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Exercise may alleviate behavioral impairments associated with neurodegenerative diseases. Studies of the mechanisms underlying exercise-mediated effects have increased in disease models, but the neurobiological background accompanying these diseases, specifically aging, is likely not considered. Here, we illustrate measures to increase the likelihood of a successful exercise paradigm in aged rats.
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Arnold, J. C., Salvatore, M. F. Getting to Compliance in Forced Exercise in Rodents: A Critical Standard to Evaluate Exercise Impact in Aging-related Disorders and Disease. J. Vis. Exp. (90), e51827, doi:10.3791/51827 (2014).
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There is a major increase in the awareness of the positive impact of exercise on improving several disease states with neurobiological basis; these include improving cognitive function and physical performance. As a result, there is an increase in the number of animal studies employing exercise. It is argued that one intrinsic value of forced exercise is that the investigator has control over the factors that can influence the impact of exercise on behavioral outcomes, notably exercise frequency, duration, and intensity of the exercise regimen. However, compliance in forced exercise regimens may be an issue, particularly if potential confounds of employing foot-shock are to be avoided. It is also important to consider that since most cognitive and locomotor impairments strike in the aged individual, determining impact of exercise on these impairments should consider using aged rodents with a highest possible level of compliance to ensure minimal need for test subjects. Here, the pertinent steps and considerations necessary to achieve nearly 100% compliance to treadmill exercise in an aged rodent model will be presented and discussed. Notwithstanding the particular exercise regimen being employed by the investigator, our protocol should be of use to investigators that are particularly interested in the potential impact of forced exercise on aging-related impairments, including aging-related Parkinsonism and Parkinson's disease.
Noninvasive lifestyle strategies that can either prevent or mitigate impairments to cognition and locomotion, both often associated with aging, are gaining traction as viable practices for maintaining health and well-being1,2. For example, moderate to rigorous exercise on a weekly and consistent basis in middle-aged men can significantly increase locomotor capabilities compared to similarly-aged peers with advancing age3. Furthermore, increasing evidence suggests that these lifestyle strategies, such as exercise, can mitigate or even reverse impairments associated with neurodegenerative diseases such as Parkinson's disease (PD)4.
Efforts to understand the molecular mechanisms of aging-related impairments have also been directed toward identifying how noninvasive strategies, like exercise, reverse or attenuate the mechanisms that contribute to such impairments. Treadmill exercise is one such strategy being increasingly employed in models of PD5-7 and cognitive impairment1, wherein the mechanisms behind improvements in locomotor or cognitive function are still being determined. However, it is important to point out that aging is the neurobiological background of PD. Thus, for any potential translation of any exercise benefit in an animal model to be realized in the human condition it must take into consideration the neurobiological background of aging. For example, compensatory mechanisms that stave off locomotor impairment during PD progression could be impaired by the process of aging8. Thus, it stands to reason that exercise paradigms must be developed that not only consider the impact of aging in either the presence or absence of disease pathology, but that also could be initiated and maintained in aged rodents.
Therefore, in consideration of aging on the neurobiological background, the selection of the rat strain should be thoughtfully considered by the investigator. Several rat strains are available for aging studies, notably the Fischer 344 and the Brown-Norway/Fischer 344 F1 (BNF) hybrid. The commonly used Sprague Dawley rat (an outbred strain) is also amenable for such use, as it is commonly used in neurodegenerative disease models, such as the 6-hydroxydopamine PD model. Our laboratory uses both the Sprague Dawley and the BNF strains in aging and neurodegenerative disease work. In this report, we will present results highlighting our exercise protocols using both strains. For those investigators strictly focusing on age-related studies, the BNF strain offers some important advantages. First, it is comparatively less vulnerable to aging-related disorders (such as tumors) and has exceptional longevity (typical life span exceeds 30 months) in comparison to other strains. They also have less variability in a variety of physiological and behavioral outcomes9, and are also suitable to investigate approaches that intervene with the process of aging. Furthermore, experiments such as forced exercise demand considerable handling by the investigator, and the gentle disposition of the BNF strain is advantageous. Aging-related changes in striatal and midbrain dopamine tissue content, as well as locomotor activity changes are similar in BNF rats and primates10-11. Our laboratory also has extensive experience with characterizing and manipulating striatal and midbrain dopamine signaling as well as locomotor activity in the BNF strain12-16. Therefore, because the risk of other neurobiologically-based diseases increases with aging, animal models of neurodegenerative disease should consider the use of rodent strains with an extensive track record of use in aging studies.
Our protocol herein also addresses some critical issues that the investigator must consider in the interpretation of their results obtained from an exercise protocol. The rodent treadmill apparatus (the use of which we will highlight in this report), is typically equipped with electric shock coils at the back of each lane of the treadmill that can be deactivated. However when these electric shock coils are activated, a small footshock is delivered to the subject as it comes in contact with the coils. This strategy is often employed in exercise studies to facilitate compliance to treadmill exercise. This is a critical point for consideration, particularly for those investigators involved in behavioral studies that are influenced by dopamine- or norepinephrine-signaling. Electrical footshock is a physiological stressor, and its impact on both neurotransmitter systems is well-documented, with increased activation of tyrosine hydroxylase17-18. Thus, increased biosynthesis of either neurotransmitter could confound the interpretation of any exercise effect, making the investigator liable for interpreting whether any observed change in behavior after exercise is strictly due to the exercise regimen or the footshock stress. Importantly, the proposed forced exercise regimen does not employ the use of footshock at any point in the treadmill acclimation or exercise training periods.
Successful exercise regimens also require maximum compliance to exercise from test subjects. The employment of footshock in order to achieve compliance could confound interpretation of experimental outcomes when the dependent measure is related to neurotransmitter signaling that is influenced by footshock (as previously discussed). Thus, the challenge is to get rodents, and in particular aged rodents, to comply with an exercise regimen. A desirable goal of any exercise regimen is to achieve nearly 100% compliance, as this will reduce the number of animals necessary to complete the exercise regimen. Specifically, maximum compliance to exercise and interpretation of exercise regimen outcomes can be obtained in our exercise regimen as a result of several pre-exercise procedures including, 1) a reverse light-dark cycle that enables animals to exercise during their active (wake) cycle, 2) ensuring locomotor performance baselines are equal prior to segregation of control and exercise groups, and 3) introducing the test subjects to an acclimation period that gradually introduces them to the requirements of the exercise regimen. Here, the aforementioned experimental considerations and steps necessary to achieve nearly 100% compliance to treadmill exercise in an aged rodent (>18 months of age) will be evaluated and presented. Finally, the environment associated with exercise may be stressful, and as such, present potential confounds to determine physiological effects specific to exercise. Our protocol also controls for the exposure to the potential stress-inducing environment of the treadmill by including the nonexercise group in every aspect of the acclimation phase (including modest treadmill running) and placing them on the stationary treadmill during the treadmill exercise training. Thus, this protocol aims to describe the measures necessary to determine the physiological impact of exercise alone.
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All of the following procedures are conducted in accordance with the Institutional Animal Care and Use Committee at LSU Health Sciences Center-Shreveport, and comply with the National Institute of Health guidelines.
1. Pre-exercise Procedures
Note: A timeline of all of the relevant procedures in this forced exercise regimen is diagrammed in Figure 1.
