College students' daily mind wandering is related to lower social well-being.

Objective: This study sought to examine how daily mind wandering is related to loneliness, felt connection to others, and school belonging among college students. Participants: Three samples (n = 209, n = 173, and n = 266) from two US campuses were recruited. Methods: Data were collected via ecological momentary assessment over the course of two academic quarters in one sample and an academic semester in two samples. Results: Social well-being declined throughout the academic term in all samples. Lower day-to-day mind wandering predicted lower loneliness at the next time point and was concurrently related to a higher felt connection to others and higher school belonging. Thoughts about the past and future were associated with lower social well-being than present-focused thoughts. Conclusions: This study supports the proposition that promoting present-centered attention can benefit college students' social well-being and alleviate their feelings of loneliness and isolation that they often experience.

Managing emotions in the age of political polarization: A randomized controlled trial comparing mindfulness to cognitive reappraisal.

Emotional appraisals of political stimuli (e.g., videos) have been shown to drive shared neural encoding, which correspond to shared, yet divisive, interpretations of such stimuli. However, mindfulness practice may entrain a form of emotion regulation that de-automatizes social biases, possibly through alteration of such neural mechanisms. The present study combined a naturalistic neuroimaging paradigm and a randomized controlled trial to examine the effects of short-term mindfulness training (MT) (n = 35) vs structurally equivalent Cognitive Reappraisal training (CT) (n = 37) on politically-situated emotions while evaluating the mechanistic role of prefrontal cortical neural synchrony. Participants underwent functional near-infrared spectroscopy (fNIRS) recording while viewing inflammatory partisan news clips and continuously rating their momentary discrete emotions. MT participants were more likely to respond with extreme levels of anger (odds ratio = 0.12, p < .001) and disgust (odds ratio = 0.08, p < .001) relative to CT participants. Neural synchrony-based analyses suggested that participants with extreme emotion reactions exhibited greater prefrontal cortical neural synchrony, but that this pattern was less prominent in participants receiving MT relative to CT (CT > MT; channel 1 ISC = .040, p = .030).

The impact of alcohol consumption on implicit racial bias.

OBJECTIVE: Researchers and theorists studying intergroup relations have been interested in the impact of alcohol on interracial responding. Theories predict that alcohol will exacerbate expressions of racial bias by increasing reliance on stereotypes and/or by decreasing controlled processing and self-monitoring. Prior studies testing these theories have often examined alcohol's effects on implicit (i.e., indirect) measures of racial bias with inconsistent results. However, previous research in this area has suffered from several methodological limitations, including small sample sizes and doses of alcohol that may have been too low to induce substantial intoxication. METHOD: Here, in more than triple the number of alcohol participants than the largest prior study, we tested whether an intoxicating dose of alcohol (target breath alcohol concentration of .08%) exacerbated implicit racial bias. Young adults who identified as races other than Black or African American (N = 207) were randomly assigned to consume an alcoholic or placebo beverage and completed the race-based Implicit Association Test (race IAT) testing implicit preference for White (vs. Black) individuals [or, conversely, bias against Black (vs. White) individuals]. RESULTS: All participants demonstrated an implicit racial bias (i.e., linking traditionally Black names with negative/unpleasant words), with no difference in this implicit racial bias across beverage conditions. Specifically, there were no differences between alcohol participants' race IAT D scores (M = 0.55, SD = 0.39), and placebo participants' race IAT D scores (M = 0.59, SD = 0.35), b = 0.05, 95%CI [-0.07, 0.18], p = .422. CONCLUSIONS: These findings challenge theories and prior studies suggesting that alcohol increases implicit racial bias. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The (In)flexible self: Psychopathology, mindfulness, and neuroscience

