Occupational and environmental exposures in the Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study.

INTRODUCTION: Sarcoidosis is a granulomatous disorder thought to be caused by exposures in genetically susceptible individuals. This study investigated whether specific exposures were associated with different sarcoidosis phenotypes. METHODS: Extensive demographic, occupational and environmental exposure data was analyzed from subjects enrolled in the NHLBI Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. RESULTS: In patients with sarcoidosis, radiation exposure was significantly associated with an increased risk of cardiac sarcoidosis versus non-cardiac sarcoidosis. No exposures were significantly associated with pulmonary only disease versus extrapulmonary disease with or without pulmonary involvement, Scadding Stage II/III/IV versus Scadding Stage 0/I, acute or remitting disease versus non-acute or non-remitting disease, nor chronic versus non-chronic disease. Although not reaching statistically significance after adjustment for multiple comparisons, there were a number of exposures associated with specific disease phenotypes, including exposures where relationships to sarcoidosis have previously been described such as rural exposures and pesticide exposures. CONCLUSIONS: Radiation exposure may be a risk factor for cardiac sarcoidosis. Other exposures may also be associated with specific phenotypes and should be further explored. The study was limited by small groups of exposed subjects for individual exposures and multiple comparisons. The development of novel and innovative exposure assessment tools is needed.

Cluster activation mapping with application to computed tomography scans of the lung.

Purpose: An open question in deep clustering is how to explain what in the image is driving the cluster assignments. This is especially important for applications in medical imaging when the derived cluster assignments may inform decision-making or create new disease subtypes. We develop cluster activation mapping (CLAM), which is methodology to create localization maps highlighting the image regions important for cluster assignment. Approach: Our approach uses a linear combination of the activation channels from the last layer of the encoder within a pretrained autoencoder. The activation channels are weighted by a channelwise confidence measure, which is a modification of score-CAM. Results: Our approach performs well under medical imaging-based simulation experiments, when the image clusters differ based on size, location, and intensity of abnormalities. Under simulation, the cluster assignments were predicted with 100% accuracy when the number of clusters was set at the true value. In addition, applied to computed tomography scans from a sarcoidosis population, CLAM identified two subtypes of sarcoidosis based purely on CT scan presentation, which were significantly associated with pulmonary function tests and visual assessment scores, such as ground-glass, fibrosis, and honeycombing. Conclusions: CLAM is a transparent methodology for identifying explainable groupings of medical imaging data. As deep learning networks are often criticized and not trusted due to their lack of interpretability, our contribution of CLAM to deep clustering architectures is critical to our understanding of cluster assignments, which can ultimately lead to new subtypes of diseases.

Drosophila p38 MAPK interacts with BAG-3/starvin to regulate age-dependent protein homeostasis.

As organisms age, they often accumulate protein aggregates that are thought to be toxic, potentially leading to age-related diseases. This accumulation of protein aggregates is partially attributed to a failure to maintain protein homeostasis. A variety of genetic factors have been linked to longevity, but how these factors also contribute to protein homeostasis is not completely understood. In order to understand the relationship between aging and protein aggregation, we tested how a gene that regulates lifespan and age-dependent locomotor behaviors, p38 MAPK (p38Kb), influences protein homeostasis as an organism ages. We find that p38Kb regulates age-dependent protein aggregation through an interaction with starvin, a regulator of muscle protein homeostasis. Furthermore, we have identified Lamin as an age-dependent target of p38Kb and starvin.

Estimation of Multiple Sclerosis lesion age on magnetic resonance imaging.

We introduce the first-ever statistical framework for estimating the age of Multiple Sclerosis (MS) lesions from magnetic resonance imaging (MRI). Estimating lesion age is an important step when studying the longitudinal behavior of MS lesions and can be used in applications such as studying the temporal dynamics of chronic active MS lesions. Our lesion age estimation models use first order radiomic features over a lesion derived from conventional T1 (T1w) and T2 weighted (T2w) and fluid attenuated inversion recovery (FLAIR), T1w with gadolinium contrast (T1w+c), and Quantitative Susceptibility Mapping (QSM) MRI sequences as well as demographic information. For this analysis, we have a total of 32 patients with 53 new lesions observed at 244 time points. A one or two step random forest model for lesion age is fit on a training set using a lesion volume cutoff of 15 mm3 or 50 mm3. We explore the performance of nine different modeling scenarios that included various combinations of the MRI sequences and demographic information and a one or two step random forest models, as well as simpler models that only uses the mean radiomic feature from each MRI sequence. The best performing model on a validation set is a model that uses a two-step random forest model on the radiomic features from all of the MRI sequences with demographic information using a lesion volume cutoff of 50 mm3. This model has a mean absolute error of 7.23 months (95% CI: [6.98, 13.43]) and a median absolute error of 5.98 months (95% CI: [5.26, 13.25]) in the validation set. For this model, the predicted age and actual age have a statistically significant association (p-value <0.001) in the validation set.