Figure 1. Forced exercise regimen timeline. This timeline details the important events of each phase of this exercise regimen during each week of the study. The pre-acclimation phase (weeks 1-2) involves experimenter handling and baseline locomotor activity. During the acclimation phase (weeks 3-4) all rats undergo 3 days of acclimation training where they sit on the stationary treadmill and then 10 days of acclimation training to the treadmill. A minimum of two rounds of exercise (1 round = 12 consecutive days) followed by a 2-week rest period is required during the exercise training phase (weeks 5-10). Behavioral and/or neurochemical measurements can be made during these rest periods. Furthermore, this regimen can be modified to include multiple rounds of exercise in this phase. Body weight is measured throughout all phases of the study on a weekly basis, and before (first session) and after (last session) each phase of this exercise regimen. Treadmill exercise training scores are assigned after all acclimation and exercise training sessions, and range from 1-4, with 4 being the highest possible score. Briefly, a training score of 4 is assigned when rats exercise the entire training session without assistance. Similarly, assign a training score of 3 when rats require minimal assistance (defined as: assistance for less than 25% of the time of the training session) from the experimenter. Assign a training score of 2 when rats require much assistance (defined as: assistance for greater than 25% of the time of the training session) from the experimenter during the exercise session. Finally, allocate a training score of 1 to rats that are noncompliant and fail to complete an exercise session.
- Upon arrival to the animal colony, separate and singly house all subjects into standard shoebox cages. Provide food and water ad libitum to subjects throughout the entire study.
- Maintain a reverse 12-hr light-dark cycle (lights on from 1800 to 0600 hr) in the animal colony, and allow subjects to acclimate to this cycle for a minimum of one week. Perform all behavioral experiments during the subject's active (dark) cycle, and 1-2 hr prior to the light-dark cycle change.
- Beginning two weeks prior to any behavioral experiments, handle all test subjects for several minutes daily to familiarize the subject with the experimenter, and to decrease novelty-induced stress to unfamiliar environments, such as the locomotor chamber and the treadmill.
- Measure each subject's body weight once a week, and immediately before (first session) and after (last session) each major interval of the exercise paradigm.
2. Baseline Locomotor Activity Assessments: Determining Forced Exercise Group Assignments
- Assess each subject's spontaneous locomotor activity for 60 min/day for 5 consecutive days to establish baseline locomotor capabilities. Conduct locomotor activity sessions in automated open-field locomotor activity chambers consisting of a plexiglass box (45 x 45 x 20 cm3) with a grid of infrared beams mounted horizontally and vertically as suggested in the product manual.
- At the beginning of each day of the locomotor activity assessments, load, and set up the computer and software program connected to the open-field locomotor activity chambers in order to record the number of beam breaks (locomotor activity) during each session.
- Add approximately 2 cups of pine-chip bedding to the floor of the locomotor chamber prior to each session.
- Transport the subjects from the animal colony to the locomotor activity chambers in their home cages immediately prior to their locomotor activity session. Load subjects into their assigned locomotor chamber under a red light, and start the 60 min session on the computer once they have been placed into the chamber.
- Upon completion of the locomotor activity session, remove subjects from the locomotor chamber and return them to their home cage under red light. Immediately return the subjects back to the animal colony.
- Remove bedding from the chamber and clean the chamber walls and floor with 50% ethanol after each session.
- Repeat steps 2.3-2.6 for additional locomotor sessions each day as needed until all subjects have been tested. Conduct all locomotor activity sessions in the dark, during the animal's active cycle, and 1-2 hr prior to the light-dark cycle change.
- To account for the possibility of habituation to the activity chambers, rotate each subject among the available chambers such that locomotor activity is measured in a different chamber from the previous day.
- If multiple sessions need to be conducted in one day, change the order of testing such that subjects are tested in a different order than the previous session.
- From the data generated by the software used to measure locomotor activity, determine each animal's baseline locomotor activity with the following 5 locomotor parameters: total distance traveled (cm), horizontal activity (number of beam breaks), movement number (number of initiated movements), time spent moving (sec), and movement speed (cm/sec).
- In order to assign exercise and nonexercise groups, calculate the mean value across all 5 sessions for each of the 5 locomotor parameters listed in step 2.9 above.
- From these 5 parameters, determine exercise and nonexercise (control) groups such that an equal range of locomotor activity is represented in both groups. In this way, pair rats together based on similar movement capabilities, and assign one rat to the exercise group and one rat to the nonexercise group. Thus, for example, pair the two rats that exhibit the highest average of all 5 locomotor parameters together, and assign one rat to the exercise group and the other to the nonexercise group (group assignments are chosen at random). Repeat this process for the remaining subjects.
- Maintain pairing throughout the entire forced exercise regimen and for all data analyses.
- If the experimenter is interested in the effects of exercise on locomotor activity, measure post-exercise locomotor activity using the same procedures described in steps 2.1-2.8.1 beginning the day after the last treadmill exercise session. NOTE: If the investigator is interested and/or the automated locomotor activity software permits, examine anxiety-related measures (i.e., time spent in periphery vs. the center of activity chamber) to assess the relative anxiety of subjects during locomotor activity assessments.
3. Acclimation to the Treadmill
- Conduct all treadmill exercise-related procedures on a motorized rodent treadmill with lanes that are separated by clear plexiglass walls during the animal's active cycle, and 1-2 hr prior to the light-dark cycle change.
- In place of the electrical shock coils located at the back of each lane, use a plexiglass backstop designed specifically to fit the treadmill so that subjects can continuously exercise without coming into contact with the electrical shock coils. To prevent the backstop from sliding during the training sessions, hold the backstop in place with a 1.5 in c-clamp.
- Due to the experimenter handling required for treadmill exercise training, conduct all treadmill exercise sessions with the lights on.
- Transport subjects in their home cage to the treadmill immediately prior to their treadmill exercise training session. When the treadmill is stationary, load rats onto the treadmill in their assigned lane by sliding up the backstop just enough that subjects can maneuver under the backstop. Slide the backstop back down to the resting position once the subject is situated on the treadmill belt. Do not start the session until all subjects have been placed in their assigned lane for that particular session.
- During the first phase of acclimation, place each rat on one of the four lanes of the stationary treadmill (as described in step 3.4) for 5-10 min/day for 3 consecutive days. Increase the time of each session with each successive day (e.g., 5 min on day 1, 7 min on day 2, and 10 min on day 3) as the rats become familiar with the treadmill apparatus and to reduce the potential for novelty stress to the treadmill apparatus. Important: Do not place rats anywhere on the treadmill (e.g., deactivated electrical shock coils) except the stationary belt at this stage.
- During the second phase of acclimation training, place each rat on one lane of the stationary treadmill in front of the backstop. When all subjects are in place, turn the treadmill on to a slow walking speed (e.g., 6 m/min). Regardless of experimental grouping, train all rats to walk on the treadmill during this phase to ensure that any potential effects observed from the forced exercise regimen result from the exercise training and not simply from the ability to exercise.
- As the belt of the treadmill begins to roll, ensure that all rats are walking in the forward direction. Assist rats as necessary by orienting or gently prodding them until they are moving forward. During the acclimation training period, train rats to walk on the treadmill such that they continuously walk on the treadmill without assistance from the experimenter.
- Acclimate all rats to the treadmill by gradually increasing the speed over a period of 5-10 min/day for 10 consecutive days. To further facilitate compliance to treadmill exercise, train the rats at low speeds (6-8 m/min) for 5-10 min during the first 5 acclimation sessions, and increase to more moderate speeds (9-10 m/min) for 5-10 min during the last 5 acclimation sessions.
- Ensure that all rats can maintain a speed of 9-10 m/min for 10 min by the last session of the acclimation training period.
- Upon completion of the treadmill acclimation session, remove subjects from the treadmill in the same manner used to load subjects as described in step 3.4. Immediately return subjects to their home cage and transport them back to the animal colony.
- Wipe down each individual lane including the walls and treadmill belt with 50% ethanol after each individual treadmill exercise training session.
- Ascertain the exercise capabilities of each rat across the exercise sessions by assigning a treadmill exercise score at the conclusion of each daily session. Assign a training score of 4 when rats exercise the entire training session without assistance. Similarly, assign a training score of 3 when rats require minimal assistance (defined as: assistance for less than 25% of the time of the training session) from the experimenter. Assign a training score of 2 when rats require much assistance (defined as: assistance for greater than 25% of the time of the training session) from the experimenter during the exercise session. Finally, allocate a training score of 1 to rats that are noncompliant and fail to complete an exercise session.