Clinical and neuroscientific evidence indicates that transdiagnostic processes contribute to the generation and maintenance of psychopathological symptoms and disorders. Rigidity (inflexibility) appears a core feature of most transdiagnostic pathological processes. Decreasing rigidity may prove important to restore and maintain mental health. One of the primary domains in which rigidity and flexibility plays a role concerns the self. We adopt the pattern theory of self (PTS) for a working definition of self. This incorporates the pluralist view on self as constituted by multiple aspects or processes, understood to constitute a self-pattern, i.e. processes organized in non-linear dynamical relations across a number of time scales. The use of mindfulness meditation in the format of Mindfulness Based Interventions (MBIs) has been developed over four decades in Clinical Psychology. MBIs are promising as evidence-based treatments, shown to be equivalent to gold-standard treatments and superior to specific active controls in several randomized controlled trials. Notably, MBIs have been shown to target transdiagnostic symptoms. Given the hypothesized central role of rigid, habitual self-patterns in psychopathology, PTS offers a useful frame to understand how mindfulness may be beneficial in decreasing inflexibility. We discuss the evidence that mindfulness can alter the psychological and behavioral expression of individual aspects of the self-pattern, as well as favour change in the self-pattern as a whole gestalt. We discuss neuroscientific research on how the phenomenology of the self (pattern) is reflected in associated cortical networks and meditation-related alterations in cortical networks. Creating a synergy between these two aspects can increase understanding of psychopathological processes and improve diagnostic and therapeutic options. (AU)

Mindfulness-Based Stress Reduction reduces pro-inflammatory gene regulation but not systemic inflammation among older adults: A randomized controlled trial.

OBJECTIVE: Aging is associated with increased pro-inflammatory gene expression and systemic inflammation, and psychosocial stress may accelerate these changes. Mindfulness interventions show promise for reducing psychosocial stress and extending healthspan. Inflammatory pathways may play a role. In a sample of lonely older adults, we tested whether mindfulness training reduces proinflammatory gene expression and protein markers of systemic inflammation. METHODS: Lonely older adults (65-85 years; N = 190) were randomly assigned to an 8-week Mindfulness-Based Stress Reduction (MBSR) or matched Health Enhancement Program (HEP). Blood was drawn pre- and post-intervention and at 3-month follow-up. In peripheral blood mononuclear cells (PBMCs), RNA profiling was used to assess transcriptional regulation by pro-inflammatory NF-kB as well as ß-adrenergic CREB, antiviral IRF, and glucocorticoid receptor (GR) transcription factors. Plasma was assayed for proinflammatory markers IL-6 and CRP. Analyses tested time (pre, post, follow-up) by condition (MBSR versus HEP) effects. RESULTS: MBSR reduced NF-kB (d = .17, p = .028) but did not alter CREB (d = .10, p = .20), IRF (d = .13, p = .086), or GR activity (d = .14, p = .063) relative to HEP over time. Contrary to predictions, there were no time × condition effects of MBSR compared to HEP on reducing circulating IL-6 or CRP. CONCLUSIONS: In lonely older adults, MBSR reduced cellular pro-inflammatory gene regulation in ways that would predict reduced disease risk. However, no similar effect was observed for circulating protein markers of inflammation. These results provide specificity about how mindfulness interventions may impact distinct inflammatory markers among aging adults in ways that may have important implications for healthspan. TRIAL REGISTRATION: Clinical Trials identifier NCT02888600.

Inside the mindful moment: The effects of brief mindfulness practice on large-scale network organization and intimate partner aggression.

Mindfulness can produce neuroplastic changes that support adaptive cognitive and emotional functioning. Recently interest in single-exercise mindfulness instruction has grown considerably because of the advent of mobile health technology. Accordingly, the current study sought to extend neural models of mindfulness by investigating transient states of mindfulness during single-dose exposure to focused attention meditation. Specifically, we examined the ability of a brief mindfulness induction to attenuate intimate partner aggression via adaptive changes to intrinsic functional brain networks. We employed a dual-regression approach to examine a large-scale functional network organization in 50 intimate partner dyads (total n = 100) while they received either mindfulness (n = 50) or relaxation (n = 50) instruction. Mindfulness instruction reduced coherence within the Default Mode Network and increased functional connectivity within the Frontoparietal Control and Salience Networks. Additionally, mindfulness decoupled primary visual and attention-linked networks. Yet, this induction was unable to elicit changes in subsequent intimate partner aggression, and such aggression was broadly unassociated with any of our network indices. These findings suggest that minimal doses of focused attention-based mindfulness can promote transient changes in large-scale brain networks that have uncertain implications for aggressive behavior.

