceptual similarity to previous conditioned stimuli. Two studies were conducted with healthy participants (study 1, n=40; study 2 n=36) to test the generalization of pain learning to novel, but perceptually and conceptually similar stimuli, respectively. The results of both studies show that learned conditioned pain modulation generalizes to perceptually and conceptually similar stimuli, and that explicit awareness of the cue-pain relationship was necessary for this effect. These findings provide evidence that pain perception can be modulated by generalization stimuli, which could also play a role in clinical placebo effects

Maturation of the functional mouse CRES amyloid from globular form

The epididymal lumen contains a complex cystatin-rich nonpathological amyloid matrix with putative roles in sperm maturation and sperm protection. Given our growing understanding for the biological function of this and other functional amyloids, the problem still remains: how functional amyloids assemble including their initial transition to early oligomeric forms. To examine this, we developed a protocol for the purification of nondenatured mouse CRES, a component of the epididymal amyloid matrix, allowing us to examine its assembly to amyloid under conditions that may mimic those in vivo. Herein we use X-ray crystallography, solution-state NMR, and solid-state NMR to follow at the atomic level the assembly of the CRES amyloidogenic precursor as it progressed from monomeric folded protein to an advanced amyloid. We show the CRES monomer has a typical cystatin fold that assembles into highly branched amyloid matrices, comparable to those in vivo, by forming β-sheet assemblies that our data suggest occur via two distinct mechanisms: a unique conformational switch of a highly flexible disulfide-anchored loop to a rigid β-strand and by traditional cystatin domain swapping. Our results provide key insight into our understanding of functional amyloid assembly by revealing the earliest structural transitions from monomer to oligomer and by showing that some functional amyloid structures may be built by multiple and distinctive assembly mechanisms

Vulnerable Dispositional Traits and Chronic Pain: Predisposing but not Predetermining

Dispositional traits can be protective or contribute to increased vulnerability in individuals with chronic pain. This study aims to evaluate the predictive utility of two dispositional trait measures, affect balance style and multi-domain trait groups specific to clinical pain, psychosocial functioning, experimental pain, and health outcomes at two years in individuals with chronic knee pain. The study is a prospective analysis of 168 community dwelling individuals aged 45-85 years old with knee pain with or at risk for knee osteoarthritis. At baseline, affect balance style and multi-domain trait groups were predictive of psychosocial and clinical pain measures with the multi-domain trait groups showing a greater range of association with clinical measures. At the two-year time point, both the affect balance style groups and the multi-domain trait groups were predictive of physical and psychosocial functioning while the multi-domain trait groups were also predictive of all clinical pain measures. Interestingly, individuals in the vulnerable trait groups showed more variability in dispositional trait status at the two-year time point compared to those in the more protective trait groups. Findings reiterate that a vulnerable trait may be predisposing but is not predetermining regarding pain-related experiences

Dispositional traits help explain individual differences in relationships between a radiographic knee osteoarthritis measure, pain, and physical function

Background: The concordance between radiograph-derived Kellgren-Lawrence (KL) scores for knee osteoarthritis (KOA) and experimental and clinical pain and KOA-related physical function is conflicting.Objectives: We investigate whether the inclusion of dispositional traits reduces variability between KOA radiographic findings, experimental pain, clinical pain, and function in individuals with knee pain.Design: This study is a cross-sectional, secondary analysis of data collected from the UPLOAD-II study.Methods: Adults aged 45-85 years with and without knee pain were enrolled. Data collected included sociodemographics, knee radiographs, experimental pain, clinical pain and function, and trait affect. Vulnerable and protective dispositional traits were classified from combined positive and negative trait affect measures. KL scores were determined from the knee radiographs. Unadjusted and adjusted (age, sex, comorbidities, and body mass index) regression analyses were completed with SAS version 9.4 (Cary, NC, USA).Results: The study included 218 individuals with a mean age of 58 years, 63.6% women, and 48.2% non-Hispanic black adults. Dispositional traits were associated with the experimental pain measures. No association between radiographic KOA and experimental pain was observed. In a combined and adjusted analysis, dispositional traits were predictive of knee punctate pain temporal summation (p = 0.0382). Both dispositional traits and radiographic KOA scores independently and combined were predictive of Graded Chronic Pain Scale pain and function, and Western Ontario and McMaster University pain and function (ps <= 0.01). Improvements in R2 were noted across all models with the inclusion of dispositional traits.Conclusion: Consideration of dispositional traits reduces the variability between radiographic KOA and pain and function. Non-pathological and associated pain-related psychological factors and dispositional traits might serve as parsimonious proxy tools to improve clinical assessments.Registration: N/A.Dispositional traits help explain individual differences in relationships between a radiographic knee osteoarthritis measure, pain, and physical functionSignificance center dot The concordance between radiographic knee osteoarthritis and experimental and clinical pain is conflicting.center dot Dispositional traits comprise the infrastructure from which an individual interprets and interacts with the environment and are predictive of sensory sensitivity, response to stress, psychopathology, and behavior.center dot Consideration of dispositional traits improves the congruence between knee osteoarthritis Kellgren-Lawrence scores, experimental pain, and clinical pain