NOTE: The exercise scoring system is adapted, in part, from other studies19.
- Exclude rats that cannot complete the acclimation phase due to noncompliance and/or an injury that prevents subjects from exercising (e.g., this includes rats that earn a treadmill exercise training score of 1 for more than one consecutive day of acclimation training).
- Average the treadmill scores across each training period (e.g., acclimation training and exercise training) to determine the exercise capabilities of each subject. Ensure that all rats are able earn a treadmill exercise score of 4 during a training session by the end of the acclimation period.
- If some rats are not compliant to the top exercise speeds maintained by others throughout a training session, adjust the speed for these rats so that they are able to continue exercising for the same amount of time but at a slower speed throughout the training sessions. In this instance, train slower rats in separate sessions and increase the speed as the subjects adjust to the slower speeds.
- To avoid the potential for lane bias on the treadmill during treadmill exercise training, rotate each rat among the available lanes of the treadmill so that they are training in a different lane with each subsequent exercise session.
4. Treadmill Exercise Training
- Begin the exercise training sessions the day following the last acclimation training session, and continue exercising rats for 12 consecutive days. Conduct these sessions during the animal's active cycle, and 1-2 hr prior to the light-dark cycle change.
- Follow the same set-up procedures for each treadmill exercise training session used during acclimation training, as described in steps 3.2 and 3.4.
- At the start of each session, turn on the treadmill to a lower, warm-up speed (8 m/min) than the training speed (9-11 m/min) that will be maintained throughout the remainder of the exercise training session. Continue with this warm-up speed for 5-10 min at the beginning of the session. Adjust the speed to 9-11 m/min for the remainder of the training session. Train subjects an average of 30 min each session for the entire 12 days of exercise training.
- After each exercise training session, assign a treadmill exercise score to all rats in the exercise group using the same exercise scoring system described in step 3.9. Do not assign a training score during the treadmill exercise training period to nonexercise rats.
- Conduct the exercise and nonexercise sessions separately. Place the nonexercise rats on the stationary treadmill for the same duration that their exercise cohort trained during each session.
- As described in step 3.11, rotate each rat among the available lanes of the treadmill so that they are training in a different lane with each subsequent exercise session.
- Upon completion of one round of exercise, rest subjects for 14 days. NOTE: This rest period was chosen based on the results from the pilot study described in Figures 2A and 2B.
- If desired, conduct various behavioral and/or neurochemical assessments at the end of the 12-day training period. Conversely, continue with subsequent rounds of exercise training following the 14 day rest period.
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Representative Results
A diagram of the timeline of events in all three phases of the forced exercise regimen is shown in Figure 1. In addition to reversing the light-dark cycle, daily handling prior to any experimental testing, and stage 1 of acclimation training, where subjects sit on the stationary treadmill for 5-10 min/day for 3 consecutive days, were implemented to increase compliance to the forced exercise regimen. These procedures were added to the protocol in order to minimize stress associated with novel environments, and so that subjects would be more inclined to walk on the moving treadmill if they were already familiar with the stationary apparatus. These procedures outlined in Figure 1 were employed following a pilot study conducted in BNF rats in which 50% of subjects were noncompliant to a forced exercise regimen previously conducted in Sprague Dawley rats. In this forced exercise regimen, 18-month-old Sprague Dawley rats were the test subjects that underwent 30 min of exercise for 12 consecutive days at speeds up to 15 m/min (Figure 2). These preliminary results indicate that one round of exercise (12 consecutive days) may increase locomotor activity (Figure 2A), with the duration of this effect of exercise on locomotor activity lasting out to one week post-exercise. Furthermore, a rebound effect of increased locomotor activity, relative to the original baseline, was observed following the same 12 day exercise regimen after one month of inactivity (Figure 2B). Thus, in the modified forced exercise regimen detailed in this protocol, one round of forced exercise consists of 12 consecutive days of exercise followed by a two week rest period. The results in Figure 2 suggest that the proposed forced exercise regimen may increase locomotor activity in rats that exercise relative to their respective baseline activity.
As discussed previously, baseline locomotor activity assessments serve two critical purposes in this forced exercise regimen. First, baseline locomotor activity is used to assign test subjects to ensure equal representation of locomotor capabilities between the exercise and nonexercise (control) groups prior to exercise intervention, so that no bias is inadvertently introduced into the study. For example, an exercise group containing subjects that exhibit a higher percentage of greater locomotor activity compared to the nonexercise group introduces experimental bias. Second, for studies with a specific interest in locomotion, it must be noted that baseline activity does vary across individuals, and therefore determining the impact of forced exercise must be done by comparing activity (or other dependent measures) post-exercise to the baseline on an individual-by-individual basis. For example, an arbitrary value of 100 on a post-exercise assessment when compared to a baseline of 50 indicates a two-fold increase in activity. However, by the same token, a post-exercise assessment of 150, while greater than 100, represents only a 1.5-fold increase against a baseline of 100. Therefore, the optimal pre-exercise baseline is illustrated in Figure 3. When paired with their respective cohort, there is no significant difference in baseline locomotor activity between the assigned groups designated for the exercise and nonexercise groups for any of the five locomotor parameters including (A) total distance traveled (cm), (n=8 per group, p=0.7142, paired two-tailed t-test), (B) horizontal activity (# of beam breaks), (n=8 per group, p=0.7767, paired two-tailed t-test), (C) movement number, (# of initiated movements), (n=8 per group, p=0.6186, paired two-tailed t-test), (D) time spent moving (sec), (n=8 per group, p=0.9307, paired two-tailed t-test), and (E) movement speed (cm/sec) (n=8 per group, p=0.655, paired two-tailed t-test). Thus, these results show that an equal range of locomotor capabilities is represented in both groups, and that both the capacity and response to exercise will not be based on any differences in locomotor activity between the groups prior to acclimation training.
As previously discussed, ~100% compliance to this forced exercise regimen can be obtained with the addition of several pre-exercise and treadmill acclimation procedures. Importantly, the steps taken to achieve compliance in this regimen increase the sensitivity of detecting an exercise effect with employment of this forced exercise regimen. One way to measure an exercise effect is through body weight measurements. In this paradigm, body weights are measured on a weekly basis, and before (first session) and after (last session) each phase of the exercise regimen. As demonstrated in Table 1, exercise rats had a mean weight loss of 4.43±0.32% compared to their pre-exercise body weight. Comparatively, nonexercise rats had a mean weight loss of 0.05±0.55% compared to their pre-exercise body weight. Thus, as expected, there is a significant difference in total weight loss and percent change in body weight throughout the forced exercise regimen between exercise and nonexercise rats (n=7 per group, p<0.01, paired two-tailed t-test). Similarly, significant differences in weight loss and percent decrease in body weight were observed during round 1 (n=7 per group, p<0.01, paired two-tailed t-test) and round 2 of forced exercise (n=7 per group, p<0.05). Notably, there were no significant differences in either parameter during the baseline or acclimation phases, indicating that only the forced exercise training periods affected body weight. This result indicates that the exercise regimen has a verifiable physiological effect on rats in the exercise group, which may be independent of other variables that the investigator is measuring. Given that body weights of these subjects ranged from 378-572 g throughout the study, a 4% decrease in body weight is not considered detrimental to the overall well-being of subjects, and also is within range of our previous pilot study forced exercise regimen with Sprague Dawley rats where a 6% decrease in body weight was observed over the same time period. Finally, we note that no significant correlation of body weight to locomotor activity has been observed in baseline assessments of individual body weights against individual locomotor activity parameters listed in Figure 3.