A multivariate twin study of the genetic association between present moment attention and subjective wellbeing.

Considerable evidence supports the role of present-moment attention, a central feature of mindfulness, in subjective wellbeing maintenance and enhancement. Yet it is not clear why such a relation exists. This study examined the genetic and environmental contributions of present-moment attention to subjective wellbeing. Consistent with the "generalist genes hypothesis" and prior evidence, we hypothesized that presence and subjective wellbeing would show a substantial genetic correlation and smaller environmental correlation. Using a large epidemiological sample of healthy 16-year-old twins in the United Kingdom (N = 1136 monozygotic (MZ) and dizygotic (DZ) twin pairs), genetic overlap was found between presence and the cognitive component of subjective wellbeing (life satisfaction), and to a lesser extent, the affective component of subjective wellbeing (operationalized as happiness). The non-shared environmental overlap between these constructs was substantial. This study provides the first evidence known to us showing that present-centered attention, a primary component of mindfulness, has both genetic and environmental overlap with subjective wellbeing. The findings have implications for understanding mechanisms by which presence is associated with positive emotions and life satisfaction, and suggest, pending additional research, that mindfulness-based interventions to enhance wellbeing may be best suited to those with a genetic propensity toward mindful presence.

Effects of Brief Mindfulness Meditation and Compassion Meditation on Parochial Empathy and Prosocial Behavior Toward Ethnic Out-Group Members.

Objectives: Relative to the tendency to empathize with and help sociocultural in-group members, there are often social and psychological barriers to responding prosocially toward out-group members. This experiment examined the roles of mindfulness instruction and compassion instruction in fostering prosocial behavior toward an ethnic out-group (non-U.S. Arabs) relative to an ethnic in-group (U.S. residents). The study also examined whether contemplative practices would predict less parochial empathy and whether parochial empathy would mediate the relations between mindfulness/compassion and prosocial behavior toward the out-group. Method: A national sample of n = 450 U.S. residents was recruited online via the Prolific platform using the standard sample function, which distributed the study to available participants on Prolific. Participants were randomly assigned to one of three brief, structurally equivalent audio-recorded instruction conditions: mindfulness meditation, compassion meditation, or a relaxation control, and then completed a series of tasks to assess prosociality toward in- and out-group members. Results: The compassion training was most effective in reducing parochial empathy when controlling for all covariates. The mindfulness training reduced parochial empathy when controlling for in-group empathy, and it led to greater out-group altruism and support for out-group immigration. Parochial empathy predicted out-group altruism; however, it was not a better predictor of support for Arab immigration than trait empathic concern. Training conditions did not differ on support for out-group cause. Exploratory moderation analyses found that those with higher trait empathic concern and intergroup contact quality were more likely to show compassion training and mindfulness training effects, respectively, on support for out-group immigration. Conclusions: Brief compassion training had the strongest effect on parochial empathy, but mindfulness training showed stronger effects on out-group altruism and support for out-group immigration. Predisposing social psychological characteristics may enhance intergroup prosociality among those receiving compassion or mindfulness instruction. Preregistration: This study is preregistered at https://osf.io/rnc97. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-023-02100-z.

The (In)flexible self: Psychopathology, mindfulness, and neuroscience.

