Tuna robotics: hydrodynamics of rapid linear accelerations.

Fish routinely accelerate during locomotor manoeuvres, yet little is known about the dynamics of acceleration performance. Thunniform fish use their lunate caudal fin to generate lift-based thrust during steady swimming, but the lift is limited during acceleration from rest because required oncoming flows are slow. To investigate what other thrust-generating mechanisms occur during this behaviour, we used the robotic system termed Tunabot Flex, which is a research platform featuring yellowfin tuna-inspired body and tail profiles. We generated linear accelerations from rest of various magnitudes (maximum acceleration of [Formula: see text] at [Formula: see text] tail beat frequency) and recorded instantaneous electrical power consumption. Using particle image velocimetry data, we quantified body kinematics and flow patterns to then compute surface pressures, thrust forces and mechanical power output along the body through time. We found that the head generates net drag and that the posterior body generates significant thrust, which reveals an additional propulsion mechanism to the lift-based caudal fin in this thunniform swimmer during linear accelerations from rest. Studying fish acceleration performance with an experimental platform capable of simultaneously measuring electrical power consumption, kinematics, fluid flow and mechanical power output provides a new opportunity to understand unsteady locomotor behaviours in both fishes and bioinspired aquatic robotic systems.

The Australian Institute of Sport (AIS) and National Eating Disorders Collaboration (NEDC) position statement on disordered eating in high performance sport.

Identification, evaluation and management of disordered eating (DE) is complex. DE exists along the spectrum from optimised nutrition through to clinical eating disorders (EDs). Individual athletes can move back and forth along the spectrum of eating behaviour at any point in time over their career and within different stages of a training cycle. Athletes are more likely to present with DE than a clinical ED. Overall, there is a higher prevalence of DE and EDs in athletes compared with non-athletes. Additionally, athletes participating in aesthetic, gravitational and weight-class sports are at higher risk of DE and EDs than those in sports without these characteristics. The evaluation and management of DE requires a cohesive team of professional practitioners consisting of, at minimum, a doctor, a sports dietitian and a psychologist, termed within this statement as the core multidisciplinary team. The Australian Institute of Sport and the National Eating Disorders Collaboration have collaborated to provide this position statement, containing guidelines for athletes, coaches, support staff, clinicians and sporting organisations. The guidelines support the prevention and early identification of DE, and promote timely intervention to optimise nutrition for performance in a safe, supported, purposeful and individualised manner. This position statement is a call to action to all involved in sport to be aware of poor self-image and poor body image among athletes. The practical recommendations should guide the clinical management of DE in high performance sport.

Kinematics of swimming of the manta ray: three-dimensional analysis of open-water maneuverability.

For aquatic animals, turning maneuvers represent a locomotor activity that may not be confined to a single coordinate plane, making analysis difficult, particularly in the field. To measure turning performance in a three-dimensional space for the manta ray (Mobula birostris), a large open-water swimmer, scaled stereo video recordings were collected. Movements of the cephalic lobes, eye and tail base were tracked to obtain three-dimensional coordinates. A mathematical analysis was performed on the coordinate data to calculate the turning rate and curvature (1/turning radius) as a function of time by numerically estimating the derivative of manta trajectories through three-dimensional space. Principal component analysis was used to project the three-dimensional trajectory onto the two-dimensional turn. Smoothing splines were applied to these turns. These are flexible models that minimize a cost function with a parameter controlling the balance between data fidelity and regularity of the derivative. Data for 30 sequences of rays performing slow, steady turns showed the highest 20% of values for the turning rate and smallest 20% of turn radii were 42.65±16.66 deg s-1 and 2.05±1.26 m, respectively. Such turning maneuvers fall within the range of performance exhibited by swimmers with rigid bodies.

Understanding Depressive Symptoms and Psychosocial Stressors on Twitter: A Corpus-Based Study.