Evolutionarily conserved transcription factors drive the oxidative stress response in Drosophila.

As organisms are constantly exposed to the damaging effects of oxidative stress through both environmental exposure and internal metabolic processes, they have evolved a variety of mechanisms to cope with this stress. One such mechanism is the highly conserved p38 MAPK (p38K) pathway, which is known to be post-translationally activated in response to oxidative stress, resulting in the activation of downstream antioxidant targets. However, little is known about the role of p38K transcriptional regulation in response to oxidative stress. Therefore, we analyzed the p38K gene family across the genus Drosophila to identify conserved regulatory elements. We found that oxidative stress exposure results in increased p38K protein levels in multiple Drosophila species and is associated with increased oxidative stress resistance. We also found that the p38Kb genomic locus includes conserved AP-1 and lola-PT transcription factor consensus binding sites. Accordingly, over-expression of these transcription factors in D. melanogaster is sufficient to induce transcription of p38Kb and enhances resistance to oxidative stress. We further found that the presence of a putative lola-PT binding site in the p38Kb locus of a given species is predictive of the species' survival in response to oxidative stress. Through our comparative genomics approach, we have identified biologically relevant putative transcription factor binding sites that regulate the expression of p38Kb and are associated with resistance to oxidative stress. These findings reveal a novel mode of regulation for p38K genes and suggest that transcription may play as important a role in p38K-mediated stress responses as post-translational modifications.

Template Creation for High-Resolution Computed Tomography Scans of the Lung in R Software.

RATIONALE AND OBJECTIVES: A standard lung template could improve population-level analyses for computed tomography (CT) scans of the lung. We develop a fully automated preprocessing pipeline for image analysis of the lungs using updated methodologies and R software that results in the creation of a standard lung template. We apply this pipeline to CT scans from a sarcoidosis population, exploring the influence of registration on radiomic analyses. MATERIALS AND METHODS: Using 65 high-resolution CT scans from healthy adults, we create a standard lung template by segmenting the left and right lungs, nonlinearly registering lung masks to an initial template mask, and using an unbiased, iterative procedure to converge to a standard lung shape (Dice similarity coefficient ≥0.99). We compare three-dimensional radiomic features between control and sarcoidosis patients, before and after registration to a study-specific lung template. RESULTS: The final lung template had a right lung volume of 2967 cm3 and left lung volume of 2623 cm3, with a median HU = -862. Registration significantly affected radiomic features, shifting the HU distribution to the left, decreasing variability, and increasing smoothness (p < 0.0001). The registration improved detective ability of radiomics; for contrast, autocorrelation, energy, and homogeneity, the group effect was significant postregistration (p < 0.05), but was not significant preregistration. CONCLUSION: The final lung template and software used for its creation are publicly available via the lungct R package to facilitate its use in practice. This study advances lung imaging by developing tools to improve population-level analyses for various lung diseases.

Radiomic measures from chest high-resolution computed tomography associated with lung function in sarcoidosis.