Clinical and neuroscientific evidence indicates that transdiagnostic processes contribute to the generation and maintenance of psychopathological symptoms and disorders. Rigidity (inflexibility) appears a core feature of most transdiagnostic pathological processes. Decreasing rigidity may prove important to restore and maintain mental health. One of the primary domains in which rigidity and flexibility plays a role concerns the self. We adopt the pattern theory of self (PTS) for a working definition of self. This incorporates the pluralist view on self as constituted by multiple aspects or processes, understood to constitute a self-pattern, i.e. processes organized in non-linear dynamical relations across a number of time scales. The use of mindfulness meditation in the format of Mindfulness Based Interventions (MBIs) has been developed over four decades in Clinical Psychology. MBIs are promising as evidence-based treatments, shown to be equivalent to gold-standard treatments and superior to specific active controls in several randomized controlled trials. Notably, MBIs have been shown to target transdiagnostic symptoms. Given the hypothesized central role of rigid, habitual self-patterns in psychopathology, PTS offers a useful frame to understand how mindfulness may be beneficial in decreasing inflexibility. We discuss the evidence that mindfulness can alter the psychological and behavioral expression of individual aspects of the self-pattern, as well as favour change in the self-pattern as a whole gestalt. We discuss neuroscientific research on how the phenomenology of the self (pattern) is reflected in associated cortical networks and meditation-related alterations in cortical networks. Creating a synergy between these two aspects can increase understanding of psychopathological processes and improve diagnostic and therapeutic options.

Meta-analytic evidence that mindfulness training alters resting state default mode network connectivity.

This meta-analysis sought to expand upon neurobiological models of mindfulness through investigation of inherent brain network connectivity outcomes, indexed via resting state functional connectivity (rsFC). We conducted a systematic review and meta-analysis of rsFC as an outcome of mindfulness training (MT) relative to control, with the hypothesis that MT would increase cross-network connectivity between nodes of the Default Mode Network (DMN), Salience Network (SN), and Frontoparietal Control Network (FPCN) as a mechanism of internally-oriented attentional control. Texts were identified from the databases: MEDLINE/PubMed, ERIC, PSYCINFO, ProQuest, Scopus, and Web of Sciences; and were screened for inclusion based on experimental/quasi-experimental trial design and use of mindfulness-based training interventions. RsFC effects were extracted from twelve studies (mindfulness n = 226; control n = 204). Voxel-based meta-analysis revealed significantly greater rsFC (MT > control) between the left middle cingulate (Hedge's g = .234, p = 0.0288, I2 = 15.87), located within the SN, and the posterior cingulate cortex, a focal hub of the DMN. Egger's test for publication bias was nonsignificant, bias = 2.17, p = 0.162. In support of our hypothesis, results suggest that MT targets internetwork (SN-DMN) connectivity implicated in the flexible control of internally-oriented attention.

Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates.

Therapeutics based on short interfering RNAs (siRNAs) delivered to hepatocytes have been approved, but new delivery solutions are needed to target additional organs. Here we show that conjugation of 2'-O-hexadecyl (C16) to siRNAs enables safe, potent and durable silencing in the central nervous system (CNS), eye and lung in rodents and non-human primates with broad cell type specificity. We show that intrathecally or intracerebroventricularly delivered C16-siRNAs were active across CNS regions and cell types, with sustained RNA interference (RNAi) activity for at least 3 months. Similarly, intravitreal administration to the eye or intranasal administration to the lung resulted in a potent and durable knockdown. The preclinical efficacy of an siRNA targeting the amyloid precursor protein was evaluated through intracerebroventricular dosing in a mouse model of Alzheimer's disease, resulting in amelioration of physiological and behavioral deficits. Altogether, C16 conjugation of siRNAs has the potential for safe therapeutic silencing of target genes outside the liver with infrequent dosing.

Mindfulness-based stress reduction increases stimulated IL-6 production among lonely older adults: A randomized controlled trial.

