Altered neuromuscular control due to compromised position sense may contribute to shoulder instability. The purpose of this study was to investigate whether unstable shoulder subjects exhibit larger errors than intact shoulder subjects in kinesthetically guided active positioning and reaching that are of greater functional significance than passive testing of shoulder position sense. Ten subjects with a history of anterior shoulder dislocation and 15 intact shoulder subjects participated in the study. Shoulder position sense was examined with three different protocols (imposed motion to remembered shoulder rotation angles and active shoulder abduction/rotation to verbally specified positions) with targets located in both the mid- and end-range of rotation. Three dimensional end-point accuracy of kinesthetically guided reaches to visually specified targets, along with the shoulder rotation angle and scapula orientations at the end-point, were also analyzed. In agreement with previous studies, unstable shoulder subjects exhibited significantly larger errors in perception of shoulder joint angles than healthy controls in a protocol involving imposed motion to remembered shoulder rotation angles. However, the clinical significance of the observed deficit is questionable because the averaged rms error differences between unstable and intact shoulders were relatively small (average: 1.8°). During tests of active positioning, unstable shoulder subjects were able to move the shoulder to verbally defined angles as accurately as healthy controls in both shoulder abduction and rotation. Unstable and intact shoulder subjects exhibited similar reaching accuracy and scapular orientations in the kinesthetically guided reaching test, but unstable shoulder subjects consistently used less shoulder rotation angle than healthy controls. However, they were able to point to a remembered target as accurately as intact shoulder subjects, suggesting that a different reaching strategy was adopted by unstable shoulder subjects to minimize shoulder rotation. Results of this study show that unstable shoulder subjects can perceive shoulder angles and reach to visually specified targets in space as accurately as healthy controls in functional activities with voluntarily arm movements. The results suggest that less sensitive joint receptors due to over-stretched shoulder stabilizers following shoulder injury have little impact on the neuromuscular control of the shoulder joint.

Nitrate is the most common ionic form of nitrogen in aquatic ecosystems. Although nitrate is known to affect ecosystems at high levels through eutrophication, hypoxia and loss of biodiversity, it is considered to be physiologically inert to the individual aquatic organism. To test the physiological effects of nitrate on aquatic life, we exposed gill tissue of the Pacific oyster, Crassostrea gigas, to nitrate and characterized changes in protein expression, using a gel-based proteomics approach. Of the 642 protein spots detected, we found that 24 proteins (15 identified) changed expression in response to a 6-hour exposure to nitrate concentrations ranging from 0-73 mg/L, values that characterize highly contaminated surface and ground waters. Proteins changing expression included the oxidative stress proteins thioredoxin and cavortin (a member of the superoxide dismutase family) as well as proteins that are involved in G-protein signaling (Rho-GDI, ADP-ribosylation factor, G-protein ß-subunit), protein homeostasis (heat shock protein 70, prohibitin, calreticulin, and proteasome &#;-type 4 subunit), glycolysis (enolase), transport of hydrophobic molecules (lipocalin) and cytoskeletal arrangements (intermediate filaments and a gelsolin-like adseverin). The most parsimonious explanation for these changes in protein expression assumes that C. gigas reduces nitrate to nitrite and nitric oxide, which reacts with superoxide anions to form the very reactive peroxynitrite. We propose that part of the cellular response to reactive nitrogen species,phagocytic hemocytes inhibit the production of reactive oxygen species, potentially compromising the immune response of oysters to invading pathogens.

Cervical vagal nerve stimulation (VNS) has been studied in the context of several conditions including epilepsy and depression. However, its effects on glucose metabolism, and its potentially beneficial effects in type II diabetes, have not yet been evaluated in humans. Efferent parasympathetic activation reduces hepatic glucose release and increases pancreatic insulin secretion, while afferent parasympathetic activation may increase hepatic glucose release and inhibit insulin secretion potentially through sympathetic activation. Thus, the effect of combined afferent and efferent cervical VNS is difficult to predict. We hypothesized that selective efferent VNS would decrease blood glucose concentration [Glu] and that selective afferent VNS would increase [Glu]. To investigate these potentially contrasting effects of efferent vs. afferent parasympathetic signaling, we recorded [Glu] and serum insulin and glucagon levels before and during 120 min of VNS in anesthetized rats. The nerve was left intact for combined afferent and efferent VNS (n=9) or sectioned proximal or distal from the stimulation electrode for selective efferent (n=8) of afferent (n=7) VNS, respectively. We found that afferent VNS caused a strong and sustained increase in [Glu] (+108.9±20.9% or +77.6±15.4% after 120 min of combined afferent and efferent VNS or selective afferent VNS) that was not accompanied by an increase in serum insulin concentration. Combined afferent and efferent VNS significantly increased serum glucagon concentration (57.6±23.4% at 120 min of VNS), while selective afferent VNS did not increase glucagon levels. Conversely, selective efferent VNS increased [Glu] only temporarily (+28.8±11.7% at 30 min of VNS). This response coincided with a transient increase in serum glucagon concentration at 30 min of VNS (31.6±8.3%) and a strong and sustained increase in serum insulin concentration (+71.2±27.0% after 120 min of VNS). These findings demonstrate that afferent VNS may increase [Glu] by suppressing pancreatic insulin release, while efferent VNS transiently increases [Glu] by stimulating glucagon secretion before reducing levels to or below baseline values by stimulating the release of insulin. Thus, selective efferent VNS may be potentially effective in the treatment of type II diabetes.