Greater socioenvironmental risk factors and higher chronic pain stage are associated with thinner bilateral temporal lobes

Abstract Introduction: Previous research indicates ethnic/race group differences in pain and neurodegenerative diseases. Accounting for socioenvironmental factors reduces ethnic/race group differences in clinical and experimental pain. In the current study sample, we previously reported that in individuals with knee pain, ethnic/race group differences were observed in bilateral temporal lobe thickness, areas of the brain associated with risk for Alzheimer's disease, and related dementias. The purpose of the study was to determine if socioenvironmental factors reduce or account for previously observed ethnic/race group differences and explore if a combined effect of socioenvironmental risk and chronic pain severity on temporal lobe cortices is evident. Methods: Consistent with the prior study, the sample was comprised of 147 adults (95 women, 52 men), 45–85 years of age, who self‐identified as non‐Hispanic Black (n = 72) and non‐Hispanic White (n = 75), with knee pain with/at risk for osteoarthritis. Measures included demographics, health history, pain questionnaires, cognitive screening, body mass index, individual‐ and community‐level socioenvironmental factors (education, income, household size, marital and insurance status, and area deprivation index), and brain imaging. We computed a summative socioenvironmental risk index. Results: Regression analyses showed that with the inclusion of socioenvironmental factors, the model was significant (p < .001), and sociodemographic (ethnic/race) group differences were not significant (p = .118). Additionally, findings revealed an additive stress load pattern indicating thinner temporal lobe cortices with greater socioenvironmental risk and chronic pain severity (p = .048). Implications: Although individual socioenvironmental factors were not independent predictors, when collectively combined in models, ethnic/race group differences in bilateral temporal lobe structures were not replicated. Further, combined socioenvironmental risk factors and higher chronic pain severity were associated with thinner bilateral temporal lobes

Cross-oncopanel study reveals high sensitivity and accuracy with overall analytical performance depending on genomic regions.

Targeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing. All panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5-20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden. This comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.All SEQC2 participants freely donated their time, reagents, and computing resources for the completion and analysis of this project. Part of this work was carried out with the support of the Intramural Research Program of the National Institutes of Health (to Mehdi Pirooznia), National Institute of Environmental Health Sciences (to Pierre Bushel), and National Library of Medicine (to Danielle Thierry-Mieg, Jean Thierry-Mieg, and Chunlin Xiao). Leming Shi and Yuanting Zheng were supported by the National Key R&D Project of China (2018YFE0201600), the National Natural Science Foundation of China (31720103909), and Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). Donald J. Johann, Jr. acknowledges the support by FDA BAA grant HHSF223201510172C. Timothy Mercer and Ira Deveson were supported by the National Health and Medical Research Council (NHMRC) of Australia grants APP1108254, APP1114016, and APP1173594 and Cancer Institute NSW Early Career Fellowship 2018/ECF013. This research has also been, in part, financially supported by the MEYS of the CR under the project CEITEC 2020 (LQ1601), by MH CR, grant No. (NV19-03-00091). Part of this work was carried out with the support of research infrastructure EATRIS-CZ, ID number LM2015064, funded by MEYS CR. Boris Tichy and Nikola Tom were supported by research infrastructure EATRIS-CZ, ID number LM2018133 funded by MEYS CR and MEYS CR project CEITEC 2020 (LQ1601).S