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We conducted a preregistered multilaboratory project ( k = 36; N = 3,531) to assess the size and robustness of ego-depletion effects using a novel replication method, termed the paradigmatic replication approach. Each laboratory implemented one of two procedures that was intended to manipulate self-control and tested performance on a subsequent measure of self-control. Confirmatory tests found a nonsignificant result ( d = 0.06). Confirmatory Bayesian meta-analyses using an informed-prior hypothesis (δ = 0.30, SD = 0.15) found that the data were 4 times more likely under the null than the alternative hypothesis. Hence, preregistered analyses did not find evidence for a depletion effect. Exploratory analyses on the full sample (i.e., ignoring exclusion criteria) found a statistically significant effect ( d = 0.08); Bayesian analyses showed that the data were about equally likely under the null and informed-prior hypotheses. Exploratory moderator tests suggested that the depletion effect was larger for participants who reported more fatigue but was not moderated by trait self-control, willpower beliefs, or action orientation.

The present work examines how judgments of others��� commitment to a goal are influenced by three factors that influence one���s own goal commitment (satisfaction, investment, and alternatives). In two studies these three factors were manipulated. The results indicated that people rate another���s goal commitment higher when goal satisfaction is high, goal investment is high and goal alternatives are low. It was also found that satisfaction and investments alter perceptions of the other���s abilities, and that this relationship is partially mediated by perceived goal commitment. The present studies offer novel findings that highlight the information we use to judge the goal commitment of others and the consequences that are incurred when these judgments are formed.

Background The 2020 COVID-19 global pandemic required significant and immediate adjustments in service delivery. For our paediatric secondary care epilepsy service most outpatient consultations were switched to virtual from face-to-face. Initially this was via phone, and then included video calls. As we have begun to live with COVID we have developed a blended approach with mixture of face to face and virtual appointments within our service. We wanted to evaluate our families' experience of this to inform service planning and design moving forwards. Objectives To evaluate families' initial experience of non-faceto-face secondary care paediatric epilepsy clinics and their subsequent reflections and experience one year on in order to inform service re-design. Methods Families of children seen virtually between 1st March and June 30th 2020 were contacted retrospectively via telephone for feedback on their experience. The questionnaire enquired into satisfaction, advantages/disadvantages over face to face and opinions on continuation of virtual appointments. Time and money savings, along with the environmental benefits were estimated. A second review of all families under the service is currently underway which includes same questions as initial survey and the Epilepsy 12 patient/patient reported experience measure (PREM). Results First phase: 24/45 families responded. 21 had telephone clinics and 3 video (video commenced mid-June). Five of those using phone clinics would have preferred video consultation. No one experienced technical difficulties. 25% (6/ 24) thought a face to face appointment might have been better but were satisfied with the consultation. All would be happy to have virtual consultations again. Advantages over face to face clinics included time savings and being less stressful for the child/young person. On average parents reported saving 136 minutes of time (range 30-180) and £18.90 (range £0-60) with virtual consultation compared to face-to-face. 20.47 miles of driving were prevented on average per patient (range 2.4-43.2). Phase two data collection is in progress at time of abstract submission but will be available to present and share at conference. Conclusions COVID has changed the way we will deliver healthcare services. We need to ensure that these changes are safe and effective as well as meet user preferences. Our initial evaluation offered overwhelming user support for the opportunity to permanently adjust the patient pathway within paediatric epilepsy services to include virtual consultation's as part of this. All families would be happy to use again and many cited they would prefer this on an on-going basis, either exclusively or combined with face-to-face. Benefits included savings in time, money and positive environmental impact. Most recent patient/parent report experience measures are to be added. As professionals we need to be satisfied that the virtual model offers adequate opportunity for privacy and consultation with the young person alone;enables the voice of the child/young person to be heard and does not adversely impact on our ability to identify and evaluate any safeguarding concerns. On-going review and wider research will be required to ensure that clinical outcomes aren't affected negatively by any change in service models.

