Childhood adversity predicts black young adults’ DNA methylation-based accelerated aging: A dual pathway model

We expand upon prior work (Gibbons et al., 2012) relating childhood stressor effects, particularly harsh childhood environments, to risky behavior and ultimately physical health by adding longer-term outcomes – deoxyribonucleic acid (DNA) methylation-based measures of accelerated aging (DNAm-aging). Further, following work on the effects of early exposure to danger (McLaughlin et al., 2014), we also identify an additional pathway from harsh childhood environments to DNAm-aging that we label the danger/FKBP5 pathway, which includes early exposure to dangerous community conditions that are thought to impact glucocorticoid regulation and pro-inflammatory mechanisms. Because different DNAm-aging indices provide different windows on accelerated aging, we contrast effects on early indices of DNAm-aging based on chronological age with later indices that focused on predicting biological outcomes. We utilize data from Family and Community Health Study participants (N = 449) from age 10 to 29. We find that harshness influences parenting, which, in turn, influences accelerated DNAm-aging through the risky cognitions and substance use (i.e., behavioral) pathway outlined by Gibbons et al. (2012). Harshness is also associated with increased exposure to threat/danger, which, in turn, leads to accelerated DNAm-aging through effects on FKBP5 activity and enhanced pro-inflammatory tendencies (i.e., the danger/FKBP5 pathway).

NI-6 Preoperative differential diagnosis of grade II and grade III in cases with astrocytoma, IDH mutant

Purpose: We attempted to differentiate between IDH-mutant astrocytoma Grade II and grade III by using methionine (MET) positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). Subjects and Methods: We retrospectively analyzed 41 adult supratentorial glioma cases with confirmed histological diagnosis and IDH status from June 2015 to June 2020. These included 21 males, with an average age of 38.5 years (19–59 years), including seven astrocytoma grade II (A-II) and 34 grade III (A-III) cases. We determined the accumulation value rate of the maximum tumor to normal cortex accumulation value (T/N ratio) in MET-PET. We obtained the peak ratios of N-acetyl aspartate (NAA)/ creatine (Cr), choline (Cho)/Cr, and Cho/NAA. We investigated the correlation between the T/N ratios and MRS parameters and examined the contrast effects on MRI. Results: There were no significant differences in the T/N ratio and MRS parameters between A-IIs and A-IIIs. Only Cho/NAA ratios were significantly correlated with the T/N ratios (r = 0.443, P = 0.0037). We divided the distribution map into four areas with the highest T/N ratio of AII (1.59) and the highest Cho/NAA ratio (3.66). That is, 1) T/N ratio ≤ 1.59 & Cho/NAA ≤ 3.66, 2) >1.59 & ≤ 3.66, 3) ≤1.59 & > 3.66, 4) &gt 1.59 & &gt 3.66. The diagnostic rates for A-III were 1) 61.1% (11/18), 2) 100% (7/7), 3) 100% (9/9), and 4) 100% (7/7). We found the contrast effects in only 7 cases (20.6%) of A-III, which were distributed in areas 2) to 4). Conclusion: A-IIs and A-IIIs distributed in area 1) were difficult to distinguish, and they need careful observation as a step before the transition to areas 2)-4). Meanwhile, A-IIIs reaching widespread distribution to areas 2)-4) because of their wide range of malignancies require clinically aggressive treatment. The method might be beneficial in grade analysis of IDH-mutant astrocytomas.

Evaluation of peripheral enhancement on contrast-enhanced CT and corresponding pathological findings in colorectal liver metastases after preoperative chemotherapy

Objective: To correlate peripheral enhancement on contrast-enhanced computed tomography (CE-CT) of post-chemotherapy colorectal liver metastases (CRLM) patients with the pathological findings. Methods: Forty-four patients with CRLM who underwent hepatic resection after preoperative chemotherapy between 2008 and 2013 were included. Two radiologists blinded to the histopathology findings performed a consensus categorization of the marginal contrast effects of CRLM on CE-CT as follows: Group 1, smooth margin without enhancement; Group 2, smooth margin with an enhanced rim; and Group 3, fuzzy margin with/without an enhanced rim. The Kruskal-Wallis test was used to compare the imaging findings with the histological findings. Results: The percentage of infarct-like necrosis was significantly higher in CRLM with smooth margins than in those with fuzzy margins (p<0.001, r=0.62). The percentage of viable cells was lowest in CRLM with smooth margins without enhancement (p<0.001, r=0.60). Conclusions: Our findings suggest that the type of necrosis is related to the nature of the margins, and the presence of residual cells are related to peripheral enhancement.