BACKGROUND: With a lifetime prevalence of 16.2%, major depressive disorder is the fifth biggest contributor to the disease burden in the United States. OBJECTIVE: The aim of this study, building on previous work qualitatively analyzing depression-related Twitter data, was to describe the development of a comprehensive annotation scheme (ie, coding scheme) for manually annotating Twitter data with Diagnostic and Statistical Manual of Mental Disorders, Edition 5 (DSM 5) major depressive symptoms (eg, depressed mood, weight change, psychomotor agitation, or retardation) and Diagnostic and Statistical Manual of Mental Disorders, Edition IV (DSM-IV) psychosocial stressors (eg, educational problems, problems with primary support group, housing problems). METHODS: Using this annotation scheme, we developed an annotated corpus, Depressive Symptom and Psychosocial Stressors Acquired Depression, the SAD corpus, consisting of 9300 tweets randomly sampled from the Twitter application programming interface (API) using depression-related keywords (eg, depressed, gloomy, grief). An analysis of our annotated corpus yielded several key results. RESULTS: First, 72.09% (6829/9473) of tweets containing relevant keywords were nonindicative of depressive symptoms (eg, "we're in for a new economic depression"). Second, the most prevalent symptoms in our dataset were depressed mood and fatigue or loss of energy. Third, less than 2% of tweets contained more than one depression related category (eg, diminished ability to think or concentrate, depressed mood). Finally, we found very high positive correlations between some depression-related symptoms in our annotated dataset (eg, fatigue or loss of energy and educational problems; educational problems and diminished ability to think). CONCLUSIONS: We successfully developed an annotation scheme and an annotated corpus, the SAD corpus, consisting of 9300 tweets randomly-selected from the Twitter application programming interface using depression-related keywords. Our analyses suggest that keyword queries alone might not be suitable for public health monitoring because context can change the meaning of keyword in a statement. However, postprocessing approaches could be useful for reducing the noise and improving the signal needed to detect depression symptoms using social media.

Functional consequences of cocaine expectation: findings in a non-human primate model of cocaine self-administration.

Exposure to stimuli and environments associated with drug use is considered one of the most important contributors to relapse among substance abusers. Neuroimaging studies have identified neural circuits underlying these responses in cocaine-dependent subjects. But these studies are often difficult to interpret because of the heterogeneity of the participants, substances abused, and differences in drug histories and social variables. Therefore, the goal of this study was to assess the functional effects of exposure to cocaine-associated stimuli in a non-human primate model of cocaine self-administration, providing precise control over these variables, with the 2-[(14) C]deoxyglucose method. Rhesus monkeys self-administered 0.3 mg/kg/injection cocaine (n = 4) under a fixed-interval 3-minute (FI 3-min) schedule of reinforcement (30 injections/session) for 100 sessions. Control animals (n = 4) underwent identical schedules of food reinforcement. Sessions were then discontinued for 30 days, after which time, monkeys were exposed to cocaine- or food-paired cues, and the 2-[(14) C]deoxyglucose experiment was conducted. The presentation of the cocaine-paired cues resulted in significant increases in functional activity within highly restricted circuits that included portions of the pre-commissural striatum, medial prefrontal cortex, rostral temporal cortex and limbic thalamus when compared with control animals presented with the food-paired cues. The presentation of cocaine-associated cues increased brain functional activity in contrast to the decreases observed after cocaine consumption. Furthermore, the topography of brain circuits engaged by the expectation of cocaine is similar to the distribution of effects during the earliest phases of cocaine self-administration, prior to the onset of neuroadaptations that accompany chronic cocaine exposure.

SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome.

Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease.

Two phases of inflammatory mediator production defined by the study of IRAK2 and IRAK1 knock-in mice.