INTRODUCTION: Pulmonary sarcoidosis is a rare heterogeneous lung disease of unknown aetiology, with limited treatment options. Phenotyping relies on clinical testing including visual scoring of chest radiographs. Objective radiomic measures from high-resolution computed tomography (HRCT) may provide additional information to assess disease status. As the first radiomics analysis in sarcoidosis, we investigate the potential of radiomic measures as biomarkers for sarcoidosis, by assessing 1) differences in HRCT between sarcoidosis subjects and healthy controls, 2) associations between radiomic measures and spirometry, and 3) trends between Scadding stages. METHODS: Radiomic features were computed on HRCT in three anatomical planes. Linear regression compared global radiomic features between sarcoidosis subjects (n=73) and healthy controls (n=78), and identified associations with spirometry. Spatial differences in associations across the lung were investigated using functional data analysis. A subanalysis compared radiomic features between Scadding stages. RESULTS: Global radiomic measures differed significantly between sarcoidosis subjects and controls (p<0.001 for skewness, kurtosis, fractal dimension and Geary's C), with differences in spatial radiomics most apparent in superior and lateral regions. In sarcoidosis subjects, there were significant associations between radiomic measures and spirometry, with a large association found between Geary's C and forced vital capacity (FVC) (p=0.008). Global radiomic measures differed significantly between Scadding stages (p<0.032), albeit nonlinearly, with stage IV having more extreme radiomic values. Radiomics explained 71.1% of the variability in FVC compared with 51.4% by Scadding staging alone. CONCLUSIONS: Radiomic HRCT measures objectively differentiate disease abnormalities, associate with lung function and identify trends in Scadding stage, showing promise as quantitative biomarkers for pulmonary sarcoidosis.

A longitudinal intervention to improve young children's liking and consumption of new foods: findings from the Colorado LEAP study.

BACKGROUND: Many interventions have been conducted to improve young children's liking and consumption of new foods however their impacts on children's consumption have been limited. Consistent evidence supports the use of repeated exposure to improve liking for new foods however longitudinal effects lasting greater than 6 months often have not been demonstrated. Here we report the eating-related findings of the Colorado Longitudinal Eating And Physical Activity (LEAP) Study, a multi-component intervention, delivered primarily in the school setting, which aimed to improve children's liking and consumption of a target food via repeated exposure and positive experiential learning. METHODS: Four sites in rural Colorado, each housing Head Start preschool programs, matched on state vital statistics for childhood obesity rates, (2 intervention and 2 control sites) took part in a quasi-experimental study design which included 4 time points (baseline, post-intervention, one-year [Y1] and two- year [Y2] follow ups). A total of 250 children and families were enrolled (n = 143 intervention and n = 107 control; 41% Hispanic and 69% low-income). A 12-week intervention, Food Friends - Fun With New Foods®, delivered by trained preschool teachers and which focuses on positive and repeated experiences with new foods, and a 5-month (1 unit/month) social marketing "booster program" was delivered in kindergarten (one-year follow up) and 1st grade (two-year follow up). Main outcome measures included change in children's liking for new foods, analyzed by ordinal regression using generalized estimating equations, and change in weighed consumption of new foods over time, analyzed using a hierarchical mixed effects model. RESULTS: The intervention was delivered with good fidelity (87%). Both intervention and control groups demonstrated an increase in liking for the target food over time (p = 0.0001). The pattern of consumption of the target food was different, over time, for intervention and control groups (p < 0.005). In particular the change in intake between baseline and post-intervention was significantly greater in the intervention compared to the control group (p < 0.0001) though this pattern of change did not hold between baseline and Y2 follow up (p = 0.1144). Children in the intervention group who liked the target food consumed nearly double their baseline consumption at post-intervention (p < 0.0001;) and maintained this increase at Y2 follow up (p < 0.0001). CONCLUSIONS: The Food Friends intervention, which utilized positive, repeated experiences with new foods, and was delivered with good fidelity by trained preschool teachers, found that larger improvements were observed in children's eating behaviors than would be expected with developmentally-based changes in eating behaviors. TRIAL REGISTRATION NUMBER: This trial is registered at ClinicalTrials.gov : NCT01937481. Date registered: 09/09/2013; Retrospectively registered. Date first participant registered: 09/15/2010.

Evaluation of the Reliability and Validity of the Social Anxiety Questionnaire for Children in Adolescents with Social Anxiety Disorder.

Little research has focused on the measurement of specific facets of social anxiety disorder (SAD) in adolescents. In this study, we report on the Social Anxiety Questionnaire for Children (SAQ-C; Caballo et al., 2016), a 24-item questionnaire which assesses six facets of social anxiety in youth: 1) Speaking in public/Interactions with teachers, 2) Interactions with the opposite sex, 3) Criticism and embarrassment, 4) Assertive expression of annoyance, disgust, or displeasure, 5) Interactions with strangers, and 6) Performing in public. The SAQ-C has been shown to have sound psychometric properties in large samples of non-clinical Latin-American and Spanish youth. The present study aimed to provide the first evaluation of the psychometric properties of the SAQ-C in a clinical sample of 58 English-speaking adolescents diagnosed with SAD in the United States. Findings support the reliability and validity of this new measure and reveal specific facets of social anxiety not adequately captured in other frequently used self- report measures. Implications of the findings for assessment and treatment are addressed.