Normative Principles for Decision-Making in Natural Environments

The decisions we make are shaped by a lifetime of learning. Past experience guides the way that we encode information in neural systems for perception and valuation, and determines the information we retrieve when making decisions. Distinct literatures have discussed how lifelong learning and local context shape decisions made about sensory signals, propositional information, or economic prospects. Here, we build bridges between these literatures, arguing for common principles of adaptive rationality in perception, cognition, and economic choice. We discuss how a single common framework, based on normative principles of efficient coding and Bayesian inference, can help us understand a myriad of human decision biases, including sensory illusions, adaptive aftereffects, choice history biases, central tendency effects, anchoring effects, contrast effects, framing effects, congruency effects, reference-dependent valuation, nonlinear utility functions, and discretization heuristics. We describe a simple computational framework for explaining these phenomena. Expected final online publication date for the Annual Review of Psychology, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Effects of acute and repeated administration of the selective M4 PAM VU0152099 on cocaine vs. food choice in male rats

Ligands that stimulate muscarinic acetylcholine receptors 1 and 4 (M1, M4) have shown promising effects as putative pharmacotherapy for cocaine use disorder in rodent assays. We have previously shown reductions in cocaine effects with acute M4 stimulation, as well as long-lasting, delayed, reductions in cocaine taking and cocaine seeking with combined M1/M4 receptor stimulation or with M1 stimulation alone. M4 stimulation opposes dopaminergic signaling acutely, but direct dopamine receptor antagonists have proved unhelpful in managing cocaine use disorder because they lose efficacy with long-term administration. It is therefore critical to determine whether M4 approaches themselves can remain effective with repeated or chronic dosing. We assessed the effects of repeated administration of the M4 positive allosteric modulator (PAM) VU0152099 in rats trained to choose between intravenous cocaine and a liquid food reinforcer, to obtain quantitative measurement of whether M4 stimulation could produce delayed and lasting reduction in cocaine taking. VU0152099 produced progressively augmenting suppression of cocaine choice and cocaine intake, but produced neither rebound nor lasting effects after treatment ended. To compare and contrast effects of M1 vs. M4 stimulation, we tested whether the M4 PAM VU0152100 suppressed cocaine self-administration in mice lacking CalDAG-GEFI signaling factor, required for M1- mediated suppression of cocaine self-administration. CalDAG-GEFI ablation had no effect on M4- mediated suppression of cocaine self-administration. These findings support the potential usefulness of M4 PAMs as pharmacotherapy to manage cocaine use disorder, alone or in combination with M1-selective ligands, and show that M1 and M4 stimulation modulate cocaine-taking behavior by distinct mechanisms.

Behavioural and electrophysiological correlates of lightness contrast and assimilation

Lightness contrast and assimilation are opposite phenomena: in contrast grey targets appear darker when bordering bright rather than dark surfaces; in assimilation grey targets appear lighter when bordering bright rather than dark surfaces. The underlying neurophysiological mechanisms of these phenomena are not known. The aim of this study was to investigate the relationship between contrast and assimilation, and the timing and levels of perceptual and cognitive processing using combined behavioural and electrophysiological methods. Thirty undergraduate students (23 female, age range 18–48 years) participated in a forced-choice (grey target is lighter/darker than a comparison square) task, using stimuli designed such that the inducers were in two configurations (small and large) and two shades (white and black). The behavioural data (more consistent and faster responses) corroborated previous findings of stronger contrast effects with white inducers and stronger assimilation effects with black inducers. According to the Event-Related Potentials (ERP) results the mean amplitude was larger in conditions with less consistent and slower behavioural responses. Thus, with contrast responses P1 amplitude was larger with black than white inducers, and N1 amplitude was larger to assimilation than contrast when the configuration of the stimulus was held constant. These results suggest contrast may occur as early as P1 (~ 110 ms) and assimilation may occur later in N2 (~ 220 ms), whereas in some conditions, differences in ERPs associated with contrast vs assimilation may happen as early as in N1 (~ 170 m), in occipital and parietal cortical sites.