The roles of IL-1R-associated kinase (IRAK)2 and IRAK1 in cytokine production were investigated using immune cells from knock-in mice expressing the TNFR-associated factor 6 (TRAF6) binding-defective mutant IRAK2[E525A] or the catalytically inactive IRAK1[D359A] mutant. In bone marrow-derived macrophages (BMDMs), the IRAK2-TRAF6 interaction was required for the late (2-8 h) but not the early phase (0-2 h) of il6 and tnfa mRNA production, and hence for IL-6 and TNF-α secretion by TLR agonists that signal via MyD88. Loss of the IRAK2-TRAF6 interaction had little effect on the MyD88-dependent production of anti-inflammatory molecules produced during the early phase, such as Dual Specificity Phosphatase 1, and a modest effect on IL-10 secretion. The LPS/TLR4-stimulated production of il6 and tnfa mRNA and IL-6 and TNF-α secretion was hardly affected, because the Toll/IL-1R domain-containing adapter-inducing IFN-ß (TRIF) signaling pathway was used instead of the IRAK2-TRAF6 interaction to sustain late-phase mRNA production. IRAK1 catalytic activity was not rate limiting for il6, tnfa, or il10 mRNA production or the secretion of these cytokines by BMDMs, but IFN-ß mRNA induction by TLR7 and TLR9 agonists was greatly delayed in plasmacytoid dendritic cells (pDCs) from IRAK1[D359A] mice. In contrast, IFN-ß mRNA production was little affected in pDCs from IRAK2[E525A] mice, but subsequent IFN-α mRNA production and IFN-α secretion were reduced. IFN-ß and IFN-α production were abolished in pDCs from IRAK1[D359A] × IRAK2[E525A] double knock-in mice. Our results establish that the IRAK2-TRAF6 interaction is rate limiting for the late, but not the early phase of cytokine production in BMDM and pDCs, and that the IRAK2-TRAF6 interaction is needed to sustain IκB-inducing kinase ß activity during prolonged activation of the MyD88 signaling network. [corrected]

Physical therapy for a child with sudden-onset choreoathetosis: a case report.

PURPOSE: This case report describes the physical therapy examination, intervention, and outcomes for a 5-year-old girl who developed choreoathetosis following mitral valve repair. CASE DESCRIPTION: This child was admitted to an inpatient short-term rehabilitation program with marked choreoathetosis and dependence for all functional mobility. She received physical therapy twice a day for 5 weeks. Physical therapy intervention included therapeutic exercise emphasizing stabilization and closed chain exercises, aquatic therapy, and functional training to improve gross motor skills and mobility. Tests and measures included the Selective Control Assessment of the Lower Extremity, 66-item Gross Motor Function Measure, and Pediatric Evaluation of Disability Inventory. OUTCOMES: At discharge, this child demonstrated improvements in her Selective Control Assessment of the Lower Extremity, Gross Motor Function Measure, and Pediatric Evaluation of Disability Inventory scores. She was independent in all functional mobility tasks. SUMMARY: This case study describes physical therapy tests and measures, intervention, and positive outcomes for a child with sudden-onset choreoathetosis.

Pellino1 is required for interferon production by viral double-stranded RNA.

Viral double-stranded RNA, a ligand for Toll-like Receptor 3 (TLR3) and the cytoplasmic RNA receptors RIG1 and MDA5, activate a signaling network in which the IKK-related protein kinase TBK1 phosphorylates the transcription factor Interferon Regulatory Factor 3 (IRF3) and the E3 ubiquitin ligase Pellino1. IRF3 then translocates to the nucleus where it stimulates transcription of the interferonß (IFNß) gene, but the function of Pellino1 in this pathway is unknown. Here, we report that myeloid cells and embryonic fibroblasts from knock-in mice expressing an E3 ligase-deficient mutant of Pellino1 produce reduced levels of IFNß mRNA and secrete much less IFNß in response to viral double-stranded RNA because the interaction of IRF3 with the IFNß promoter is impaired. These results identify Pellino1 as a novel component of the signal transduction network by which viral double-stranded RNA stimulates IFNß gene transcription.

Cardiorespiratory response during physical therapist intervention for infants and young children with chronic respiratory insufficiency.

PURPOSE: To document physical therapist intervention activities and cardiorespiratory response for young children with chronic respiratory insufficiency. METHODS: Twelve children born prematurely, 6 to 30 months chronological age and admitted to inpatient pulmonary rehabilitation for oxygen and/or ventilation weaning, were included. During 3 intervention sessions, a second physical therapist recorded intervention activity and heart rate (HR), oxygen saturation (SaO2), and respiratory rate. Total time and median HR, SaO2, and respiratory rate for each activity were calculated. An analysis of variance was used to compare HR and SaO2 across activity based on intersession reliability. RESULTS: Sitting activities were most frequent and prone least frequent. Median cardiorespiratory measures were within reference standards for age. No adverse effects were seen during intervention and no significant difference was found in HR and SaO2 among intervention activities. CONCLUSION: Young children with chronic respiratory insufficiency are able to tolerate intervention with close monitoring by the physical therapist.