Treadmill exercise scores are assigned after each acclimation and treadmill exercise session, and enable the experimenter to ascertain the exercising capabilities of every subject throughout this regimen. For example, a treadmill exercise score of 4 is indicative of maximum compliance to the regimen for a particular session, whereas a treadmill exercise score of 1 is indicative of noncompliance to the regimen for a particular session. Thus, when the compliance criteria are employed in this regimen, treadmill exercise scores should reflect exercise compliance which is demonstrated by assigning scores of 3 or 4. During acclimation training, both exercise and nonexercise rats are trained to exercise on the treadmill and treadmill exercise scores are assigned for both groups during this phase only. Conversely, treadmill exercise scores are only assigned to exercise rats during each round of forced exercise. Results of treadmill exercise scores from both acclimation and treadmill exercise training are presented in Figure 4. During acclimation training, there is no significant difference in the mean treadmill exercise score between the exercise and nonexercise groups (n=7 per group, p=0.656, paired two-tailed t-test) as shown in Figure 4A. This indicates that both exercise and nonexercise rats were both compliant and able to acclimate to treadmill exercise similarly. Figure 4B demonstrates that exercise rats were compliant to treadmill exercise through two rounds of treadmill exercise training, as the mean treadmill exercise scores were not significantly different between these two rounds (n=7, p=0.2336, paired two-tailed t-test). Thus, once they were acclimated to exercise training, exercise rats remained compliant through two rounds of forced exercise. Finally, it is important to note that given the high average of treadmill exercise scores in both acclimation training (combined average exercise score =3.09) and exercise training (combined average exercise score=3.80), investigator involvement, in terms of assisting test subjects, during individual training sessions is minimal after the first few sessions of acclimation training.
Figure 1. Forced exercise regimen timeline. This timeline details the important events of each phase of this exercise regimen during each week of the study. The pre-acclimation phase (weeks 1-2) involves experimenter handling and baseline locomotor activity. During the acclimation phase (weeks 3-4) all rats undergo 3 days of acclimation training where they sit on the stationary treadmill and then 10 days of acclimation training to the treadmill. A minimum of two rounds of exercise (1 round = 12 consecutive days) followed by a two week rest period is required during the exercise training phase (weeks 5-10). Behavioral and/or neurochemical measurements can be made during these rest periods. Furthermore, this regimen can be modified to include multiple rounds of exercise in this phase. Body weight is measured throughout all phases of the study on a weekly basis, and before (first session) and after (last session) each phase of this exercise regimen. Treadmill exercise training scores are assigned after all acclimation and exercise training sessions, and range from 1-4, with 4 being the highest possible score. Briefly, a training score of 4 is assigned when rats exercise the entire training session without assistance. Similarly, assign a training score of 3 when rats require minimal assistance (defined as: assistance for less than 25% of the time of the training session) from the experimenter. Assign a training score of 2 when rats require much assistance (defined as: assistance for greater than 25% of the time of the training session) from the experimenter during the exercise session. Finally, allocate a training score of 1 to rats that are noncompliant and fail to complete an exercise session.
Figure 2. Pilot study of the impact of 12 days of forced exercise on locomotor activity for one week and the impact of the same regimen when initiated after one month of inactivity. Eighteen-month-old male Sprague Dawley rats underwent baseline locomotor assessment during their inactive cycle (nonwake period) under full nominal environmental lighting in an open-field locomotor chamber. The average of 5 daily, 60 min sessions was attained for each rat, and rats were then segregated to the nonexercise group (NE) or the exercise group (E). Baseline movement number (B) in the rats of the nonexercise group (NE-B) or exercise group (E-B) was not significantly different. Following 12 consecutive days of forced exercise (30 min/day, 12-15 m/min), locomotor activity was assessed during their active (wake) cycle (with dimmed lights). Testing subjects during their active cycle provided a natural stimulus that induces movement enabling comparisons against baseline measures wherein locomotor activity is predictably less when assessed during the sleep cycle and with ambient lighting. Rats that exercised (E-round 1) for 12 consecutive days exhibited 41% greater locomotor activity relative to their original individual baseline (n=5 per group, p<0.01, t=8.25, paired two-tailed t-test), whereas rats in the nonexercise group (NE-round 1) exhibited locomotor activity trending toward an increase, but not significantly different from their baseline (n=5 per group, p=0.11, t=2.05, paired two-tailed t-test). After one month of inactivity, the same rats underwent an identical second exercise regimen and rats in the exercise group (E-round 2) exhibited a 61% increase in locomotor activity compared to their respective original individual baseline activity levels (n=4 per group, p<0.05, t=5.34, paired two-tailed t-test), compared with a nonsignificant trend toward an increase in the nonexercise group (NE-round 2) (n=4 per group, p=0.13, t=2.08, paired two-tailed t-test).
Figure 3. Comparison of baseline locomotor activity parameters in exercise and nonexercise groups. To establish baseline locomotor activity, 5 locomotor trials (60 min/day; 5 days) were conducted for in 18-month-old male BNF rats prior to treadmill acclimation training. The mean values of the five locomotor trials were determined for all five locomotor parameters measured. The means of the locomotor parameters were used to assign exercise and nonexercise (control) groups such that there was an equal range of locomotor activity represented in both groups. Subjects were paired based on similar mean values for all locomotor parameters. Once the pairs and groups were assigned a paired two-tailed t-test was performed for each of the 5 parameters to ensure that there were no significant differences in locomotor capabilities between the two groups. In sum, a paired two-tailed t-test showed no significant differences in (A) total distance traveled (cm), (n=8 per group, p=0.7142, t=0.3815), (B) horizontal activity (# of beam breaks), (n=8 per group, p=0.7767, t=0.2948), (C) movement number, (# of initiated movements), (n=8 per group, p=0.6186, t=0.5207), (D) time spent moving (sec), (n=8 per group, p=0.9307, t=0.9011), and (E) movement speed (cm/sec) (n=8 per group, p=0.655, t=0.4569). These results ensured that an equal range of locomotor capabilities was represented in both groups, and that both the capacity and response to exercise was not based on any differences in locomotor activity between the groups prior to acclimation training.
Figure 4. Treadmill exercise scores during acclimation (A) and treadmill exercise training (B). Treadmill exercise scores are assigned after every acclimation and treadmill exercise training period, and serve as an indicator of compliance during each session. Scores range from 1-4, with 4 being the highest. A score of 4 is assigned when subjects exercise the entire session without assistance. Scores of 3 and 2 are assigned when subjects exercise with minimal or maximal assistance from the experimenter, respectively. Finally, a score of 1 is assigned to subjects that do not finish the exercise session. Both exercise and nonexercise rats undergo acclimation training, and thus, both groups of rats are assigned treadmill exercise scores during acclimation. As shown in (A), there is no significant difference in the mean treadmill exercise scores between exercise and nonexercise rats. This suggests that both groups of rats were able to acclimate to treadmill exercise similarly, and furthermore, that both groups were compliant to acclimation training (n=7 per group, p=0.656, t=2.270, paired two-tailed t test). During treadmill exercise training, only the exercise rats are assigned treadmill exercise scores since nonexercise rats do not exercise in this phase. (B) demonstrates that exercise rats were able to maintain treadmill exercise scores of 3-4 through two rounds of exercise training. Similarly, mean treadmill exercise scores were not significantly different between the two rounds of exercise (n=7, p=0.2336, t=1.234, paired two-tailed t-test) and were compliant through two rounds of forced exercise.
|Nonexercise (n=8)
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|Weight Loss (g)
|Percent change in body weight (%)
Table 1. Body weight measurements during the forced exercise regimen. In this paradigm, body weights are measured on a weekly basis and before (first session) and after (last session) each phase of the exercise regimen to provide a measure of the physiological effects of this forced exercise regimen. Values are represented as mean±SEM, and a paired two-tailed t-test was used to analyze differences between exercise and nonexercise groups after each phase of the regimen. In total, exercise rats had a mean weight loss of 21.14±1.93 g and a 4.43±0.32% decrease in body weight. Comparatively, nonexercise rats have a mean weight loss of 1.88±2.63%, and a 0.05±0.55% decrease in body weight. Thus, there is a significant difference in total weight loss (n=7 per group, p=0.0016, t=5.417, paired two-tailed t-test) and percent decrease in body weight (n=7 per group, p=0.0021, t=5.158, paired two-tailed t-test) throughout this forced exercise regimen between exercise and nonexercise rats. Significant differences in weight loss (n=7 per group, p=0.0036, t=4.633, paired two-tailed t-test) and percent decrease in body weight (n=7 per group, p=0.0037, t=4.603, paired two-tailed t-test) were observed during round 1. Similar results were observed during round 2 of forced exercise in that there was as significant difference in weight loss (n=7 per group, p=0.0163, t=3.305, paired two-tailed t-test) and percent decrease in body weight (n=7 per group, p=0.0174, t=3.255, paired two-tailed t-test) between exercise and nonexercise groups. However, no significant differences were observed in either parameter during the baseline or acclimation periods, demonstrating that only the forced exercise training periods exert physiological effects on rats in the exercise group.