This study examined if people's own beliefs regarding the malleability of traits is influenced by the beliefs of surrounding others. Consistent with the idea of social contagion, people who read a vignette of someone espousing an incremental view (i.e., perceive traits as malleable) were more likely to endorse an incremental view themselves than those who read a vignette of someone with an entity view (i.e., perceive traits as fixed). Results indicated this contagion effect is not domain specific and can spread from one skill domain (e.g., athletics) to another (e.g., mathematics). Furthermore, others who espoused an incremental view were perceived to be more inspiring and therefore more likely to serve as positive role models than those who espoused an entity view. Overall, these results provide a bridge between the largely disparate literature areas of implicit trait beliefs, social contagion, and role models and indicate one potential source for the origination of these trait beliefs.

BackgroundDepression is a heterogeneous disorder with multiple aetiological pathways and multiple therapeutic targets. This study aims to determine whether atypical depression (AD) characterized by reversed neurovegetative symptoms is associated with a more pernicious course and a different sociodemographic, lifestyle, and comorbidity profile than nonatypical depression (nonAD).MethodsAmong 157 366 adults who completed the UK Biobank Mental Health Questionnaire (MHQ), N = 37 434 (24%) met the DSM-5 criteria for probable lifetime major depressive disorder (MDD) based on the Composite International Diagnostic Interview Short Form. Participants reporting both hypersomnia and weight gain were classified as AD cases (N = 2305), and the others as nonAD cases (N = 35 129). Logistic regression analyses were conducted to examine differences between AD and nonAD in depression features, sociodemographic and lifestyle factors, lifetime adversities, psychiatric and physical comorbidities.ResultsPersons with AD experienced an earlier age of depression onset, longer, more severe and recurrent episodes, and higher help-seeking rates than nonAD persons. AD was associated with female gender, unhealthy behaviours (smoking, social isolation, low physical activity), more lifetime deprivation and adversity, higher rates of comorbid psychiatric disorders, obesity, cardiovascular disease (CVD), and metabolic syndrome. Sensitivity analyses comparing AD persons with those having typical neurovegetative symptoms (hyposomnia and weight loss) revealed similar results.ConclusionsThese findings highlight the clinical and public health significance of AD as a chronic form of depression, associated with high comorbidity and lifetime adversity. Our findings have implications for predicting depression course and comorbidities, guiding research on aetiological mechanisms, planning service use and informing therapeutic approaches.

Background Persons living with HIV (PLWH) are frequently hospitalized for reasons often unrelated to HIV. Transitioning of antiretroviral therapy (ART) while inpatient may not always be an immediate priority due to lack of knowledge, formulary restrictions, and patient status. This could lead to medication errors and gaps in therapy, which can persist at discharge, and could lead to viral rebound and disease progression. The purpose of this study was to identify effects of hospitalization on ART for PLWH. Methods This was an IRB approved, multi-center, retrospective cohort study of patients with HIV and/or AIDS based on ICD codes. Patients were included if they were at least 18 years old, receiving outpatient ART prior to admission, and hospitalized between March 2016 and March 2018. Patients were excluded if they were pregnant and only received intravenous zidovudine during their hospitalization. The primary objective was to determine the rate of ART restarted during hospitalization. Secondary objectives included rate at which inpatient ART was modified compared to outpatient regimen, and risk factors associated with regimen modification. Results Of 400 patients screened, 295 (74%) patients were on an outpatient ART regimen and were included in the study. Approximately half, 51%, were on a single tablet regimen (STR) outpatient. This population was majority male (59%) and of black race (87%). Median age was 49 years. Median CD4 count was 160 cells/mm3, while median HIV RNA for those with detectable viral load was 57,095 copies/mL. 236 of 295 patients (80%) received ART during their inpatient stay. However, 70 (30%) of these patients received a regimen that differed from their outpatient ART regimen. 69% of regimens were modified for reasons other than to optimize therapy. Patient sex, place of admission, and receipt of a STR or multi-tablet regimen (MTR) as an outpatient did not significantly impact rate of regimen modification. Conclusion Ensuring appropriate transition of ART during hospitalization remains an area in need of improvement. No one specific factor was associated with whether outpatient ART was appropriately and accurately restarted during hospitalization. Thus, there are many opportunities to improve transitions of care and antiretroviral stewardship. Disclosures All Authors: No reported disclosures