Loneliness is a potent psychosocial stressor that predicts poor health and mortality among older adults, possibly in part by accelerating age-related declines in immunocompetence. Mindfulness interventions have shown promise for reducing loneliness and improving markers of physical health. In a sample of lonely older adults, this two-arm parallel trial tested whether mindfulness training enhances stimulated interleukin-6 (IL-6) production, a measure of innate immune responsivity. Lonely older adults (65-85 years; N = 190) were randomized to an 8-week Mindfulness-Based Stress Reduction (MBSR) or control Health Enhancement Program (HEP) intervention. Lipopolysaccharide (LPS)-stimulated production of IL-6 was measured in vitro by blinded outcome assessors at pre-intervention, post-intervention, and 3-month follow-up. Mixed-effects linear models tested time (pre, post, follow-up) by condition (MBSR vs. HEP) effects. As predicted, a significant time × condition effect on stimulated IL-6 production was observed across pre, post, and follow-up timepoints. Significant MBSR vs. HEP differences emerged from pre- to post-intervention (p =.009, d = 0.38) and from pre-intervention to 3-month follow-up (p =.017, d = 0.35), with larger increases in IL-6 production following MBSR compared to HEP. No study-related adverse events were reported. Results show that mindfulness training may be effective for boosting innate immunocompetence among lonely older adults. Given that immunocompetence tends to decline with age, mindfulness training may help to counteract the effects of aging and psychosocial stress on infection risk and recovery from injury.

Comparing impacts of meditation training in focused attention, open monitoring, and mindfulness-based cognitive therapy on emotion reactivity and regulation: Neural and subjective evidence from a dismantling study.

Commonly conducted mindfulness-based trainings such as Mindfulness-based Stress Reduction (MBSR) and Mindfulness-based Cognitive Therapy (MBCT) highlight training in two key forms of meditation: focused attention (FA) and open monitoring (OM). Largely unknown is what each of these mindfulness practices contributes to emotional and other important training outcomes. This dismantling trial compared the effects of structurally equivalent trainings in MBCT, FA, and OM on neural and subjective markers of emotional reactivity and regulation among community adults, with the aim to better understand which forms of training represent active ingredients in mindfulness trainings. Participants with varying levels of depressive symptoms were randomized to one of the three trainings. Before and after each 8-week training, N = 89 participants completed a modified version of the Emotional Reactivity and Regulation Task while electroencephalographic (EEG) and self-reported emotional responses to negative, positive, and neutral photographic images were collected. Examination of EEG-based frontal alpha band asymmetry during passive viewing (reactivity) and active regulation phases of the task showed that FA and MBCT trainings produced significant leftward hemispheric shifts in frontal alpha asymmetry, commonly associated with a shift toward approach-based positive affect. Self-reported emotional responses to negative images corroborated these results, suggesting salutary changes in both emotional reactivity and regulation. OM training had limited beneficial effects, restricted to the subjective outcomes. The findings suggest that MBCT may derive its greatest benefit from training in FA rather than OM. Discussion highlights the potential value of FA training for emotional health.

Punishment on Pause: Preliminary Evidence That Mindfulness Training Modifies Neural Responses in a Reactive Aggression Task.

Reactive aggression, a hostile retaliatory response to perceived threat, has been attributed to failures in emotion regulation. Interventions for reactive aggression have largely focused on cognitive control training, which target top-down emotion regulation mechanisms to inhibit aggressive impulses. Recent theory suggests that mindfulness training (MT) improves emotion regulation via both top-down and bottom-up neural mechanisms and has thus been proposed as an alternative treatment for aggression. Using this framework, the current pilot study examined how MT impacts functional brain physiology in the regulation of reactive aggression. Participants were randomly assigned to 2 weeks of MT (n = 11) or structurally equivalent active coping training (CT) that emphasizes cognitive control (n = 12). Following training, participants underwent functional magnetic resonance imaging (fMRI) during a retaliatory aggression task, a 16-trial game in which participants could respond to provocation by choosing whether or not to retaliate in the next round. Training groups did not differ in levels of aggression displayed. However, participants assigned to MT exhibited enhanced ventromedial prefrontal cortex (vmPFC) recruitment during punishment events (i.e., the aversive consequence of losing) relative to those receiving active CT. Conversely, the active coping group demonstrated greater dorsomedial prefrontal cortex (dmPFC) activation when deciding how much to retaliate, in line with a bolstered top-down behavior monitoring function. The findings suggest that mindfulness and cognitive control training may regulate aggression via different neural circuits and at different temporal stages of the provocation-aggression cycle. Trial Registration: identification no. NCT03485807.

