P62 accumulates through neuroanatomical circuits in response to tauopathy propagation.

In Alzheimer's disease and related tauopathies, trans-synaptic transfer and accumulation of pathological tau from donor to recipient neurons is thought to contribute to disease progression, but the underlying mechanisms are poorly understood. Using complementary in vivo and in vitro models, we examined the relationship between these two processes and neuronal clearance. Accumulation of p62 (a marker of defective protein clearance) correlated with pathological tau accumulation in two mouse models of tauopathy spread; Entorhinal Cortex-tau (EC-Tau) mice where tau pathology progresses in time from EC to other brain regions, and PS19 mice injected with tau seeds. In both models and in several brain regions, p62 colocalized with human tau in a pathological conformation (MC1 antibody). In EC-Tau mice, p62 accumulated before overt tau pathology had developed and was associated with the presence of aggregation-competent tau seeds identified using a FRET-based assay. Furthermore, p62 accumulated in the cytoplasm of neurons in the dentate gyrus of EC-Tau mice prior to the appearance of MC1 positive tauopathy. However, MC1 positive tau was shown to be present at the synapse and to colocalize with p62 as shown by immuno electron microscopy. In vitro, p62 colocalized with tau inclusions in two primary cortical neuron models of tau pathology. In a three-chamber microfluidic device containing neurons overexpressing fluorescent tau, seeding of tau in the donor chamber led to tau pathology spread and p62 accumulation in both the donor and the recipient chamber. Overall, these data are in accordance with the hypothesis that the accumulation and trans-synaptic spread of pathological tau disrupts clearance mechanisms, preceding the appearance of obvious tau aggregation. A vicious cycle of tau accumulation and clearance deficit would be expected to feed-forward and exacerbate disease progression across neuronal circuits in human tauopathies.

PAC1 receptor-mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain.

Accumulation of pathological tau in synapses has been identified as an early event in Alzheimer's disease (AD) and correlates with cognitive decline in patients with AD. Tau is a cytosolic axonal protein, but under disease conditions, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, we found accumulation of seed-competent tau predominantly in postsynaptic compartments. Tau-mediated toxicity in postsynaptic compartments was exacerbated by impaired proteasome activity detected by measuring lysine-48 polyubiquitination of proteins targeted for proteasomal degradation. To combat the accumulation of tau and proteasome impairment in the postsynaptic compartments of rTg4510 mouse brain, we stimulated the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) with its ligand PACAP administered intracerebroventricularly to rTg4510 mice. We observed enhanced synaptic proteasome activity and reduced total tau in postsynaptic compartments in mouse brain after PACAP treatment. The clearance of tau from postsynaptic compartments correlated with attenuated tauopathy and improved cognitive performance of rTg4510 transgenic mice on two behavioral tests. These results suggest that activating PAC1R could prevent accumulation of aggregate-prone tau and indicate a potential therapeutic approach for AD and other tauopathies.

Music Perception and Speech-in-Noise Skills of Typical Hearing and Cochlear Implant Listeners.

Purpose Adult cochlear implant (CI) users rate music as one of the most important auditory stimuli, second to speech perception. However, few studies simultaneously examine music perception and speech-in-noise perception in adult CI recipients. This study explores the effect of auditory status on music perception and speech-in-noise perception recognition in noise as well as the relationship among music engagement, music perception, and speech-in-noise perception. Method Participants include 10 adults with typical hearing (TH) and 10 adults with long-term CI use. All participants completed the Music-Related Quality of Life Questionnaire, which assesses subjective music experiences and their importance; the Pitch Direction Discrimination, Familiar Melody Recognition, and Timbre Recognition subtests of the Clinical Assessment of Music Perception for Cochlear Implants; the Unfamiliar Melody Recognition subtest of the Profile of Music Perception Skills; and the Bamford-Kowal-Bench Speech-in-Noise Test. Results The TH group significantly outperformed the CI group for speech-in-noise perception and on all four music perception tasks. The CI group exhibited not only significantly poorer mean scores but also greater variability in performance compared to the TH group. Only Familiar Melody Recognition and Unfamiliar Melody Recognition subtests significantly correlated with speech-in-noise scores. Conclusions Patients and professionals should not assume speech perception and music perception in adult CI users derive from the same auditory or cognitive foundations. The lack of significant relationships among music engagement, music perception, and speech-in-noise perception scores in adult CI users suggests this population enjoys music despite poor and variable performance in discrete music tasks.