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There is evidence to suggest that lifestyle strategies, such as exercise, may reduce the risk for chronic age-related diseases and their cardinal symptoms, including those of the neurodegenerative diseases like Alzheimer's disease and PD20. The benefit of forced exercise on a treadmill, as opposed to voluntary exercise on a running wheel, is that the investigator can determine the frequency, the rate, and/or intensity of exercise, and duration of the exercise session. Thus, specific post-exercise effects, such as increased locomotor or cognitive performance, may be predicted or expected following the employment of a given regimen. Furthermore, the translation of results from forced treadmill exercise to the human condition is very probable. In fact, recent studies in PD patients demonstrate that when the patient complies with an exercise regimen set forth by a trainer on a tandem bike, these patients exhibit improved locomotor scores in comparison to PD patients who only exercise at their own pace4.
The incidence of neurodegenerative diseases significantly increases with aging. Thus, age is an important consideration when designing studies that aim to translate any potential results to the human condition. For example, studies that utilize adolescent or adult animal models to study neurodegenerative disease do not take into consideration that aging is the neurobiological background of such diseases. This potentially confounds the translation of any observable effects clinically because the physiological factor of age has not been fully considered in such studies. Therefore, studies examining the effects of exercise on either locomotor or cognitive performance, should consider using aged animal models since cognitive and locomotor impairments are also associated with age-related deficits in neurochemical indices within the central nervous system10,12,16. This would allow for a more germane understanding of the neurobiological effects of exercise on locomotor and cognitive function with aging in either the presence or absence of disease pathology.
Finally, in order to ascertain the impact of exercise alone on post-exercise measures in cognitive or locomotor performance, three practices are essential to obtain nearly 100% compliance to an exercise regimen. First, it is important to maintain a reverse light-dark cycle throughout all phases of the forced exercise regimen. This ensures that test subjects are training during their active (wake) cycle. Second, it is vital that the test subjects are slowly acclimated to both the treadmill environment and the equipment used to determine their locomotor or cognitive performance. Here, the investigator should follow the procedures outlined in Figure 1 in the timeline recommended. Finally, the electric footshock apparatus should never be used during any phase of this forced exercise regimen. Instead, as highlighted in the protocol, a plexiglass backstop can be utilized to encourage subjects to continue exercising during the treadmill exercise sessions. At this juncture, the exercise regimen described should be considered a starting point for any laboratory, with the expectation that the frequency and duration of the exercise regimen can be varied according to the investigator's paradigm. The limits to the longevity of this forced exercise regimen certainly have yet to be realized, but one may assume that barring injury, compliant rats should be able to maintain adherence to the exercise regimen for a number of months. However, it should be noted that the speed at which test subjects may execute treadmill exercise within a given time frame (30 min in this regimen) may require adjustment and maximum speeds have not exceeded 15 m/min the aforementioned studies. The best compliance is likely to be realized at speeds that do not exceed 11 m/min. Indeed, if we are to translate the exercise findings to the middle-aged and aging population, we might expect the most representative animal protocol is one that focuses on longevity and compliance, rather than speed.
To summarize, this forced exercise protocol is one that can be employed in virtually any laboratory, particularly for those with a focus on neurodegenerative disease and aging. The test subjects used in this report were all 18 months of age at the start of the study. Furthermore, the essential steps needed to obtain virtually 100% compliance in the test subjects have also been discussed. Obviously acquiring 100% compliance is a significant benefit to the investigator, primarily because one will only have to use the number of subjects required to test a given hypothesis at the desired power. Moreover, achieving 100% compliance in this regimen does not require the employment of electric footshock. Indeed, elimination of electric footshock is imperative in order to interpret the impact of exercise on behavioral measures that depend upon catecholamines, especially dopamine, given the long-known impact of stressors like footshook upon catecholamine biosynthesis17-18.
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The authors declare no conflicts of interest.
Funding for this work was provided in part by a research grant awarded to M. F. Salvatore from the National Institute on Aging (AG040261). The authors would also like to acknowledge Victoria Fields for her assistance with the behavioral experiments associated with the work presented and Mackenzie Orchard for his assistance with construction of the backstop for the treadmill.
|Catalog Number
|Exer-4 Treadmill for Rats
|Columbus Instruments
|Columbus has a variety of treadmills for animals with varying numbers of lanes and other options such as metabolic measurements
|Animal Activity Meter: Opto-Varimex 4-Auto Track
|Columbus Instruments
|Columbus has several options for activity chambers with varying arena sizes, beam spacing, and sensors
- Erickson, K. I., et al. Exercise training increases size of hippocampus and improves memory. Proc. Natl. Acad. Sci. U.S.A. 108, (7), 3017-3022 (2011).
- Zigmond, M. J., Cameron, J. L., Hoffer, B. J., Smeyne, R. J. Neurorestoration by physical exercise: Moving forward. Parkinsonis., and Related Dis. 18, (S1), S147-S150 (2012).
- Savela, S. L., et al. Physical activity at midlife and health-related quality of life in older men. Arch. Intern. Med. 170, (13), 1171-1172 (2010).
- Ridgel, A. L., Vitek, J. L., Alberts, J. L. Forced, not voluntary, exercise improves motor function in Parkinson's disease patients. Neurorehabil. Neural Repair. 23, (6), 600-608 (2009).
- Demirel, H. A., Serova, L., Sabban, E. L., Broxson, C. S., Powers, S. K. Gene expression of catecholamine biosynthetic enzymes following exercise: modulation by age. Neuroscience. 103, (3), 703-711 (2001).
- Petzinger, G. M., et al. Effects of treadmill exercise on dopaminergic transmission in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of basal ganglia injury. J. Neurosci. 27, (20), 5291-5300 (2007).
- Yoon, M. C., et al. Treadmill exercise suppresses nigrostriatal dopaminergic neuronal loss in 6-hydroxydopamine-induced Parkinson's rats. Neurosci. Lett. 423, (1), 12-17 (2007).
- Collier, T. J., et al. Aging-related changes in the nigrostriatal dopamine system and the response to MPTP in nonhuman primates: Diminished compensatory mechanisms as a prelude to parkinsonism. Neurobiol. Dis. 26, (1), 56-65 (2007).
- Phelan, J. P., Austad, S. N. Selecting animal models of human aging: inbred strains often exhibit less biological uniformity than F1 hybrids. J. Gerontol. 49, (1), B1-B11 (1994).
- Yurek, D. M., Hipkens, S. B., Hebert, M. A., Gash, D. M., Gerhardt, G. A. Age-related decline in striatal dopamine release and motoric function in brown Norway/Fischer 344 hybrid rats. Brain Res. 791, (1-2), 246-256 (1998).
- Spangler, E. L., Waggie, K. S., Hengemihle, J., Roberts, D., Hess, B., Ingram, D. K. Behavioral assessment of aging in male Fischer 344 and brown Norway rats strains and their F1 hybrid. Neurobiol. Aging. 15, (3), 319-328 (1994).