Attention Bias Modification Treatment for Adolescents With Social Anxiety Disorder.

Social anxiety disorder (SAD) tends to emerge during the early teenage years and is particularly refractory to change even when standard evidence-based CBT treatments are delivered. Efforts have been made to develop novel, mechanistic-driven interventions for this disorder. In the present study, we examined Attention Bias Modification Treatment (ABMT) for youth with SAD. Participants were 58 adolescents (mean age = 14.29 years) who met diagnostic criteria for SAD and who were randomized to ABMT or a placebo control condition, Attention Control Training (ACT). We predicted that ABMT would result in greater changes in both threat biases and social anxiety symptoms. We also explored potential moderators of change including the severity of social anxiety symptoms, the level of threat bias at pretreatment, and the degree of temperament-defined attention control. Contrary to our hypotheses, changes in attention bias were not observed in either condition, changes in social anxiety symptoms and diagnosis were small, and significant differences were not observed between the ABMT and ACT conditions. Little support for the proposed moderators was obtained. Reasons for our failure to find support for ABMT and its potential moderators are explored and recommendations for changes in the ABMT paradigm are suggested.

Have Phobias, Will Travel: Addressing One Barrier to the Delivery of an Evidence-Based Treatment.

Although a host of evidence-based treatments exist for youth with anxiety disorders, less than 30% of youth and their families receive these treatments. One of the main barriers to receiving these treatments is the lack of access to care, due largely to the absence of mental health professionals who have expertise in the delivery of these treatments in certain geographic locales. The current study examined whether a brief intensive treatment for specific phobias (SPs), Augmented One-Session Treatment (OST-A), would result in comparable treatment gains for families who traveled a considerable distance to receive this treatment when compared to families who resided in our local community. Participants included 76 youth with a clinically confirmed diagnosis of SP (38 local families and an age- and sex-matched sample of 38 nonlocal families). Although SP severity at pretreatment was significantly greater for the nonlocal youth than the local youth, both nonlocal and local youth showed commensurate improvement and maintenance of treatment gains over a 6-month period across several clinical outcome measures. Findings from this study show that OST-A is effective when families choose to travel for treatment, addressing at least one of the barriers to use of this evidence-based treatment.

The Interaction Between Child Behavioral Inhibition and Parenting Behaviors: Effects on Internalizing and Externalizing Symptomology.

Both child temperament and parenting have been extensively researched as predictors of child outcomes. However, theoretical models suggest that specific combinations of temperament styles and parenting behaviors are better predictors of certain child outcomes such as internalizing and externalizing symptoms than either temperament or parenting alone. The current qualitative review examines the interaction between one childhood temperamental characteristic (child behavioral inhibition) and parenting behaviors, and their subsequent impact on child psychopathology. Specifically, the moderating role of parenting on the relationship between child behavioral inhibition and both internalizing and externalizing psychopathology is examined, and the methodological variations which may contribute to inconsistent findings are explored. Additionally, support for the bidirectional relations between behavioral inhibition and parenting behaviors, as well as for the moderating role of temperament on the relationships between parenting and child outcomes, is briefly discussed. Finally, the clinical applicability of this overall conceptual model, specifically in regard to future research directions and potential clinical interventions, is considered.

The mediating role of changes in harm beliefs and coping efficacy in youth with specific phobias.

Individuals with specific phobias (SPs) often experience catastrophic cognitions and compromised efficacy regarding their ability to cope when in the presence of the phobic object/situation. In the current study, 165 children (7-16 years; 62% male) received either One Session Treatment or Educational Support Therapy for their SP. The children identified their feared belief and rated "how bad" it was, "how likely" it was to occur, and their ability to cope if it did occur. All of these ratings were reduced from pre-treatment to 6-month follow-up, across both treatment conditions. However, ratings of "how bad" and "how likely" reduced to a significantly greater degree for children who received OST. Greater change in each of the three beliefs predicted lower clinician severity ratings (CSRs) at post-treatment and 6-month follow-up. Additionally, changes in "how bad" and "how likely" the children rated their beliefs, and their reported ability to cope, partially mediated the relationship between treatment and post-treatment and follow-up CSRs. Overall, these findings suggest that although both treatment conditions produced changes in harm beliefs and coping efficacy, OST elicited greater changes and these changes may be important mechanisms in reduction of SP clinical severity.