Identification of pannexin 1-regulated genes, interactome, and pathways in rhabdomyosarcoma and its tumor inhibitory interaction with AHNAK.

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, is an aggressive cancer with a poor prognosis. Despite current management, the 5-year survival rate for patients with metastatic RMS is ∼30%; underscoring the need to develop better treatment strategies. We have recently reported that pannexin 1 (PANX1) levels are downregulated in RMS and that restoring its expression inhibits RMS progression. Here, we have surveyed and characterized the molecular changes induced by PANX1 re-expression in RMS. We cataloged transcriptomic changes in this context by RNA sequencing. At the protein level, we unveiled PANX1 interactors using BioID, complemented by co-immunoprecipitation coupled to high-performance liquid chromatography/electrospray ionization tandem mass spectrometry performed in PANX1-enriched fractions. Using these data, we generated searchable public databases for the PANX1 interactome and changes to the RMS transcriptome occurring when PANX1 expression is restored. STRING network analyses revealed a PANX1 interactome involving plasma membrane and cytoskeleton-associated proteins including the previously undescribed interactor AHNAK. Indeed, AHNAK knockdown abrogated the PANX1-mediated reduction in RMS cell viability and migration. Using these unbiased approaches, we bring insight to the mechanisms by which PANX1 inhibits RMS progression, identifying the cell migration protein AHNAK as a key modifier of PANX1-mediated changes in RMS malignant properties.

A test of psychological and electrodermal changes immediately after the delivery of 3 analgesic treatment messages.

INTRODUCTION: Placebo analgesia often results when a pain reduction treatment message is delivered to a patient or research participant. Little information exists regarding the psychological changes that are immediately triggered by the delivery of a treatment message. OBJECTIVES: This experiment tested the impact of 3 different analgesic treatment messages on the expectations, feelings, and electrodermal activity of participants anticipating a pain stimulus. METHODS: In laboratory sessions, healthy participants (N = 138) were randomly assigned to 1 of 4 conditions in a between-subject design. The design included a no treatment message control condition and 3 treatment message conditions: a standard analgesic message, an analgesic treatment with side-effect message, and a double-blind analgesic message. After the treatment message manipulation, measures were taken of: treatment efficacy expectations, pain experience expectations, pretask anxiety, positive affect, negative affect, and electrodermal activity. RESULTS: Overall, the dependent measures showed relatively few correlations. Furthermore, across all 3 message conditions, treatment-specific expectations were greatly increased compared with the control condition. Finally, participants in the double-blind message condition displayed elevated negative affect. CONCLUSION: All 3 analgesic treatment messages produced a stronger immediate influence on treatment efficacy expectations than on the other dependent measures. Treatment messages can alter negative affect along with expectancies. The low correlations found between dependent measures suggest that different patterns of psychological responses may emerge from analgesic treatment messages depending on contextual factors.

A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology.

Excitatory neurons are preferentially impaired in early Alzheimer's disease but the pathways contributing to their relative vulnerability remain largely unknown. Here we report that pathological tau accumulation takes place predominantly in excitatory neurons compared to inhibitory neurons, not only in the entorhinal cortex, a brain region affected in early Alzheimer's disease, but also in areas affected later by the disease. By analyzing RNA transcripts from single-nucleus RNA datasets, we identified a specific tau homeostasis signature of genes differentially expressed in excitatory compared to inhibitory neurons. One of the genes, BCL2-associated athanogene 3 (BAG3), a facilitator of autophagy, was identified as a hub, or master regulator, gene. We verified that reducing BAG3 levels in primary neurons exacerbated pathological tau accumulation, whereas BAG3 overexpression attenuated it. These results define a tau homeostasis signature that underlies the cellular and regional vulnerability of excitatory neurons to tau pathology.