Some mitochondrial long noncoding RNAs (lncRNAs) are encoded by nuclear DNA, but the mechanisms that mediate their transport to mitochondria are poorly characterized. Using affinity RNA pull-down followed by mass spectrometry analysis, we found two RNA-binding proteins (RBPs), HuR (human antigen R) and GRSF1 (G-rich RNA sequence-binding factor 1), that associated with the nuclear DNA-encoded lncRNA RMRP and mobilized it to mitochondria. In cultured human cells, HuR bound RMRP in the nucleus and mediated its CRM1 (chromosome region maintenance 1)-dependent export to the cytosol. After RMRP was imported into mitochondria, GRSF1 bound RMRP and increased its abundance in the matrix. Loss of GRSF1 lowered the mitochondrial levels of RMRP, in turn suppressing oxygen consumption rates and modestly reducing mitochondrial DNA replication priming. Our findings indicate that RBPs HuR and GRSF1 govern the cytoplasmic and mitochondrial localization of the lncRNA RMRP, which is encoded by nuclear DNA but has key functions in mitochondria.

Mitofusin 2 (Mfn2), a mitochondrial protein, was shown to have antiproliferative properties when overexpressed. In this article, we show that activation of resting human peripheral blood T cells caused downregulation of Mfn2 levels. This downregulation of Mfn2 was blocked by different inhibitors (mTOR inhibitor rapamycin, PI3K inhibitor LY294002, and Akt inhibitor A443654), producing cells that were arrested in the G0/G1 stage of the cell cycle. Furthermore, the activation-induced downregulation of Mfn2 preceded the entry of the cells into the cell cycle, suggesting that Mfn2 downregulation is a prerequisite for activated T cell entry into the cell cycle. Accordingly, small interfering RNA–mediated knockdown of Mfn2 resulted in increased T cell proliferation. Overexpression of constitutively active AKT resulted in the downregulation of Mfn2, which can be blocked by a proteasome inhibitor. Akt-mediated downregulation of Mfn2 was via the mTORC1 pathway because this downregulation was blocked by rapamycin, and overexpression of wild-type, but not kinase-dead mTOR, caused Mfn2 downregulation. Our data suggested that activation-induced reactive oxygen species production plays an important role in the downregulation of Mfn2. Collectively, our data suggest that the PI3K-AKT-mTOR pathway plays an important role in activation-induced downregulation of Mfn2 and subsequent proliferation of resting human T cells.

Background As HIV has become a chronic condition, management of the disease and preventing resistance is paramount to improving patient outcomes. Medication errors can lead to suboptimal therapy and potential development of resistance. The purpose of this study was to identify the rate of antiretroviral (ART)-related medication errors in hospitalized people living with HIV (PWLH). Methods This was a multi-center, retrospective cohort study of patients diagnosed with HIV and/or AIDS based on International Classification of Diseases codes. Patients were included if they were at least 18 years old and hospitalized between March 2016 and March 2018. Patients were excluded if they were pregnant and only received intravenous zidovudine during their hospitalization. Of the patients eligible for inclusion, 400 were randomly selected and included in this study. The primary objective was to determine the rate of inpatient ART-related medication errors. Secondary objectives included the type of errors and rate of error resolution prior to discharge. Results A total of 203 ART-related medication errors occurred during the study period (mean 0.9 ± 1.2 errors per patient). Incorrect schedule was the most common type of error followed by incorrect or incomplete regimen. More errors occurred in male patients (P = 0.01), those known to be infected with HIV on admission (P < 0.05), and in patients with an undetectable viral load (P = 0.01). Approximately 30% of ART-related medication errors were resolved prior to discharge, of which pharmacists were responsible for 25%. Incorrect schedule, incorrect or incomplete regimen, and clinically significant drug-drug interaction (DDI) were the most common medication errors that persisted at discharge. Among resolved errors, resolution of clinically significantly DDI or incorrect/incomplete ART were the most common interventions. Conclusion ART-related medication errors continue to occur in hospitalized PLWH and frequently persist at discharge. Interventions should be developed to reduce rates of ART-related medication errors on admission. Antimicrobial stewardship programs serve as an ideal platform to incorporate ART stewardship into routine activities to help minimize errors while inpatient and during transitions of care. Disclosures All authors: No reported disclosures.