Nurse perceptions of the Diabetes Get Checked programme.

AIM: The Diabetes Get Checked programme provided a free annual diabetes check to people diagnosed with diabetes. The aim of the present study was to ascertain the impact this programme had on the practice of nurses; identify factors that nurses consider contributed to the success or failure of the programme in their work setting; and to elicit nurses' suggestions for future improved management and outcomes for people with diabetes. METHOD: An observational study utilising an online survey was undertaken. A total of 748 people completed the survey - the majority being nurses. Data were analysed descriptively. RESULTS: The Diabetes Get Checked programme was shown to have had a substantial impact on the practice of nurses, enabling the development of new models of nursing care, improved educational levels among nurses (and doctors), improved confidence in the management of diabetes, and increased satisfaction in their work. Nurses in the study suggested future interventions and programmes designed to support people with diabetes. These include implementation of a multi-disciplinary wrap-around approach, enhanced case management and self-management, implementing direct funding for nurse-led services, and improving population-based approaches such as policy changes and social marketing. DISCUSSION: The study sought nurse's perspectives with regard to a recently terminated programme designed to provide care to people with diabetes. It identified areas that worked well in programme implementation and those that could be improved. These findings provide useful information for funders and planners developing new programmes designed to support people with diabetes.

Residual deficits in functional brain activity after chronic cocaine self-administration in rhesus monkeys.

Previous studies in humans and in animals have shown dramatic effects of cocaine on measures of brain function that persist into abstinence. The purpose of this study was to examine the neurobiological consequences of abstinence from cocaine, using a model that removes the potential confound of cocaine cues. Adult male rhesus monkeys self-administered cocaine (0.3 mg/kg/injection; N = 8) during daily sessions or served as food-reinforcement controls (N = 4). Two times per week, monkeys were placed in a neutral environment and presented with a cartoon video for ~30 min, sometimes pre- and sometimes post-operant session, but no reinforcement was presented during the video. After ~100 sessions and when the cocaine groups had self-administered 900 mg/kg cocaine, the final experimental condition was a terminal 2-[14C]-deoxyglucose procedure, which occurred in the neutral (cartoon video) environment; for half of the monkeys in each group, this occurred after 1 day of abstinence and for the others after 30 days of abstinence. Rates of local cerebral glucose metabolism were measured in 57 brain regions. Global rates of cerebral metabolism were significantly lower in animals 1 day and 30 days post-cocaine self-administration when compared to those of food-reinforced controls. Effects were larger in 30- vs. 1-day cocaine abstinence, especially in prefrontal, parietal and cingulate cortex, as well as dorsal striatum and thalamus. Because these measures were obtained from monkeys while in a neutral environment, the deficits in glucose utilization can be attributed to the consequences of cocaine exposure and not to effects of conditioned stimuli associated with cocaine.

Prolonged exposure to cocaine self-administration results in a continued progression of alterations in functional activity in a nonhuman primate model.

Background: Studies of nonhuman primates with exposures of up to 100 days of cocaine self-administration (SA) have provided evidence that the central effects of cocaine progress over time. These durations of cocaine exposure, however, may be insufficient to capture the extent of the neurobiological alterations observed in cocaine users, many of whom use the drug for years. The goal of the present study was to determine whether 1.5 years of cocaine SA would result in further progression of alterations in functional brain activity. Methods: Adult male rhesus monkeys were exposed to 300 sessions of high-dose cocaine SA over 1.5 years. Following the final session rates of local cerebral glucose utilization (LCGU) were assessed with the 2-[14C]-deoxyglucose method and compared to rates of LCGU in control monkeys who responded for food reinforcement. In addition, LCGU in these animals was compared to a previously published group of monkeys that had self-administered cocaine or food for 100 sessions over a 4-5 month period. Results: Compared to 100 days of exposure, 300 days of cocaine SA further reduced LCGU in the post-commissural striatum and produced reductions in areas unaffected by the shorter duration of exposure, such as the hypothalamus, all of the amygdala, and large expanses of cortex. Conclusions: These findings demonstrate a clear progression of the impact of cocaine on functional activity with increasing durations of drug experience and have important implications for the development of potential strategies for the treatment of cocaine use disorder.