Adolescent Physical Activity: Moderation of Individual Factors by Neighborhood Environment.

INTRODUCTION: Less than a third of U.S. adolescents meet federal physical activity (PA) guidelines. Understanding correlates of PA at multiple levels of the Social Ecological Model could improve PA interventions among youth. This study examines (1) associations between factors across the Social Ecological Model including psychosocial factors, perceived neighborhood physical and social environment characteristics, and adolescent moderate to vigorous PA (MVPA) and (2) whether perceived neighborhood characteristics moderate associations between psychosocial factors and MVPA. METHODS: A national sample of adolescents (aged 12-17 years) in the 2014 Family Life, Activity, Sun, Health, and Eating Study was used to examine associations between psychosocial characteristics, perceived neighborhood social and physical characteristics, and self-reported weekly minutes of MVPA. Analyses were conducted in 2015. Interaction terms between psychosocial and neighborhood variables were added to multiple linear regression models to examine moderation hypotheses. RESULTS: Significant two-way interactions revealed that neighborhoods with features perceived as supportive of PA strengthened several psychosocial-MVPA associations. The positive associations between MVPA and friend norms, friend support, and attitudes were strengthened for adolescents living in neighborhoods with high versus low PA resource availability (all p<0.05). Furthermore, the association between controlled and autonomous motivation and MVPA was strengthened under conditions of shops/stores near (versus distant from) adolescents' homes (p<0.05). CONCLUSIONS: The association between some psychosocial factors and adolescent MVPA may be environment dependent. Neighborhood physical and social environments supportive of PA are important to consider when developing targeted PA interventions and may strengthen the association between psychosocial-level factors and adolescent MVPA.

Using an Internet-Based Breast Cancer Risk Assessment Tool to Improve Social-Cognitive Precursors of Physical Activity.

BACKGROUND: Internet-based cancer risk assessment tools might serve as a strategy for translating epidemiological risk prediction research into public health practice. Understanding how such tools affect key social-cognitive precursors of behavior change is crucial for leveraging their potential into effective interventions. PURPOSE: To test the effects of a publicly available, Internet-based, breast cancer risk assessment tool on social-cognitive precursors of physical activity. METHODS: Women (N = 132) aged 40-78 with no personal cancer history indicated their perceived risk of breast cancer and were randomly assigned to receive personalized ( www.yourdiseaserisk.wustl.edu ) or nonpersonalized breast cancer risk information. Immediately thereafter, breast cancer risk perceptions and physical activity-related behavioral intentions, self-efficacy, and response efficacy were assessed. RESULTS: Personalized information elicited higher intentions, self-efficacy, and response efficacy than nonpersonalized information, P values < 0.05. Self-efficacy and response efficacy mediated the effect of personalizing information on intentions. Women who received personalized information corrected their inaccurate risk perceptions to some extent, P values < 0.05, but few fully accepted the information. CONCLUSION: Internet-based risk assessment tools can produce beneficial effects on important social-cognitive precursors of behavior change, but lingering skepticism, possibly due to defensive processing, needs to be addressed before the effects can be maximized.

Myasthenia Gravis Presentation After a Cervical Laminectomy With Fusion.

Myasthenia gravis is a chronic neuromuscular disorder that causes skeletal muscle weakness. Typically, myasthenia gravis affects the ocular, bulbar, neck, proximal limbs, and respiratory muscles. Although the presentation is typically observed with complaints of vision and bulbar symptoms such as diplopia, dystonia, and dysphagia, this article presents a case study of an elderly man with a history of increasing upper extremity weakness with complaints of worsening hand dexterity and intermittent episodes of expressive aphasia. After cervical laminectomy with fusion, this gentleman was admitted to the medical intensive care unit, in a complete myasthenic crisis.