Implication of the intestinal microbiome as a potential surrogate marker of immune responsiveness to experimental therapies in autoimmune diabetes.

Type 1 diabetes (T1D) is an autoimmune proinflammatory disease with no effective intervention. A major obstacle in developing new immunotherapies for T1D is the lack of means for monitoring immune responsiveness to experimental therapies. The LEW1.WR1 rat develops autoimmunity following infection with the parvovirus Kilham rat virus (KRV) via mechanisms linked with activation of proinflammatory pathways and alterations in the gut bacterial composition. We used this animal to test the hypothesis that intervention with agents that block innate immunity and diabetes is associated with a shift in the gut microbiota. We observed that infection with KRV results in the induction of proinflammatory gene activation in both the spleen and pancreatic lymph nodes. Furthermore, administering animals the histone deacetylase inhibitor ITF-2357 and IL-1 receptor antagonist (Anakinra) induced differential STAT-1 and the p40 unit of IL-12/IL-23 gene expression. Sequencing of bacterial 16S rRNA genes demonstrated that both ITF-2357 and Anakinra alter microbial diversity. ITF-2357 and Anakinra modulated the abundance of 23 and 8 bacterial taxa in KRV-infected animals, respectively, of which 5 overlapped between the two agents. Lastly, principal component analysis implied that ITF-2357 and Anakinra induce distinct gut microbiomes compared with those from untreated animals or rats provided KRV only. Together, the data suggest that ITF-2357 and Anakinra differentially influence the innate immune system and the intestinal microbiota and highlight the potential use of the gut microbiome as a surrogate means of assessing anti-inflammatory immune effects in type 1 diabetes.

Harm beliefs and coping expectancies in youth with specific phobias.

Catastrophic beliefs and lowered coping expectancies are often present in individuals with specific phobias (SPs). The current study examined these beliefs and expectancies in 251 youth who received One Session Treatment for one of the three most common types of SP in youth (animals, natural environment, and situational). We compared the children's subjective beliefs to objective ratings of the likelihood of occurrence and the dangerousness of the feared events. Results revealed pre-treatment differences in the youths' beliefs across phobia types and age. Specifically, children with animal phobias rated their beliefs as more likely to occur than did children with environmental and situational phobias. In addition, older children rated their beliefs as more dangerous than younger children. However, regardless of phobia type or child age, the beliefs improved following treatment. Changes in catastrophic beliefs and coping expectancies were related to changes in clinical severity following treatment but not 6-months following treatment. Moreover, at pre-treatment, children viewed their beliefs as significantly more catastrophic and likely to occur than did independent coders of these beliefs; however, these differences were no longer evident following treatment. Clinical implications are discussed, highlighting how changes in beliefs and expectancies might be associated with treatment outcomes.

Does the Presence of Anxiety and ADHD Symptoms Add to Social Impairment in Children with Autism Spectrum Disorder?

Children with autism spectrum disorder (ASD) experience internalizing and externalizing problems at higher rates than typically developing children, which could worsen social impairment. The present study compared impairment scores (social responsiveness scale, 2nd edition; SRS-2 scores) in 57 children (3-17 years, 82.5% male) with ASD, either with or without heightened levels of anxiety or ADHD symptoms, all per parent report. Children with heightened anxiety problems showed higher scores on four SRS-2 subscales (Social Cognition, Social Communication, Social Motivation, and Restricted Interests and Repetitive Behavior). Children with heightened ADHD traits showed higher scores on two subscales (Social Communication and Social Awareness). These findings suggest similarities and differences in how social deficits in ASD may worsen with anxiety or ADHD symptoms.

One session treatment for specific phobias in children: Comorbid anxiety disorders and treatment outcome.