- Salvatore, M. F., Pruett, B. S., Spann, S. L., Dempsey, C. Aging reveals a role for nigral tyrosine hydroxylase ser31 phosphorylation in locomotor activity generation. PLoS One. 4, (1), (2009).
- Pruett, B. S., Salvatore, M. F. GFR α-1 receptor expression in the aging nigrostriatal and mesoaccumbens pathways. J. Neurochem. 115, (3), 707-715 (2010).
- Salvatore, M. F., Pruett, B. S., Dempsey, C., Fields, V. Comprehensive profiling of dopamine regulation in substantia nigra and ventral tegmental area. J. Vis. Exp. (66), e4171 (2012).
- Salvatore, M. F., Pruett, B. S. Dichotomy of tyrosine hydroxylase and dopamine regulation between somatodendritic and terminal field areas of nigrostriatal and mesoaccumbens pathways. PLoS One. 7, (1), e29867 (2012).
- Pruett, B. S., Salvatore, M. F. Nigral GFR α-1 infusion in aged rats increases locomotor activity, nigral tyrosine hydroxylase, and dopamine content in synchronicity. Mol. Neurobiol. 47, (3), 988-999 (2013).
- Abercrombie, E. D., Zigmond, M. J. Chapter 31: Modification of central categcholaminergic systems by stress and injury: Functional significance and clinical implications. Psychopharmacology: The Fourth Generation of Progress. Bloom, ,F. .E., Kupfer, D. .J. 31, Raven Press Ltd. New York. 355-361 (1995).
- Ong,, et al. Neurobiological consequences of acute footshock stress; effects on tyrosine hydroxylase phosphorylation and activation in the rat brain and adrenal medulla. J. Neurochem. (2013).
- Al-Jarrah, M., et al. Endurance exercise promotes cardiorespiratory rehabilitation without neurorestoration in the chronic mouse model of parkinsonism with severe neurodegeneration. J. Neurosci. 149, (1), 28-37 (2007).
- Dishman, R. K., et al. Neurobiology of exercise. Obesity. 14, (3), 345-356 (2006).
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CONTACT: Bryce C. Campbell
Creative Alley Productions
(310) 858-8678
For Immediate Release
August 12, 2003
Keiber Called To Red Carpet
Creative Alley's cofounder will attend premiere of his new movie 'Wasabi Tuna'
Hollywood, Ca.- Aug. 12th, 2003 - It was announced today that Christian Keiber will be attending the red carpet screening of 'Wasabi Tuna' starring Keiber, Tim Meadows, Antonio Sabato, Jr. and featuring Anna Nicole Smith on Wednesday August 20th at the Arclight Theatre in Hollywood, Ca.
"It was a great cast to work with and had me laughing the whole time we were making the movie," says Keiber. "Hats off to executive producer Celia Fox for really pulling this film together."
Other notables attending the premiere include the films co-stars, Barney Cheng, Jason London, Alanna Ubach, and Guillermo Diaz. Creative Alley cofounder Bryce C. Campbell and head of development for Creative Alley, Michelle Mellgren, are also expected to attend, as well as many other notable names.
"This is what it's all about. We support each other whether we're working through Creative Alley or individually," adds Campbell. "It's going to be an enormous event, and I'm looking forward to the after party.
'Wasabi Tuna' is an action-packed comedy caper that centers on a plot to kidnap Anna Nicole Smith's dog and hold it for ransom. Keiber plays Detective Becker, who is assigned to the case.
The event starts at 7pm. and is being held at the Cinerama Dome at the Arclight Theatre, 6360 W. Sunset Blvd. Los Angeles, CA 90028. For more information on this event including possibly attending, please visit the 'Wasabi Tuna' movie website at www.wasabituna.com.
About Creative Alley Productions
Creative Alley Productions is an independent film production company co-founded by Christian Keiber and Bryce Campbell. With a collective thirty-nine years of experience in the entertainment industry, Keiber and Campbell are creating the quality of films that inspired them to be a part of the entertainment industry. Creative Alley Productions' main offices are located in Los Angeles with satellite offices located in New York City.
For more information, contact Creative Alley Productions. Phone and Fax: (310) 858-8678. Email: email@example.com Web: www.creativealleyproductions.com.
NOTE: Creative Alley Productions is a service mark of Creative Alley Productions, Inc. All other names and trademarks are property of their respective owners.

subset: commoncrawl


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Fungicide Resistance Management in Potato Late Blight
The Fungicide Resistance Action Group - UK (FRAG-UK) is a forum to look at fungicide resistance issues and to publish information and advice relevant to the UK.
The latest version of the version of our Resistant Management Guidelines can be found on the link below:
Fungicide ResistanceFungicide Resistance Management in Potato Late BlightBlightBlight May 2018
Comparison of sensitivity to a range of fungicides in contemporary genotypes of Phytophthora infestans (2018)
Project Ref: 11120047
In 2018 fungicides belonging to a range of FRAC fungicide groups were tested for their ability to inhibit late blight in the laboratory. A limited number of isolates of P. infestans belonging to lineages known to be either established, or relatively new in GB were tested.
Results of testing genotype 37_A2 provided supporting evidence of its resistance to fluazinam, as previously reported. It was found that, overall, isolates of genotype 36_A2 were more difficult to inhibit than those of the other genotypes across several active ingredients and appeared to be relatively aggressive.
These findings do not provide evidence of specific or multiple shifts in resistance in genotype 36_A2 or mean that performance using products at field rates will necessarily be affected. Therefore, recommendations on use for 2018/19 remained unchanged.
A presentation summarising the results was made at the Agronomists' Conference in Dec 2018


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If you own a vehicle, then you know that repair can be a pain. Either you're going to spend quite a bit of money getting someone to fix things for you, or you'll have to spend your energy and time getting repairs done. Both methods can be stressful to use, but you'll have a lot easier time when doing auto repairs once you've read this article.
You do not have to contact a mechanic every time you have issues with your car. There are many things you can fix easily. Try troubleshooting the issue on the Internet or talk to your friends to see if they have an idea of what could be wrong with your vehicle. If it's a quick repair to make, you can save yourself some cash by doing it yourself.
Be aware of a mechanic who makes unneeded repairs to your car. A reliable mechanic will tell you if any parts are worn down and need replacing. But, they should ask for your approval before replacing them. Never return to a mechanic that ripped you off.
Before dropping your car off for repairs, remove any valuables. The technicians may have to move out these things to fix your car, and they cannot be held liable if anything goes missing. You want to remove items from your trunk also.
Repair Person
Your repair person should be upfront and honest with you. If you have trouble getting a straight answer out of them, (or if, even worse, they refuse to answer questions to your satisfaction) they probably aren't the kind of people you want to work with. It's best to feel that you trust your repair person, so don't hesitate to move on.
Verify that a prospective mechanic is familiar with your specific car. There can be a lot of differences between vehicles, even though the base components are similar. If you don't think the shop you are going to really knows what they are doing, take your car to the dealer instead.
Repair Shops
If you are having extensive repairs done, make sure that you get several estimates. Although most repair shops can be trusted, you do not want to have to spend some more unnecessary repairs. Search for a reliable shops that is knowledgeable with your kind of car. These repair shops are better equipped to understand and repair any problem your car has.
Replacing the bulbs on your taillights or headlights yourself can save you both time and money. While it is different with each vehicle, it is much cheaper to do it yourself. Speak with people that you're familiar with if you know they're good at repairs.
Before going with a particular shop, get auto repair feedback from your friends. Personal recommendations are usually honest and forthright. Don't rely entirely on what your friends tell you, though; do your own research. You should at least check out the mechanic's reputation online.
Take all those fun and fluffy keychains off, or make it possible to remove your car key from the bunch. The ignition in your car isn't designed to take a bunch of weight even if your car keys don't feel that heavy. When the key begins to stick in position, you have to replace all of the tumblers or endure more serious damage.