Comparing the Maryland Comprehensive Cancer Control Plan With Federal Cancer Prevention and Control Recommendations.

INTRODUCTION: Since the introduction of the Affordable Care Act (ACA) in 2012, 11 million more Americans now have access to preventive services via health care coverage. Several prevention-related recommendations issued by the US Preventive Services Task Force (USPSTF), Centers for Disease Control and Prevention (CDC), and Advisory Committee on Immunization Practices (ACIP) are covered under the ACA. State cancer plans often provide prevention strategies, but whether these strategies correspond to federal evidence-based recommendations is unclear. The objective of this article is to assess whether federal evidence-based recommendations, including those covered under the ACA, are included in the Maryland Comprehensive Cancer Control Plan (MCCCP). METHODS: A total of 19 federal recommendations pertaining to cancer prevention and control were identified. Inclusion of federal cancer-related recommendations by USPSTF, CDC, and ACIP in the MCCCP's goals, objectives, and strategies was examined. RESULTS: Nine of the federal recommendations were issued after the MCCCP's publication. MCCCP recommendations corresponded completely with 4 federal recommendations and corresponded only partially with 3. Reasons for partial correspondence included specification of less restrictive at-risk populations or different intervention implementers. Three federal recommendations were not mentioned in the MCCCP's goals, objectives, and strategies. CONCLUSION: Many cancer-related federal recommendations were released after the MCCCP's publication and therefore do not appear in the most current version. We recommend that the results of this analysis be considered in the update of the MCCCP. Our findings underscore the need for a periodic scan for changes to federal recommendations and for adjusting state policies and programs to correspond with federal recommendations, as appropriate for Marylanders.

Prior experience with a pain stimulus as a predictor of placebo analgesia.

Placebo effects are important in pain reduction, but the effects are inconsistent. Prior experience with a pain stimulus may moderate placebo analgesia. The current study tests the effect of prior experience with a pain stimulus on placebo analgesia during a laboratory pain task. Healthy normotensive undergraduates (66 women, 68 men) who either did or did not report prior experience with pain from submerging a limb in cold water were enrolled. In the laboratory, an experimenter applied an inert, medicinal-smelling cream to participants' non-dominant hand. Participants randomized to the no-expectation group were told that the cream was a hand cleanser. Participants randomized to the placebo expectation group were told that the cream would reduce the pain associated with the cold pressor task. Participants then completed the cold pressor task and reported their pain on the short form of the McGill Pain Questionnaire. Analysis of variance revealed a main effect of expectation (p < .05), such that participants in the placebo expectation group reported less pain. An interaction was also found between expectation and prior experience (p < .05), such that participants with prior experience with pain from cold water immersion showed no difference in pain reports between expectation groups. In a pain context, prior experience with the pain stimulus may prevent a placebo expectation from reducing the experience of pain.

Dispositional and comparative optimism interact to predict avoidance of a looming health threat.

Research indicates that when confronted with a health threat, individuals high in both dispositional and comparative optimism employ a more avoidant style of coping than individuals high in dispositional but low in comparative optimism. We examined the hypothesis that threat distance moderates this interactive optimism association. In two studies, participants were randomly assigned to a looming or distant threat condition. Study 1 revealed that in the looming threat condition, participants high in both forms of optimism were more likely to minimise the threat and less inclined to seek additional health information relative to participants high in dispositional but low in comparative optimism. In Study 2, the same interaction pattern emerged on a measure of psychological abstraction suggesting these variables combine to alter broad information processing strategies. Implications for considering multiple forms of optimism when delivering health status information are discussed.

Why does choice enhance treatment effectiveness? Using placebo treatments to demonstrate the role of personal control.