The role of TBK1 and IKKε in the expression and activation of Pellino 1.

Mammalian Pellino isoforms are phosphorylated by IRAK (interleukin receptor associated kinase) 1/IRAK4 in vitro, converting them into active E3 ubiquitin ligases. In the present paper we report a striking enhancement in both transcription of the gene encoding Pellino 1 and Pellino 1 protein expression when murine BMDMs (bone-marrow-derived macrophages) are stimulated with LPS (lipopolysaccharide) or poly(I:C). This induction occurs via a TRIF [TIR (Toll/interleukin-1 receptor)-domain-containing adaptor-inducing interferon-ß]-dependent IRAK-independent pathway and is prevented by inhibition of the IKK [IκB (inhibitor of nuclear factor κB) kinase]-related protein kinases, TBK1 {TANK [TRAF (tumour-necrosis-factor-receptor-associated factor)-associated nuclear factor κB activator]-binding kinase 1} and IKKε. Pellino 1 is not induced in IRF3 (interferon regulatory factor 3)-/- BMDMs, and its induction is only reduced slightly in type 1 interferon receptor-/- BMDMs, identifying Pellino 1 as a new IRF3-dependent gene. We also identify Pellino 1 in a two-hybrid screen using IKKε as bait, and show that IKKε/TBK1 activate Pellino 1 in vitro by phosphorylating Ser76, Thr288 and Ser293. Moreover, we show that the E3 ligase activity of endogenous Pellino 1 is activated in LPS- or poly(I:C)-stimulated macrophages. This occurs more rapidly than the increase in Pellino 1 mRNA and protein expression, is prevented by the inhibition of IKKε/TBK1 and is reversed by phosphatase treatment. Thus IKKε/TBK1 mediate the activation of Pellino 1's E3 ligase activity, as well as inducing the transcription of its gene and protein expression in response to TLR3 and TLR4 agonists.

Identification of the phosphorylation sites on the E3 ubiquitin ligase Pellino that are critical for activation by IRAK1 and IRAK4.

The E3 ubiquitin ligase Pellino can be activated by phosphorylation in vitro, catalyzed by IL-1 receptor-associated kinase 1 (IRAK1) or IRAK4. Here, we show that phosphorylation enhances the E3 ligase activity of Pellino 1 similarly with any of several E2-conjugating enzymes (Ubc13-Uev1a, UbcH4, or UbcH5a/5b) and identify 7 amino acid residues in Pellino 1 whose phosphorylation is critical for activation. Five of these sites are clustered between residues 76 and 86 (Ser-76, Ser-78, Thr-80, Ser-82, and Thr-86) and decorate a region of antiparallel beta-sheet, termed the "wing," which is an appendage of the forkhead-associated domain that is thought to interact with IRAK1. The other 2 sites are located at Thr-288 and Ser-293, just N-terminal to the RING-like domain that carries the E3 ligase activity. Unusually, the full activation of Pellino 1 can be achieved by phosphorylating any one of several different sites (Ser-76, Thr-86, Thr-288, or Ser-293) or a combination of other sites (Ser-78, Thr-80, and Ser-82). These observations imply that dephosphorylation of multiple sites is required to inactivate Pellino 1, which could be a device for prolonging Pellino's E3 ubiquitin ligase activity in vivo.

Role of the caudal peduncle in a fish-inspired robotic model: how changing stiffness and angle of attack affects swimming performance.

In fish, the tail is a key element of propulsive anatomy that contributes to thrust during swimming. Fish possess the ability to alter tail stiffness, surface area and conformation. Specifically, the region at the base of the tail, the caudal peduncle, is proposed to be a key location of fish stiffness modulation during locomotion. Most previous analyses have focused on the overall body or tail stiffness, and not on the effects of changing stiffness specifically at the base of the tail in fish and robotic models. We used both computational fluid dynamics analysis and experimental measurements of propulsive forces in physical models with different peduncle stiffnesses to analyze the effect of altering stiffness on the tail angle of attack and propulsive force and efficiency. By changing the motion program input to the tail, we were able to alter the phase relationship between the front and back tail sections between 0° and 330°. Computational simulations showed that power consumption was nearly minimized and thrust production was nearly maximized at the kinematic pattern whereφ= 270°, the approximate phase lag observed in the experimental foils and in free swimming tuna. We observed reduced thrust and efficiency at high angles of attack, suggesting that the tail driven during these motion programs experiences stalling and loss of lift. However, there is no single peduncle stiffness that consistently maximizes performance, particularly in physical models. This result highlights the fact that the optimal caudal peduncle stiffness is highly context dependent. Therefore, incorporating the ability to control peduncle stiffness in future robotic models of fish propulsion promises to increase the ability of robots to approach the performance of fish.