Glyptemys insculpta (Wood Turtle) is listed as imperiled in West Virginia and designated as endangered under the IUCN Red List. We studied a population of Wood Turtles in the Eastern Panhandle of West Virginia from May 2010 to July 2011. We captured 25 turtles at 2 sites: 12 males, 9 females, 3 juveniles, and 1 hatchling. We fitted 10 adults with radio transmitters, 9 of which also received temperature-data loggers. Our 249 total observations include the 10 initial captures of the equipped turtles with 218 subsequent radio locations, and 15 unequipped turtles that were captured, and then recaptured 6 times. Morphometrics of Wood Turtles at the study location were similar to those reported for another West Virginia population. The home range for both males and females was approximately 6 ha; there were no significant intersexual differences. Turtles entered hibernacula in late October when temperatures were approximately 10 °C and remained inactive until mid-March when temperatures were approximately 5 °C. Our study provides a baseline assessment of the Wood Turtle in an unstudied upper-elevation Eastern Panhandle location.

Goal fusion refers to the perception that a goal is integrated within one's self-concept. We created a new measure of goal fusion and examined how incremental differences in such fusion results in positive and negative goal-relevant consequences. A pilot study supported the measure's test–retest reliability. Study 1 found that goal fusion uniquely contributed to participants' goal-relevant cognitions and behaviors above and beyond the effects of other related constructs. Study 2 found that higher goal fusion predicted greater goal investments and goal achievement 1 month later. Study 3 found that goal success and failure differentially impacted peoples' self-concept clarity depending on whether they were or were not fused with the goal. Collectively, the findings indicate our goal fusion assessment is a reliable, valid and useful measure.

This article aims to bridge the circadian and self-control literatures by suggesting that people’ ss elf-control performance varies as a function of their circadian preferences (i.e.,chronotype). We review evidence for this assertion across a wide range of self-control domains, including cognitive processing, emotion regulation, interpersonal relationships, and social influence. Across these widely ranging behaviors, the results indicate that when people’s circadian preference matches the time of day, a synchrony effect occurs, and self-control performance is at its peak. Therefore, people are more likely to display self-regulatory failures and give in to temptations when there is a mismatch between their circadian preferences and time of day. Overall, this article offers new insights into the relationship between circadian preferences and self-control and suggests novel and exciting new directions for future research.

Storybook tales, movies, and beauty magazines often communicate the message that beauty is malleable. Malleable beliefs are generally found to be beneficial, but this is not the case in the beauty domain. Across two studies, we found that the “beauty is malleable” belief puts women (but not men) at risk for harmful appearance concerns, such as basing their selfworth on physical attractiveness, increased appearance anxiety, and increased interest in cosmetic surgery. These results were found when beauty beliefs were measured (Study 1) and manipulated (Study 2). Thus, the message that beauty is malleable has a potentially harmful effect on women's lives. This work also suggests that the typical finding that malleable beliefs are beneficial may reverse when the domain in question has unattainable standards.

Constructs typically used to understand commitment between individuals were used to elucidate individual differences in goal commitment. In Study 1, 299 college students completed assessments of goal satisfaction, investments, alternatives and commitment regarding an academic goal. Structural equation modeling demonstrated confirmatory evidence for satisfaction’s, investments’, and alternatives’ collective impact on people’s goal commitment. In Study 2, the model components were manipulated by having 236 college students considered the goal to learn a new language and read information suggesting they were high or low in satisfaction, investments, and alternatives. Results demonstrated all three factors had a causal impact on people’s level of goal commitment. Both studies found an individual’s level of goal commitment was strongest when satisfaction and investments were high and the impact of alternatives was low.

The reality that American public schools are not meeting the needs of all students and the increasing incongruity between student and teacher demographics demand increased efforts to prepare teacher candidates to work with students who are ethnically, culturally and linguistically diverse. Teacher preparation programs are charged with this work and have responded by addressing diversity through multiple methods (e.g., discrete courses, infused content, and culturally and linguistically diverse field experiences). These efforts are commendable but may approach cultural competency from a one size fits all perspective. This pilot study explores the possibilities for purposeful preparation of culturally competent educators through a developmental approach allowing for differentiated experiences leading to higher levels of intercultural sensitivity. The rationale for use of a developmental approach and corresponding assessment tool is provided along with pre-and post-assessment results from one student cohort. Implications for teacher preparation and recommendations for future research are also presented.