In modern health care, individuals frequently exercise choice over health treatment alternatives. A growing body of research suggests that when individuals choose between treatment options, treatment effectiveness can increase, although little experimental evidence exists clarifying this effect. Four studies were conducted to test the hypothesis that exercising choice over treatment alternatives enhances outcomes by providing greater personal control. Consistent with this possibility, in Study 1 individuals who chronically desired control reported less pain from a laboratory pain task when they were able to select between placebo analgesic treatments. Study 2 replicated this finding with an auditory discomfort paradigm. In Study 3, the desire for control was experimentally induced, and participants with high desire for control benefited more from a placebo treatment when they were able to choose their treatment. Study 4 revealed that the benefit of choice on treatment efficacy was partially mediated by thoughts of personal control. This research suggests that when individuals desire control, choice over treatment alternatives improves treatment effectiveness by enhancing personal control.

The liver connexin32 interactome is a novel plasma membrane-mitochondrial signaling nexus.

Connexins are the structural subunits of gap junctions and act as protein platforms for signaling complexes. Little is known about tissue-specific connexin signaling nexuses, given significant challenges associated with affinity-purifying endogenous channel complexes to the level required for interaction analyses. Here, we used multiple subcellular fractionation techniques to isolate connexin32-enriched membrane microdomains from murine liver. We show, for the first time, that connexin32 localizes to both the plasma membrane and inner mitochondrial membrane of hepatocytes. Using a combination of immunoprecipitation-high throughput mass spectrometry, reciprocal co-IP, and subcellular fractionation methodologies, we report a novel interactome validated using null mutant controls. Eighteen connexin32 interacting proteins were identified. The majority represent resident mitochondrial proteins, a minority represent plasma membrane, endoplasmic reticulum, or cytoplasmic partners. In particular, connexin32 interacts with connexin26 and the mitochondrial protein, sideroflexin-1, at the plasma membrane. Connexin32 interaction enhances connexin26 stability. Converging bioinformatic, biochemical, and confocal analyses support a role for connexin32 in transiently tethering mitochondria to connexin32-enriched plasma membrane microdomains through interaction with proteins in the outer mitochondrial membrane, including sideroflexin-1. Complex formation increases the pool of sideroflexin-1 that is present at the plasma membrane. Together, these data identify a novel plasma membrane/mitochondrial signaling nexus in the connexin32 interactome.

Comparative and dispositional optimism as separate and interactive predictors.

Comparative optimism and dispositional optimism are typically studied separately and little is known regarding their unique and combined predictive abilities. We examined how these two types of optimism predict cognitive and affective reactions following unpleasant dental health feedback (Studies 1 and 2) and neutral feedback (Study 2). In Study 1, dispositional optimism and a measure of dental health comparative optimism interacted to predict appraisals of dental health feedback. In Study 2, dispositional optimism and dental health comparative optimism interacted to predict appraisals of new dental health information following negative dental health feedback - but not following neutral feedback. Individuals scoring high in dispositional optimism and low in dental health comparative optimism were more interested in and receptive to the dental health feedback than those scoring high in both types of optimism. Finally, greater dental health comparative optimism was associated with less negative affect following the dental health feedback, whereas dispositional optimism was associated with greater positive affect under all conditions. The results indicate that comparative and dispositional optimism are unique as well as interactive predictors.

Beliefs about expectations moderate the influence of expectations on pain perception.

BACKGROUND: Expectations congruently influence, or bias, pain perception. Recent social psychological research reveals that individuals differ in the extent to which they believe in expectation biases and that individuals who believe in expectation biases may adjust for this bias in their perceptions and reactions. That is, idiosyncratic beliefs about expectations can moderate the influence of expectations on experience. PURPOSE: Prior research has not examined whether idiosyncratic beliefs about expectations can alter the degree to which one's expectations influence pain perception. Using a laboratory pain stimulus, we examined the possibility that beliefs about expectation biases alter pain responses following both pain- and placebo-analgesic expectations. METHODS: Participants' beliefs about expectation biases were measured. Next, participants were randomly assigned to receive either a pain expectation or a placebo-analgesia expectation prior to a cold-pressor task. After the task, participants rated their pain. RESULTS: Beliefs about expectation biases significantly influenced pain reports. Specifically, pain reports were more influenced by provided expectations the less participants believed in expectation biases (i.e., pain expectations resulted in more pain than analgesia expectations). CONCLUSIONS: Beliefs about the expectation bias are an important and under-examined predictor of pain and placebo analgesia.