BACKGROUND AND OBJECTIVES: One-Session Treatment (OST) for specific phobias has been shown to be effective in reducing phobia severity; however, the effect of different types of co-occurring anxiety disorders on OST outcomes is unknown. The present study examined (1) the effects of co-occurring generalized anxiety disorder (GAD), social anxiety disorder (SAD), or another non-targeted specific phobia (OSP) on the efficacy of OST for specific phobias, and (2) the effects of OST on these co-occurring disorders following treatment. METHODS: Three groups of 18 youth (7-15 years) with a specific phobia and comorbid GAD, SAD, or OSP were matched on age, gender, and phobia type. Outcome measures included diagnostic status and severity, and clinician rated improvement. RESULTS: All groups demonstrated an improvement in their specific phobia following treatment. Treatment was equally effective regardless of co-occurring anxiety disorder. In addition, comorbid anxiety disorders improved following OST; however, this effect was not equal across groups. The SAD group showed poorer improvement in their comorbid disorder than the GAD group post-treatment. However, the SAD group continued to improve and this differential effect was not evident six-months following treatment. LIMITATIONS: The current study sample was small, with insufficient power to detect small and medium effect sizes. Further, the sample only included a portion of individuals with primary GAD or SAD, which may have attenuated the findings. CONCLUSIONS: The current study demonstrated that co-occurring anxiety disorders did not interfere with phobia treatment. OST, despite targeting a single specific phobia type, significantly reduced comorbid symptomatology across multiple anxiety disorders.

Correlation of Left Atrial Appendage Ejection Velocities with the CHADS2 and CHA2DS2-VASc Scores.

BACKGROUND: In patients with atrial fibrillation or flutter, a left atrial appendage ejection velocity measured via transesophageal echocardiography equal to or less than 40 cm/sec has been shown to correlate with an increased risk of developing left atrial appendage thrombus while velocities greater than 40 cm/sec are at lower risk. The CHADS2 and CHA2DS2-VASc scores calculated from clinical variables have been developed to risk stratify patients with atrial fibrillation/flutter in regard to the need for anticoagulation. This study was designed to assess whether a relationship exists between left atrial appendage ejection velocities and the respective CHADS2 and CHA2DS2-VASc scores, and whether this relationship is affected by the presence of atrial fibrillation or atrial flutter. METHODS: A retrospective chart review was performed on patients in the last 5 years who had undergone a transesophageal echocardiogram in which LAA velocity was measured. Once these patients were identified, relevant clinical information allowing for the calculation of the CHADS2 and CHA2DS2-VASc scores was also extracted from the medical record. RESULTS: Data from a total of 151 patients were included in the study. A statistically significant correlation between LAA velocity and CHADS2 score (P = 0.942) or between LAA velocity and CHA2DS2-VASc scores (P = 0.723) was not found. CONCLUSIONS: We could not identify a relationship between either the CHADS2 or CHA2DS2-VASc scores and LAA velocities. This was true regardless of whether patients were in sinus rhythm or AF at the time of the TEE. While reduced LAA velocities increase the risk of LAA thrombus, the development of stroke in patients with AF is secondary to a complex interplay of multiple clinical variables.

p38 MAP kinase regulates circadian rhythms in Drosophila.

The large repertoire of circadian rhythms in diverse organisms depends on oscillating central clock genes, input pathways for entrainment, and output pathways for controlling rhythmic behaviors. Stress-activated p38 MAP Kinases (p38K), although sparsely investigated in this context, show circadian rhythmicity in mammalian brains and are considered part of the circadian output machinery in Neurospora. We find that Drosophila p38Kb is expressed in clock neurons, and mutants in p38Kb either are arrhythmic or have a longer free-running periodicity, especially as they age. Paradoxically, similar phenotypes are observed through either transgenic inhibition or activation of p38Kb in clock neurons, suggesting a requirement for optimal p38Kb function for normal free-running circadian rhythms. We also find that p38Kb genetically interacts with multiple downstream targets to regulate circadian locomotor rhythms. More specifically, p38Kb interacts with the period gene to regulate period length and the strength of rhythmicity. In addition, we show that p38Kb suppresses the arrhythmic behavior associated with inhibition of a second p38Kb target, the transcription factor Mef2. Finally, we find that manipulating p38K signaling in free-running conditions alters the expression of another downstream target, MNK/Lk6, which has been shown to cycle with the clock and to play a role in regulating circadian rhythms. These data suggest that p38Kb may affect circadian locomotor rhythms through the regulation of multiple downstream pathways.