Carbonylation is the covalent, non-reversible modification of the side chains of cysteine, histidine, and lysine residues by lipid peroxidation end products such as 4-hydroxy- and 4-oxononenal. In adipose tissue the effects of such modifications are associated with increased oxidative stress and metabolic dysregulation centered on mitochondrial energy metabolism. To address the role of protein carbonylation in the pathogenesis of mitochondrial dysfunction, quantitative proteomics was employed to identify specific targets of carbonylation in GSTA4-silenced or overexpressing 3T3-L1 adipocytes. GSTA4-silenced adipocytes displayed elevated carbonylation of several key mitochondrial proteins including the phosphate carrier protein, NADH dehydrogenase 1α subcomplexes 2 and 3, translocase of inner mitochondrial membrane 50, and valyl-tRNA synthetase. Elevated protein carbonylation is accompanied by diminished complex I activity, impaired respiration, increased superoxide production, and a reduction in membrane potential without changes in mitochondrial number, area, or density. Silencing of the phosphate carrier or NADH dehydrogenase 1α subcomplexes 2 or 3 in 3T3-L1 cells results in decreased basal and maximal respiration. These results suggest that protein carbonylation plays a major instigating role in cytokine-dependent mitochondrial dysfunction and may be linked to the development of insulin resistance in the adipocyte.

Oxidative stress is linked to the production of reactive lipid aldehydes that non-enzymatically alkylate cysteine, histidine, or lysine residues in a reaction termed protein carbonylation. Reactive lipid aldehydes and their derivatives are detoxified via a variety of phase I and phase II systems, and when antioxidant defenses are compromised or oxidative conditions are increased, protein carbonylation is increased. The resulting modification has been implicated as causative in a variety of metabolic states including neurodegeneration, muscle wasting, insulin resistance, and aging. Although such modifications usually result in loss of protein function, protein carbonylation may be regulatory and activate signaling pathways involved in antioxidant biology and cellular homeostasis.

In machine learning there are numerous supervised techniques that extend naturally to analogous unsupervised methods, such as clustering. In this paper, we consider so-called rare-weak models, in which the number of important features is small (or rare) and the signal strength of each important feature is minimal (or weak). When classical clustering is applied crudely in "big data" scenarios, significant problems can arise, including long computational run times and significant clustering errors. One solution is to use feature selection (FS) to reduce dataset dimensionality before clustering. We introduce two novel unsupervised feature selection methods, one parametric and one nonparametric, based on what we call bimodal feature selection. These methods produce ranked lists of features based on their univariate multi-modality. Unlike previously developed univariate FS methods, which have typically been restricted to 2-cluster scenarios, our method has been adapted and tested to discriminate binary and higher level clusterings. The method is particularly advantageous in rare-weak settings, since reducing data dimensionality allows classical clustering methods to be applied computationally faster and with greater accuracy.

The ability to effectively regulate one’s thoughts, feelings, and behavior is at the heart of human agency. Numerous insights in self-regulation have recently been gained utilizing the strength, or limited-resource, model of self-control. Much of this work has focused on the intrapersonal impact of self-control; however, an emerging body of work has begun to shift attention toward the interpersonal realm with similar success. In this article, we review the role that regulatory strength has in social influence. Work from persuasion, compliance, and conformity demonstrate that (1) resisting social influences consumes regulatory resources and (2) when these resources are depleted, people become more susceptible to social influences. We conclude by highlighting important implications that remain unanswered and suggest potential areas of future development.

The influence of vitamin E and selenomethionine (SeMet) on lipid oxidation in frozen-raw and cooked omega-3 enriched dark chicken meat was evaluated. Feed was supplemented with 2 levels of vitamin E (250 and 50 IU/kg of feed) and selenium (0.1 mg of sodium selenite/kg of feed and 0.3 mg of SeMet/kg of feed). An extruded linseed product was used as the alpha-linolenic acid source. Fatty acid (FA) profile, oxysterols, and thiobarbituric reactive acid substances (TBARs) were analyzed in frozen-raw, boiled, pan-fried, and roasted meat. After 6 mo of storage, oxysterols in frozen-raw meat remained stable with either high or low levels of dietary antioxidants. During cooking, high levels of vitamin E reduced oxysterol formation, whereas high levels of SeMet were inconsistent and even increased oxysterols during roasting. TBARs in frozen-raw meat stored for 6 mo were inhibited by high levels of either antioxidant. Conversely, no protective effect during cooking was observed at this time of storage. After 12 mo at -30 degrees C no antioxidant protection was observed.