Healthy aging influences peripheral and central levels of the neuromotor system. These age-related changes contribute to the decline in dexterous manual behavior. Difficulty in performing activities of daily living increases reliance on external assistance. Understanding specific mechanisms leading to the decline in fine manual performance is crucial for their rehabilitation. In this thesis, we have attempted to increase our awareness of the causes underlying manual disability in old age. The first study investigated how old adults apply forces and moments on a freely-movable object using a precision grip (thumb and index finger) during functionally-relevant tasks. During the grasp-lift task old adults misaligned their thumb and finger contacts and produced greater grip force, greater external moments on the object around its roll axis, and oriented force vectors differently compared with young adults. During a precision-orientation task of inserting a slot on the object over a bar (`key-slot' task), old adults were more variable in digit-tip force directions and performed the key-slot task more slowly. With practice old adults aligned their digits, reduced their grip force, and minimized external moments on the object. We conclude that with old age comes with a reduced ability to control the forces and moments applied to objects during precision grasp and manipulation. This may contribute to the ubiquitous slowing and deteriorating manual dexterity in healthy aging. Another study investigated the effects of transcranial direct current stimulation (tDCS) to the contralateral M1 combined with motor training (MP) on changes in the forces applied to the object during grasp and manipulation. We also measured performances on functional tasks in healthy elderly individuals. Our results indicate that anodal tDCS+MP facilitates retention of learning on a skillful manual task in healthy old adults. Furthermore, improved retention on the pegboard test was associated with reduced force variability on the key-slot task that demanded similar precise control over the forces applied to the object. These findings suggest that the improvement in force steadiness is one of the potential mechanisms through which short-term anodal tDCS during motor training improved performance on a functional task that outlasted the intervention period. Furthermore, anodal tDCS over M1 in combination with motor practice also influenced motor response to tasks that critically depend on sensory signals in healthy old adults. Finally, we found that, in healthy elderly individuals, the memory representations scaling the lift force for the grip and lift task generalized, while the training-based learning on the ballistic task showed an incomplete transfer to the contralateral hand. These differences may indicate task-dependent interhemispheric transfer of learning in old age. Collectively, the work presented in this thesis demonstrates that the performance on dexterous manual tasks in healthy old adults may depend on how they configure their grasp, and control their finger forces (both linear and rotational) applied to the grasped object, specifically how smooth is the applied force.

No description available.

Motor learning is an important component of daily life: humans are constantly adjusting their movements and acquiring new skills in order to meet the demands of their environment. Motor learning also contributes to neurorehabilitation, so it is therefore important to understand the neural mechanisms underlying motor learning so that these mechanisms can be exploited to promote neurorehabilitation after central nervous system injury. This dissertation focuses on three distinct methods of improving motor learning in healthy adults. In Chapter 2, we tested the effects of perturbation schedule on retention of a locomotor adaptation. The results of this work demonstrated that introducing a perturbation slowly and incrementally versus introducing a perturbation abruptly produces similar behavioral expression of locomotor memories across days. In Chapter 3, we tested whether administering 200 mg of caffeine immediately after practicing a novel motor skill enhances retention of that skill 24 hours later. However, we found that post-practice caffeine administration did not significantly improve retention of the motor skill. In combination with previous reports, these results suggest that the effects of post-practice caffeine administration are likely task-specific. In Chapter 4, we examined the interactions between hand use, practice-dependent plasticity and motor learning. We found that experimentally immobilizing the left hand for 8 hours facilitates subsequent practice-dependent changes in corticospinal excitability in a topographically-specific manner. In contrast, immobilization did not facilitate practice-dependent changes in TMS-evoked thumb movements, nor did it promote learning or retention of a ballistic motor skill. Although it is thought that practice-dependent changes in corticospinal excitability are an important and potentially causal contributor to motor memory, the results of this work indicate that experimentally enhancing practice-dependent changes in corticospinal excitability is not sufficient to promote motor learning. In sum, although none of the experimental interventions tested here substantially improved motor learning, these experiments highlight the influence of various mechanisms on motor learning in the intact nervous system.