Tunabot Flex: a tuna-inspired robot with body flexibility improves high-performance swimming.

Tunas are flexible, high-performance open ocean swimmers that operate at high frequencies to achieve high swimming speeds. Most fish-like robotic systems operate at low frequencies (≤3 Hz) resulting in low swim speeds (≤1.5 body lengths per second), and the cost of transport (COT) is often one to four orders of magnitude higher than that of tunas. Furthermore, the impact of body flexibility on high-performance fish swimming remains unknown. Here we design and test a research platform based on yellowfin tuna (Thunnus albacares) to investigate the role of body flexibility and to close the performance gap between robotic and biological systems. This single-motor platform, termed Tunabot Flex, measures 25.5 cm in length. Flexibility is varied through joints in the tail to produce three tested configurations. We find that increasing body flexibility improves self-propelled swimming speeds on average by 0.5 body lengths per second while reducing the minimum COT by 53%. The most flexible configuration swims 4.60 body lengths per second with a tail beat frequency of 8.0 Hz and a COT measuring 18.4 J kg-1m-1. We then compare these results in addition to the midline kinematics, stride length, and Strouhal number with yellowfin tuna data. The COT of Tunabot Flex's most flexible configuration is less than a half-order of magnitude greater than that of yellowfin tuna across all tested speeds. Tunabot Flex provides a new baseline for the development of future bio-inspired underwater vehicles that aim to explore a fish-like, high-performance space and close the gap between engineered robotic systems and fish swimming ability.

Chronic phenmetrazine treatment promotes D2 dopaminergic and α2-adrenergic receptor desensitization and alters phosphorylation of signaling proteins and local cerebral glucose metabolism in the rat brain.

Phenmetrazine (PHEN) is a putative treatment for cocaine and psychostimulant recidivism; however, neurochemical changes underlying its activity have not been fully elucidated. We sought to characterize brain homeostatic adaptations to chronic PHEN, specifically on functional brain activity (local cerebral glucose utilization), G-Protein Coupled Receptor-stimulated G-protein activation, and phosphorylation of ERK1/2Thr202/Tyr204, GSK3ßTyr216, and DARPP-32Thr34. Male Sprague-Dawley rats were implanted with sub-cutaneous minipumps delivering either saline (vehicle), acute (2-day) or chronic (14-day) low dose (25 mg/kg/day) or high dose (50 mg/kg/day) PHEN. Acute administration of high dose PHEN increased local cerebral glucose utilization measured by 2-[14C]-deoxyglucose uptake in basal ganglia and motor-related regions of the rat brain. However, chronically treated animals developed tolerance to these effects. To identify the neurochemical changes associated with PHEN's activity, we performed [35S]GTPγS binding assays on unfixed and immunohistochemistry on fixed coronal brain sections. Chronic PHEN treatment dose-dependently attenuated D2 dopamine and α2-adrenergic, but not 5-HT1A, receptor-mediated G-protein activation. Two distinct patterns of effects on pERK1/2 and pDARPP-32 were observed: 1) chronic low dose PHEN decreased pERK1/2, and also significantly increased pDARPP-32 levels in some regions; 2) acute and chronic PHEN increased pERK1/2, but chronic high dose PHEN treatment tended to decrease pDARPP-32. Chronic low dose, but not high dose, PHEN significantly reduced pGSK3ß levels in several regions. Our study provides definitive evidence that extended length PHEN dosage schedules elicit distinct modes of neuronal acclimatization in cellular signaling. These pharmacodynamic modifications should be considered in drug development for chronic use.