Mindfulness and Attention Deficit Hyperactivity Disorder: A Neuropsychological Perspective.

ABSTRACT: Understanding the underlying mechanisms of mindfulness has been a hot topic in recent years, not only in clinical fields but also in neuroscience. Most neuroimaging findings demonstrate that critical brain regions involved in mindfulness are responsible for cognitive functions and mental states. However, the brain is a complex system operating via multiple circuits and networks, rather than isolated brain regions solely responsible for specific functions. Mindfulness-based treatments for attention deficit hyperactivity disorder (ADHD) have emerged as promising adjunctive or alternative intervention approaches. We focus on four key brain circuits associated with mindfulness practices and effects on symptoms of ADHD and its cognitive dysfunction, including executive attention circuit, sustained attention circuit, impulsivity circuit, and hyperactivity circuit. We also expand our discussion to identify three key brain networks associated with mindfulness practices, including central executive network, default mode network, and salience network. We conclude by suggesting that more research efforts need to be devoted into identifying putative neuropsychological mechanisms of mindfulness on how it alleviates ADHD symptoms.

Mindfulness-Based Stress Reduction Buffers Glucocorticoid Resistance Among Older Adults: A Randomized Controlled Trial.

OBJECTIVE: Mindfulness interventions have been effective for improving a range of health outcomes; however, pathways underlying these effects remain unclear. Inflammatory processes may play a role, possibly through increased resistance of immune cells to the anti-inflammatory effects of glucocorticoids (i.e., glucocorticoid resistance, or GCR). Here, we conducted an initial examination of whether mindfulness training mitigates GCR among lonely older adults. METHODS: Lonely older adults (65-85 years; n = 190) were randomly assigned to an 8-week Mindfulness-Based Stress Reduction (MBSR) or a matched Health Enhancement Program (HEP). Whole blood drawn before and after the intervention and at 3-month follow-up was incubated with endotoxin and varying concentrations of dexamethasone, and interleukin-6 production was assessed using enzyme-linked immunosorbent assay. GCR was assessed as the concentration of dexamethasone required to decrease the stimulated interleukin-6 response by 50% (half maximal inhibitory concentration), with higher concentrations indicating greater GCR. Mixed-effects linear models tested time (pre, post, follow-up) by condition (MBSR versus HEP) effects. RESULTS: There was no overall time by condition effect on GCR across all time points. However, a significant time by condition effect was observed from preintervention to postintervention (d = 0.29), such that MBSR buffered increases in GCR observed in the HEP group. Although MBSR showed small, nonsignificant reductions in GCR from preintervention to 3-month follow-up, group differences were not maintained at the 3-month follow-up (d = 0.10). CONCLUSIONS: Results suggest that MBSR may protect against declines in the sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids among at-risk lonely older adults and show value in studying this biological mechanism in future trials.Trial Registration: Clinical Trials identifier NCT02888600.

Mindfulness interventions improve momentary and trait measures of attentional control: Evidence from a randomized controlled trial.