Age-related increases in arterial stiffness are mediated in part by mitochondrial dysfunction. Sirtuin 3 (SIRT3) is a mitochondrial NAD+-dependent deacetylase that regulates mitochondrial function. SIRT3 deficiency contributes to physiological dysfunction in a variety of pathological conditions. Here, we tested the hypothesis that age-associated arterial stiffness, assessed by aortic pulse wave velocity (PWV), would be accompanied with decreased renal and aortic SIRT3 expression and activity due to decreased NAD+ levels. We further tested whether boosting NAD+ concentration with nicotinamide riboside (NR), a NAD+ precursor, for 6 months would reverse the effects of aging. Old (~26 mo, n = 9) C57BL/6 male mice had higher PWV vs. young (6 mo, n = 10) (448 ± 14 vs 382 ± 13, p < 0.005), which was associated with reduced arterial SIRT3 protein (0.365 ± 0.088 AU’s vs 1.000 ± 0.000); p < 0.05). Furthermore, SIRT3 deficient male mice demonstrated higher PWV compared to age-matched control mice (480 ± 21 n = 6 vs. 391 ±12 n = 7, p < 0.005). Aortic SIRT3 protein was negatively correlated with PWV (r=-0.7798, p < 0.005). Old mice also exhibited reduced kidney SIRT3 protein (0.73 ± 0.10 AU’s) compared to young controls (1.00 ± 0.00; p = 0.0192) and reduced NAD+ (918.6 ± 50.5 pmol/mg vs. young 1302.0 ± 56.6 pmol/mg, p = 0.0036). Old mice supplemented with NR had increased NAD+ concentration in kidney tissue (1303.0 ± 90.2 pmol/mg) however, had no effect on normalizing age-associated arterial stiffness (402 ± 18 old with NR vs 418 ± 15 old; p = 0.78). Here we show for that SIRT3 protein correlates with aortic stiffness and may be required for the maintenance of healthy arteries and for the first time that supplementation with NR, a commercially available supplement, ameliorates age-associated decreases in renal NAD+ demonstrating therapeutic potential in kidney disease.

Abdominal pumping is a widespread behavior in insects. However, there remains ambiguity surrounding the abdominal pumping behavior, both in terms of describing what exactly abdominal pumping is (i.e., if various modes of operation exist) and also what function(s) abdominal pumping serves (and if function is conserved across groups of insects). In some insects respiratory patterns have been correlated with abdominal movements, although the specific mechanical effects of these movements on the animal\'s respiratory system are generally unknown. Conversely, some insects (such as beetles, ants, and crickets) create convection in the respiratory system by compressing their tracheal tubes, yet the underlying physiological mechanisms of tracheal collapse are also unknown. This study aimed to investigate the relationship between abdominal pumping and the compression of tracheal tubes in the darkling beetle, Zophobas morio. I observed the movements of the abdomen and tracheal tubes using synchrotron x-ray imaging and video cameras, while concurrently monitoring CO2 expiration. I identified and characterized two distinct abdominal movements differentiated by the synchrony (the pinch movement) or lack of synchrony (the wave movement) of abdominal tergite movement. Tracheal tube compressions (and corresponding CO2 pulses) occurred concurrently with every pinch movement. This study provides evidence of a mechanistic linkage between abdominal movements and tracheal tube compressions in the ground beetle, Zophobas morio. / Master of Science

In our studies we found that stabilized expression of HIF-1α in heart led to better recovery of function and less tissue death after 30 minutes of global ischemia, via mechanisms that preserve the mitochondrial polarization. Our group previously showed that HIF-1α conferred ischemic tolerance by allowing cardiomyocytes to use fumarate as an alternative terminal electron acceptor to sustain anaerobic mitochondrial polarization. The source of fumarate was identified as the purine nucleotide cycle (PNC). Here we discovered that HIF-1α upregulates AMP deaminase 2 (AMPD2), the entry point to the PNC. The combination of glycolysis and the PNC may protect the heart's nucleotide resources. We subsequently examined the effects that HIF-1α exerts on nucleotide metabolism in the ischemic heart. We found that HIF-1α expression reduces adenosine accumulation in the ischemic heart. As ATP is depleted during ischemia, AMP accumulates. Our results suggest that AMP metabolism is shunted towards AMPD2 rather than the adenosine producing 5'-nucleotidase pathway. Subsequently, we treated hearts with the PNC inhibitor hadacidin followed by 30 minutes of global ischemia. Inclusion of hadacidin reduced ATP and adenylate energy charge in the hearts. These findings allow us to propose that activity of the PNC prevents the F0F1 ATP synthase from consuming glycolytic ATP in order to maintain mitochondrial polarization during ischemia. Thus, the PNC provides ATP sparing effects and preserves the energy charge in the ischemic heart. The fact that ATP and adenylate energy charge is better preserved during the initial 20 minutes of ischemia in HIF-1α expressing hearts is supportive of our observation that HIF-1α upregulates the PNC. HIF-1α also upregulates adenosine deaminase, which degrades adenosine. The limitation of adenosine accumulation may help HIF-1α expressing hearts avoid toxicity due to chronic adenosine exposure. Finally, we found that HIF-1α induces the expression of the nucleotide salvage enzyme hypoxanthine phosphoribosyl transferase (HPRT). Upon reperfusion HPRT serves to reincorporate the nucleotide degradation product, hypoxanthine, into the adenylate pool and may prevent the production of reactive oxygen species. Collectively, HIF-1α robustly protects the heart from ischemic stress and it upregulates several pathways whose cardioprotective role may extend beyond the remodeling of nucleotide metabolism.