OBJECTIVE Peripheral insulin resistance is linked to an increase in reactive oxygen species (ROS), leading in part to the production of reactive lipid aldehydes that modify the side chains of protein amino acids in a reaction termed protein carbonylation. The primary enzymatic method for lipid aldehyde detoxification is via glutathione S-transferase A4 (GSTA4) dependent glutathionylation. The objective of this study was to evaluate the expression of GSTA4 and the role(s) of protein carbonylation in adipocyte function. RESEARCH DESIGN AND METHODS GSTA4-silenced 3T3-L1 adipocytes and GSTA4-null mice were evaluated for metabolic processes, mitochondrial function, and reactive oxygen species production. GSTA4 expression in human obesity was evaluated using microarray analysis. RESULTS GSTA4 expression is selectively downregulated in adipose tissue of obese insulin-resistant C57BL/6J mice and in human obesity-linked insulin resistance. Tumor necrosis factor-α treatment of 3T3-L1 adipocytes decreased GSTA4 expression, and silencing GSTA4 mRNA in cultured adipocytes resulted in increased protein carbonylation, increased mitochondrial ROS, dysfunctional state 3 respiration, and altered glucose transport and lipolysis. Mitochondrial function in adipocytes of lean or obese GSTA4-null mice was significantly compromised compared with wild-type controls and was accompanied by an increase in superoxide anion. CONCLUSIONS These results indicate that downregulation of GSTA4 in adipose tissue leads to increased protein carbonylation, ROS production, and mitochondrial dysfunction and may contribute to the development of insulin resistance and type 2 diabetes.

Fusion refers to the sense that a construct is integrated into the self-concept. When a person feels fused with a construct, there is a perceived “oneness” with the construct, and as a result, the construct is treated as an extension of the self. This concept of fusion has been explored across a wide range of constructs and within a number of subfields in psychology. The goal of this article is to provide a comprehensive view of the fusion process and to connect these disparate areas of literature underneath a single unifying theme. Specifically, we focus on five constructs that researchers have explored in terms of fusion: objects, thoughts, goals, significant others, and groups. In our review, we discuss the ways that fusion is typically measured and highlight the consequences that occur as a result of such fusion. We conclude by highlighting questions that remain unanswered and suggest potential areas of future development.

The nature and frequency of voter fraud figure prominently in many ongoing policy debates about election laws in the United States. Policy makers frequently cite allegations of voter fraud reported in the press during these debates. While recent studies find that voter fraud is a rare event, a substantial segment of the public believes that voter fraud is a rampant problem in the United States. It stands to reason that public beliefs are shaped by news coverage of voter fraud. However, there is very little extant academic research on how the news media, at any level, covers allegations or documented cases of voter fraud. This paper examines local newspaper attention to voter fraud in each of the 50 states during the 2008 and 2012 US elections. The results show that local coverage of voter fraud during the 2012 elections was greatest in presidential swing states and states that passed restrictive voting laws prior to the 2012 election. No evidence that newspaper attention is related to the rate of actual voter fraud cases in each state was found. The findings are consistent with other studies indicating that parties and campaigns sought to place voter fraud on the political agenda in strategically important states to motivate their voting base ahead of the election.

The mammalian RNA-binding protein AUF1 (AU-binding factor 1, also known as heterogeneous nuclear ribonucleoprotein D [hnRNP D]) binds to numerous mRNAs and influences their posttranscriptional fate. Given that many AUF1 target mRNAs encode muscle-specific factors, we investigated the function of AUF1 in skeletal muscle differentiation. In mouse C2C12 myocytes, where AUF1 levels rise at the onset of myogenesis and remain elevated throughout myocyte differentiation into myotubes, RNP immunoprecipitation (RIP) analysis indicated that AUF1 binds prominently to Mef2c (myocyte enhancer factor 2c) mRNA, which encodes the key myogenic transcription factor MEF2C. By performing mRNA half-life measurements and polysome distribution analysis, we found that AUF1 associated with the 3′ untranslated region (UTR) of Mef2c mRNA and promoted MEF2C translation without affecting Mef2c mRNA stability. In addition, AUF1 promoted Mef2c gene transcription via a lesser-known role of AUF1 in transcriptional regulation. Importantly, lowering AUF1 delayed myogenesis, while ectopically restoring MEF2C expression levels partially rescued the impairment of myogenesis seen after reducing AUF1 levels. We propose that MEF2C is a key effector of the myogenesis program promoted by AUF1.