Mindfulness interventions have been shown to improve several subcomponents of attention; however, the psychological mechanisms driving these improvements are unknown. Mindfulness interventions train individuals to monitor present moment experiences while adopting an attitude of acceptance toward these experiences. We conducted a theoretically driven randomized controlled trial to test the putative mechanisms of mindfulness training that drive improvements in attentional control. Participants were randomly assigned to 1 of 3 conditions: (a) monitor and accept (MA) training, a standard 8-week mindfulness-based stress reduction (MBSR) intervention that included cultivation of both monitoring and acceptance skills; (b) monitor only (MO) training, a well-matched modified 8-week MBSR-adapted intervention that focused on monitoring skills only; or (c) no treatment (NT) control. Momentary attentional control was measured via ecological momentary assessment for 3 days at baseline and postintervention. Trait attentional control was assessed at baseline and postintervention using traditional self-report. Participants also completed a dichotic listening task to assess sustained attention at baseline and postintervention. We found that MA and MO participants improved in momentary and trait attentional control (but not attention task performance) relative to NT participants. Analyses of indirect effects were consistent with the possibility that increased momentary attentional control partially accounts for MA/MO intervention-related increases in trait attentional control. This randomized controlled trial provides one of the first experimental tests of the mechanisms of mindfulness interventions that drive improvements in attention outcomes. These findings support the notion that present-focused monitoring skills training drives mindfulness intervention-related improvements in momentary attentional control, which in turn fosters greater trait attentional control. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Self-Regulation Without Force: Can Awareness Leverage Reward to Drive Behavior Change?

To reach longer-term goals and live aligned with their values, people typically must regulate their behavior. Effortful self-control is one way to achieve this and is usually framed as a forceful struggle between lower-level impulses and higher-level cognitive control processes. For example, people may restrain themselves from eating cake in order to lose weight. An alternative avenue of self-regulation draws on autonomous motivation: Individuals eat healthfully because it is values-congruent or intrinsically satisfying. Recent advances in the understanding of reward valuation on a neural level (e.g., ventromedial prefrontal cortex/orbitofrontal cortex) and emerging treatments on a clinical level (e.g., mindfulness training) suggest a possible mechanistic convergence between brain and behavior that is consistent with a shift from forced to unforced behavior change. Here we propose how an overlooked aspect of reinforcement learning can be leveraged using a simple yet critical feature of experience that is not reliant on willpower: Bringing awareness to one's subjective experience and behavior can produce a change in valuation of learned but unhealthy behaviors, leading to self-regulatory shifts that result in sustainable behavior change without force.

RT-qPCR Methods to Support Pharmacokinetics and Drug Mechanism of Action to Advance Development of RNAi Therapeutics.

The goal of this study was to develop a reverse transcription quantitative polymerase chain reaction (RT-qPCR) method for the accurate quantification of chemically modified small interfering RNA (siRNA) including but not restricted to thermally destabilizing modifications such as glycol nucleic acid (GNA). RT-qPCR was found to be superior to mass spectrometry-based siRNA detection in terms of sensitivity and throughput. However, mass spectrometry is still the preferred method when specific metabolite detection is required and is also insensitive to siRNA chemical modifications such as GNA. The RT-qPCR approach can be optimized to take chemical modifications into account and works robustly in different matrices without optimization, unlike mass spectrometry. RT-qPCR and mass spectrometry both have their strengths and weaknesses for the detection of siRNA and must be used appropriately depending on the questions at hand. Considerations such as desired throughput, assay sensitivity, and metabolite identification must be weighed when choosing which methodology to apply.

Evaluation of electrophoretic mobility shift assay as a method to determine plasma protein binding of siRNA.

Aim: The electrophoretic mobility shift assay (EMSA) was evaluated as an alternative to ultrafiltration (UF) to assess plasma protein binding (PPB) of small interfering RNAs (siRNA) and antisense oligonucleotides (ASO). Results & methodology: EMSA analysis showed that PPB depended on siRNA and plasma concentration. Conversely, when analyzed by ultrafiltration, siRNA bound the filtration device nonspecifically and PPB remained >98% across physiologically relevant siRNA concentrations. Using EMSA, siRNA exhibited charge-based interactions with plasma proteins, while ASO remained highly bound to plasma proteins or albumin in the presence of 500 mM salt. Conclusion: PPB characteristics of siRNA and ASO can be distinguished using EMSA. Characterization of siRNA PPB by EMSA enhances our knowledge of siRNA absorption, distribution, metabolism and excretion and advanced development of RNA interference therapeutics.