Before giving your car to a shop, ask them about their fees. Make sure you're asking questions if you're not sure about the shop's rates. You should understand how you are billed by your mechanic. Are the repair times established? Other shops may charge an inflated rate for a minor repair that should be done within a shorter period of time.
If you are short on funds and need repairs done on your car, consider taking your vehicle to a vocational school. You will pay a very low rate to have students fix your car while being supervised by a licensed mechanic.
Original Equipment Manufacturer is usually referred to using the acronym OEM. Remember this when you need a part replaced on your car. Informing your mechanic that you require OEM replacement parts will demonstrate your familiarity with repair services. This tells the mechanic that you know what you're talking about and don't want used parts.
If you just bought a car, and you realize there is a problem, get in touch with the manufacturer. You may find that there is already a manufacturer's recall to fix this problem. If there is not yet a recall, your report of the problem may help lead to one. The manufacturer may fix the problem at no cost to you.
Auto Repair
If you would like some security when dealing with an auto repair, consider joining AAA. AAA can be very useful when you need a tow, or are looking for a deal with an auto repair service shop. In many cases, you'll even find that AAA membership reduces your overall auto repair expenses thanks to member discounts.
Auto repair is something that isn't easy to do all the time, but you can be sure auto repairs are easier. Use the advice mentioned above in regards to your auto repairs. Your car will receive better repair work and you will be happier.


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Building the Right Environment to Support AI, Machine Learning and Deep Learning
Bad news for the mobile development industry: the market analysts at IDC say that growth in worldwide smartphone sales will slow considerably this year. In 2014, smartphone shipments increased 27.6 percent, but in 2015, the firm expects only an 11.3 percent increase.
They blame the slowdown on the Chinese market, where smartphone shipments actually decreased in the first quarter of this year. "This has implications for Android because China has been a critical market for Android smartphone shipments in recent years, accounting for 36 percent of total volume in 2014, said Ryan Reith, Program Director with IDC's Worldwide Quarterly Mobile Phone Tracker.
Currently the biggest growth markets for smartphones are India, Indonesia, the Middle East and South Africa. Some areas of South America have growth potential as well, although the market in Brazil is maturing.
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As a nurse practitioner in the Gastroenterology Department, Kelly Dickinson, FNP-C, works closely with Trinity's GI specialists and other clinicians to provide comprehensive care for patients with gastrointestinal and liver disorders. Originally from Texas, she moved to Minot when she was 16 and attended Minot High School. She earned a Bachelor of Science in Nursing in 2010 from Minot State University and began her nursing career at Trinity Hospital, caring for patients in the med/surg, ICU, and GI/Same Day Surgery units. Her Master of Science/Family Nurse Practitioner degree was completed at the University of North Dakota in Grand Forks. A member of Sigma Theta Tau Honor Society of Nursing and the North Dakota Nurse Practitioners Association, Kelly enjoys running, volunteering at her church and going to the lake with her husband and three children.
Gastroenterology is the branch of medicine whereby the digestive system and its disorders are studied, this includes the esophagus, stomach, intestines, biliary system, gallbladder, pancreas and liver.


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Jim Broadbent (born 24 May 1949[1][2][3]) played the Eleventh Doctor in The Curse of Fatal Death. He had previously played a version of the Doctor in Doctor Who and Crayola a sketch in Victoria Wood As Seen On TV. This is included on the VHS release of The Curse of Fatal Death and the DVD release of The Greatest Show in the Galaxy.
The Emmy- and Academy Award-winning character actor has appeared in many popular films, including Iris and the musical Moulin Rouge. He won an Oscar for the former in 2002 (were Curse of Fatal Death to have been valid, this would have made Broadbent the first actor to win an Oscar after having appeared in the series). Other roles in popular series have included Professor Kirke in the 2005 movie The Lion, the Witch and the Wardrobe and Charles Stanforth in Indiana Jones and the Kingdom of the Crystal Skull. Most recently, he has played Professor Slughorn in the Harry Potter film series. He also played Roy "the Slag" Slater in BBC sitcom Only Fools and Horses.
External links
- ↑ Jim Broadbent. Encyclopaedia Britannica. Retrieved on 15 July 2017.
- ↑ Jim Broadbent 1949 -. BBC. Retrieved on 15 July 2017.
- ↑ Macnab, Geoffrey (18 December 2015). Jim Broadbent, profile: Our greatest character actor takes on Scrooge. The Independent. Retrieved on 15 July 2017.


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The Alpine Camp is a single-day adventure that include knowledge and skills sessions along the way; navigation, route-finding, terrain and hazard recognition, decision making, etc.
- $199
- July 7, 6:45am at Capra
- We take care of all the planning and logistics
- You are responsible for food, water, and lift tickets (if applicable)
- Reviews
- Shipping
Region Carrier Cost Squamish In-store Pickup $0.00 Within BC FedEx 2-Day $12.00 Canada-wide FedEx 2-Day $17.00 U.S. (Continental) FedEx Ground $22.00 International FedEx International Quote
Rates will automatically be applied at checkout.
View detailed shipping information.


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An experienced digital marketer and content strategist, Robert Katai not only is hosting his own podcast but shouting out loud and evangelizing the benefits of this emerging type of media. The podcast is past its buzzword days and Robert shows us how to work with it to generate attention, engagement and revenue.
INTERVIEW | John Espirian: "B2B shouldn't be a dry and stuffy arena."
John Espirian built a large community around his personal brand on LinkedIn in recent years. Being the "relentlessly helpful copywriter", he offers knowledge and practical advice for B2B writers & marketers all over the world. And this interview is no exception. Read, learn & enjoy!
INTERVIEW | Eliza Dumitrache: "As an app marketer you live in three worlds – customers, product, and marketing."
App marketing is arguably the coolest branch of digital marketing. Join Eliza, an experienced practitioner who is giving us the grand tour sharing the know-how, strategies and 2019 trends. Learn what app marketers do and what it takes to become one.
INTERVIEW | Xenia Muntean, CEO Planable: "Social media must be aligned with business results"
Planable, the social media collaboration platform, is once again under the spotlight as Forbes featured them in their "2019 EUROPE 30 UNDER 30: MEDIA & MARKETING" section. Xenia Muntean, CEO Planable talks startup life and journey to success. A story about hard work, mentorship and a lot of courage.
INTERVIEW | How Content Marketing Works for B2B
A content first marketing strategy is embraced by more and more companies in B2B. Get valuable insights, actionable takeaways and learn about 2019 trends from Sabina Varga, an experienced Content Marketer and Storyteller.


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STAMFORD, Conn. – official press release –
In an unprecedented offering, NBC Sports Group will present dual national coverage of the 2015 NASCAR Sprint Cup Championship race from Homestead-Miami Speedway on November 22.
While NBC provides the primary broadcast of Jeff Gordon's quest to close out his Hall of Fame career in storybook fashion, NBCSN offers a simultaneous live feed dedicated to each of the Championship 4 drivers racing for a historic victory on Sunday in South Florida. Live race coverage on both NBC and NBCSN begins at 3 p.m. ET.
The NBCSN Hot Pass multi-window display provides viewers an in-depth look at Gordon, Kevin Harvick, Kyle Busch and Martin Truex, Jr., with up to three different angles from in-car cameras. A dynamic track map keeps viewers aware of Championship 4 driver positions and changes throughout the field, while a pane of race facts and figures illustrates live point differentials and key shifts in the race.
Race announcer Leigh Diffey and NASCAR Hall of Fame driver Dale Jarrett host NBCSN Hot Pass coverage as the Championship 4 compete for the 2015 NASCAR Sprint Cup Championship.
"Get ready to experience history in real time from the drivers' headset and perspective," said Dan Steir, SVP of Production for NBCSN. "NBCSN Hot Pass will deliver a constant spotlight on the Championship 4 drivers and allow the race fan to access the strategy and drama in a more focused manner."