The ability to learn and form memories depends on specific patterns of synaptic activity and is in part transcription dependent. However, the signal transduction pathways that connect signals generated at synapses with transcriptional responses in the nucleus are not well understood. In the present report, we discuss three signal transduction pathways: the Ca2+/calmodulin-dependent kinase (CaMK) pathway, the Ras/ERK pathway, and the SAPK pathways that might function to couple synaptic activity to long-term adaptive responses, in part through the regulation of new gene expression. Evidence suggests that these pathways become activated in response to stimuli that regulate synaptic function such as the influx of extracellular Ca2+ and certain neurotrophin growth factors such as brain-derived neurotrophic factor. Once activated, the CaMK, Ras/ERK, and SAPK pathways lead to the phosphorylation and activation of transcription factors in the nucleus such as the cyclic AMP response element binding protein (CREB). Genes regulated by CREB or other transcription factor targets of the CaMK, Ras/ERK, and SAPK pathways could mediate important adaptive responses to changes in synaptic activity such as changes in synaptic strength and the regulation of neuronal survival and death. J. Neurosci. Res. 58:88–95, 1999. © 1999 Wiley-Liss, Inc.

Calorie restriction is the most powerful method currently known to delay aging-associated disease and extend lifespan. Use of this technique in combination with genetic models has led to identification of key metabolic regulators of lifespan. Limiting energy availability by restricting caloric intake leads to redistribution of energy expenditure and storage. The signaling required for these metabolic changes is mediated in part by the sirtuins at both the posttranslational and transcriptional levels, and consequently, sirtuins are recognized as instigating factors in the regulation of lifespan. This family of class III protein deacetylases is responsible for directing energy regulation based on NAD(+) availability. However, there are many effectors of NAD(+) availability, and hence sirtuin action, that should be considered when performing experiments using calorie restriction. The methods outlined in this chapter are intended to provide a guide to help the aging community to use and interpret experimental calorie restriction properly. The importance of healthspan and the use of repeated measures to assess metabolic health during lifespan experiments are strongly emphasized.

Cytochrome b5 reductases (CYB5R) are required for the elongation and desaturation of fatty acids, cholesterol synthesis and mono-oxygenation of cytochrome P450 enzymes, all of which are associated with protection against metabolic disorders. However, the physiological role of CYB5R in the context of metabolism, healthspan and aging remains ill-defined. We generated CYB5R-overexpressing flies (CYB5R-OE) and created a transgenic mouse line overexpressing CYB5R3 (CYB5R3-Tg) in the C57BL/6J background to investigate the function of this class of enzymes as regulators of metabolism and age-associated pathologies. Gender- and/or stage-specific induction of CYB5R, and pharmacological activation of CYB5R with tetrahydroindenoindole extended fly lifespan. Increased expression of CYB5R3 was associated with significant improvements in several metabolic parameters that resulted in modest lifespan extension in mice. Diethylnitrosamine-induced liver carcinogenesis was reduced in CYB5R3-Tg mice. Accumulation of high levels of long-chain polyunsaturated fatty acids, improvement in mitochondrial function, decrease in oxidative damage and inhibition of chronic pro-inflammatory pathways occurred in the transgenic animals. These results indicate that CYB5R represents a new target in the study of genes that regulate lipid metabolism and healthspan.

Polyglutamine (polyQ) stretches exceeding a threshold length confer a toxic function to proteins that contain them and cause at least nine neurological disorders. The basis for this toxicity threshold is unclear. Although polyQ expansions render proteins prone to aggregate into inclusion bodies, this may be a neuronal coping response to more toxic forms of polyQ. The exact structure of these more toxic forms is unknown. Here we show that the monoclonal antibody 3B5H10 recognizes a species of polyQ protein in situ that strongly predicts neuronal death. The epitope selectively appears among some of the many low-molecular-weight conformational states assumed by expanded polyQ and disappears in higher-molecular-weight aggregated forms, such as inclusion bodies. These results suggest that protein monomers and possibly small oligomers containing expanded polyQ stretches can adopt a conformation that is recognized by 3B5H10 and is toxic or closely related to a toxic species. © 2011 Nature America, Inc. All rights reserved.

Corrigendum: Identifying polyglutamine protein species in situ that best predict neurodegeneration