Choice and placebo expectation effects in the context of pain analgesia.

The current experiment examined whether having choice over treatment options facilitates or inhibits the strength of placebo expectations in the context of pain perception. All participants were exposed to an aversive stimulus (i.e., the cold pressor task), and participants in some conditions were given expectations for two pain-relieving treatments (actually the same inert ointment mixture). Critically, participants in these expectation conditions were also given a choice or not about which of the two treatments they preferred to use. Participants in a control condition were not provided with a treatment expectation. Despite receiving the same inert treatment, participants who had a choice over treatments showed increased placebo analgesia as compared to participants not given a choice and participants in the control condition. Moreover, this effect was mediated by changes in anxiety. Explanations and implications for these results are discussed.

Concept priming and pain: an experimental approach to understanding gender roles in sex-related pain differences.

Prior research has found that sex differences in pain are partially due to individual variations in gender roles. In a laboratory study, we tested the hypothesis that the presence of covert gender role cues can also moderate the extent to which women and men experience pain. Specifically, we varied gender role cues by asking male and female participants to write about instances in which they behaved in a stereotypically feminine, masculine, or neutral manner. Pain and cardiovascular reactivity to the cold pressor task were then assessed. Results revealed that, when primed with femininity, men reported less pain and anxiety from the cold pressor task than women. However, no differences existed between the sexes in the masculine or neutral prime conditions. The results indicate that covert gender cues can alter pain reports. Further, at least in some situations, feminine role cues may be more influential on pain reports than masculine role cues.

Placebo expectations and the detection of somatic information.

In a laboratory study we examined the hypothesis that placebo expectations enhance the initial identification of placebo-relevant sensations over placebo-irrelevant sensations. Participants (N = 102) were randomly assigned to one of three expectation groups. In the first group, participants ingested a placebo capsule and were told it was caffeine (deceptive expectation). In a second group, participants ingested a placebo capsule and were told it may be caffeine or it may be a placebo (double-blind expectation). Participants in the third group were given no expectation. All participants then tallied the placebo-relevant and placebo-irrelevant sensations they experienced during a 7-min period. Participants in the deceptive expectation group identified more placebo-relevant sensations than placebo-irrelevant sensations. No-expectation participants identified more placebo-irrelevant sensations than placebo-relevant sensations. Participants given the double-blind expectation identified an equal amount of placebo-relevant and irrelevant sensations. The amount of both placebo-relevant and placebo-irrelevant sensations detected mediated the relationship between the expectation manipulation and subsequent symptom reports. These data support the position that expectations cause placebo responding, in part, by altering how one identifies bodily sensations.

Dispositional optimism predicts placebo analgesia.

UNLABELLED: Based on prior research identifying dispositional optimism as a predictor of placebo responding, the present study tested the hypothesis that individuals high in optimism would be more likely to respond to a placebo analgesic. Optimists and pessimists were randomly assigned to a placebo expectation condition or a no expectation condition before a cold pressor task. Blood pressure and heart rate were recorded before and during the cold pressor task, and participant ratings of pain and expectations were obtained immediately after the task. Analysis of the expectation manipulation revealed that the placebo instruction was successful in altering participant expectancy during the cold pressor. Supporting the main hypothesis, dispositional optimism was associated with lower pain ratings in the placebo condition but not in the control condition. Because dispositional optimism can alter placebo responding to laboratory pain, future studies should examine the potential role that this individual difference factor may play in patient responsivity to pharmacological and nonpharmacological treatments for clinical pain. PERSPECTIVE: This study examined the possibility that individual differences can predict placebo analgesia. Participants were randomly assigned to receive either a placebo expectation or no expectation before a cold pressor task. Dispositional optimism was related to less cold pressor pain in the placebo condition as compared with the control condition.