Purpose: Accelerometry is commonly used to objectively measure physical activity (PA), however, differential data collection methods and analysis techniques yield dissimilar outcomes. The aims of this research were to (1) understand how accelerometer output varies among accelerometers worn on the non-dominant wrist (NDW), dominant wrist (DW), and hip; (2) develop site-specific algorithms to predict activity type classification, activity intensity classification, and estimates of metabolic intensity; and (3) compare the algorithms in a free-living setting. Methods: Forty participants (16.8 – 64.2 yr) completed a sequence of sedentary and physical activities in a laboratory while wearing accelerometers on the NDW, DW, and hip. Participants also wore a portable metabolic analyzer to objectively measure oxygen consumption (VO2). One-second accelerometer output was compared across wear locations by activity type and intensity classifications (Aim 1). Accelerometer output data were transformed into variables related to the magnitude (ϒ), horizontal angle (φ), and inclination (θ) of acceleration, and used to develop algorithms for the NDW, DW, and hip. Random forest algorithms were developed to predict activity type classification (i.e., sedentary, lifestyle, and ambulatory) and activity intensity classification (i.e., sedentary, light, moderate, and vigorous), and regression models were built to predict VO2 (Aim 2). Following the laboratory visit, participants simultaneously wore an accelerometer at each of the three locations for three days of free-living data collection. The site-specific algorithms developed in Aim 2 were compared for equivalence (Aim 3). Aim 1 Results: Analysis of variance indicated that accelerometer output differed between the NDW, DW, and hip for all activities completed, except for lying supine. Differences were expected; thus, Pearson correlation coefficients were calculated between the NDW, DW, and hip, and compared across activity type and intensity classifications. For activity type, the relationships between all wear locations were different for all activity types (i.e., sedentary, lifestyle PA, and ambulatory PA). For activity intensity, the relationships between the wrists were significantly different between sedentary and light activities. Additionally, relationships between the NDW, DW, and hip differed between light and moderate, and light and vigorous PA for all wear locations. The disparate correlations indicated that accelerometer signals do not just increase in magnitude as intensity increases; rather they increase differentially by wear location and activity type. Aim 2 Results: Site-specific random forest algorithms were developed to predict activity type and intensity classification. The algorithms utilized 10-15 features of the accelerometer signal related to variability, location, and central tendency. The hip had prediction accuracies of 84.9% for activity type classification and 80.2% for activity intensity classification. The dominant wrist had activity type prediction accuracy of 83.6% and intensity prediction accuracy of 78.9%. The non-dominant wrist had prediction accuracies of 83.1% and 78.0% for activity type and intensity, respectively. The VO2 prediction algorithms had Mean Absolute Errors of 2.96 ml/kg/min for the hip, 3.34 ml/kg/min for the NDW, and 3.49 ml/kg/min for the DW. This equates to an average error of 0.93 metabolic equivalents (METs); algorithms currently used in practice yield errors of 0.89 to 2.00 METs. Aim 3 Results: The site-specific prediction algorithms were applied to free-living data. Using the random forest algorithms, activity type classification estimates differed by 2 to 82 minutes/day, and activity intensity classification estimates differed by 0 to 83 minutes/day; however, these differences were not significantly different. The VO2 prediction models provided estimates of PA within 0 to 57 minutes/day of one another. The hip provided the lowest estimates of MVPA, while the NDW provided the highest estimates, however the VO2 estimates from all wear locations were statistically equivalent to one another. Conclusion: The differential relationships among accelerometer outputs from the NDW, DW, and hip indicate that output differs based on activity type and intensity. This non-systematic error prevents scaling or comparing data collected at different wear locations and supports the need for site-specific analysis methods. Site-specific prediction algorithms provided comparable to improved performance over currently-utilized analysis methods in PA research, and the PA estimates were equivalent across wear locations. This research provides a more nuanced understanding of the impact of wear location on accelerometer output and alternative methods for analysis. Importantly, the algorithms created allow for comparisons to be made among data collected at the NDW, DW, and hip, which has not previously been possible.