NBCSN Hot Pass also provides a simultaneous cycle of in-car audio, showcasing team communications between the driver, crew chief and spotter as each Championship 4 driver turns laps around the 1.5-mile track. Diffey and Jarrett punctuate the in-car audio, explaining key situations and communications among the four teams.
NBCSN Hot Pass and NBC's broadcast of the NASCAR Sprint Cup Championship race are both available for live stream via NBC Sports Live Extra.
CREDIT: NBC Sports


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Online Marketing Consultant, Worked with Start-ups in Austin, TX and coached 100's of entrepreneurs to get their businesses online.
I have coached 100's of entrepreneurs to bring their businesses to life online. I make the process of getting your online presence up, running and set for growth. With me, you get the knowledge and skills to 'think' like a marketer so you can grow your own brand and not be dependent on a marketing agency. I've worked with billion-dollar food companies and the largest law firms in the world and I want to teach you how to do what they do in marketing for your small business.


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Save More on Credit Card Interest
Members interested in receiving the best rate possible can apply for our Low Rate Credit Card program. This card is a good fit for anyone looking to transfer balances from a high rate credit card to a lower rate program to save on interest payments.
Program Features:
- No annual fee
- 25 day grace period for purchases
- Low monthly payment – 3% of the outstanding balance or
$25 Review account activities, check balances, and make
payments within It'sMe247 Online Banking anytime
and anywhere you have an Internet connection
- Worldwide acceptance
- Mastercard's zero liability policy
Mastercard® Platinum Low Rate Credit Card*
Interest rates and interest charges
|Annual Percentage Rate (APR) for Purchases
|7.15% to 18%* when you open your account, based on your creditworthiness. After that your APR will vary with the market based on your credit score and the Prime Rate, but will not exceed 17.75%.
|APR for Balance Transfer
|7.15% to 18%*, based on your creditworthiness. Your APR will vary with the market based on the Prime Rate.
|APR for Cash Advances
|7.15% to 18%*, based on your creditworthiness. Your APR will vary with the market based on the Prime Rate.
|Penalty APR and When it Applies
|How to Avoid Paying Interest on Purchases
|Your due date is at least 25 days after the close of each billing cycle. We will not charge you any interest on purchases if you pay your entire balance by the due date each month.
|Minimum Interest Charge
|For Credit Card Tips from the Consumer Financial Protection Bureau
|To learn more about factors to consider when applying for or using a credit card, visit the website of the Consumer Financial Protection Bureau at http://www.consumerfinance.gov/learnmore/.
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How We Will Calculate Your Balance: We use a method called "average daily balance (including new purchases)
To obtain a copy of our Credit Card agreement disclosures please call us at 888-7-Viriva or 215-333-1201 for local calls. You can also email email@example.com. Please include your name, address, and daytime phone number in your request.
*The approval and the Annual Percentage Rate (APR) offered to you for this product will be based upon your credit evaluation. All advances are subject to a Variable Rate which is based on the highest Prime Rate as published in the Money Rates section of the Wall Street Journal on the first business day of each calendar month ("Index") plus a margin from 5.90-17.90 (for the Rewards Card Program), 3.90-15.90 (for the Low Rate Card Program), and 7.90 (for the Secured Card). The Index plus the Margin equals the Interest Rate. Changes in the Index will cause changes in the Interest Rate on the first day of the billing cycle that immediately follows any such change in the Index. Increases or decreases in the Interest Rate will cause like increases or decreases in the Finance Charge and will affect the number of your regularly scheduled payments. This disclosure is accurate as of April 1, 2020, and is subject to change after that date. To find out if any changes in this information have occurred, please call us at 888-7-Viriva (215-333-1201 for local calls), or write to us at 157 York Road Warminster, PA 18974


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It's tough to get out of paying payroll taxes. When you withhold tax money from employees but fail to give it to the IRS, they will come after you. Quite rightly, the IRS views it as government money, a trust fund belonging to the IRS.
In a cash-strapped business, keeping the lights on or the warehouse stocked can seem more important. It may be tempting to think you can always pay the IRS later. But these problems have a way of snowballing, so it's best to keep payroll taxes current at all times. Consider using a payroll service that directly pays the money over to the IRS.
One more good reason to be careful?
Personal Liability. Business owners and other "responsible persons" have personal liability for these taxes and excuses are rarely accepted. In Colosimo v. U.S., the Eighth Circuit Court of Appeals refused to take sympathy on a company owner who claimed he was duped by his bookkeeper.
More recently, in Jenkins v. U.S., the Court of Federal Claims held the majority owner and CEO of a publishing company responsible for payroll taxes. Although he didn't exercise day-to-day control, he had the authority to do so and he knew payroll taxes were unpaid. You can be liable even if have no knowledge the IRS is not being paid. See What Is The Trust Fund Recovery Penalty?
The IRS can assess a Trust Fund Recovery Assessment---also known as a 100-percent penalty---against every "responsible person." See Section 6672(a). In determining "willfulness," courts focus on whether you had knowledge of the non-payment of taxes or showed reckless disregard whether they were being paid. But a person need not actually perform the withholding and payment functions to be considered "responsible."
If you have signature authority but don't exercise it, that can be enough to result in liability. Factual nuances matter, so one person may get stuck while another gets off scot-free. The IRS often makes an assessment against every officer, watching them turn on each other.
For example, in Johnson v. U.S., the IRS went after two employees for a casino's payroll taxes. Brian Toms was the secretary/treasurer responsible for making tax deposits and electronic transfers for payroll taxes. Bonnie Johnson was the CFO but was not a member of the board, nor an officer or shareholder. She was authorized to pay vendors in the morning before Brian arrived, but otherwise paid vendors only when Brian instructed.
Brian was held liable for the taxes but Bonnie was not. She had check-signing authority and even prepared and signed tax returns. However, she did not have control of the payroll, could not authorize tax deposits, and did not have authority to sign contracts. The court found that she did not have the authority to pay the IRS without permission from Brian.
Huge numbers of businesses each year get caught in this no-win situation. See Personal Tax Liability When A Business Goes Under. Disputes are expensive and often do not go well. Be careful out there.
For more, see:
IRS Penalties Despite Dead/Embezzling Accountant!
Employers Who Violate Tax Law May Go To Jail
IRS Nightmare: What Employment Taxes?
Personal Tax Liability When A Business Goes Under
Supreme Court Deaf To Payroll Tax Woes
IRS Pursues Payroll Tax PyramidingRobert W. Wood practices law with Wood LLP, in San Francisco. The author of more than 30 books, including Taxation of Damage Awards & Settlement Payments (4th Ed. 2009, Tax Institute), he can be reached at firstname.lastname@example.com. This discussion is not intended as legal advice, and cannot be relied upon for any purpose without the services of a qualified professional.


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Wacky Packages | Wonder Bread | Posters | T-Shirts | Wacky Ads | Lost Wackys | New Series | Original Series | Wacky Magazines | What's New? | Erasers
Wacky Packages were released in Canada in 1974 under the O-Pee-Chee name.
O-Pee-Chee, also known as OPC, is regarded as the Canadian equivalent of Topps. OPC was founded in London, Ontario in 1911 by two brothers, John and Duncan McDermid. The name was taken from "Opechee", the robin's name in the Henry Wadsworth Longfellow poem "The Song of Hiawatha".
Like many gum companies, O-Pee-Chee got into trading cards in the 1930's, and put out a few baseball sets from 1933 to 1937. After that brief period, OPC stayed out of the card market until 1965, when they made arrangements with Topps for a license to print and distribute Topps products in Canada.
Beginning with baseball cards, the O-Pee-Chee cards were simply a rebranded version of the Topps design and marked "Printed in Canada". OPC also reprinted Topps' non-sports sets, such as tattoos and the 1966 Batman series. In 1968, the license was extended to hockey, and O-Pee-Chee began producing it's own cards for Canadian football, something Topps had been doing earlier.
In 1970, OPC cards became bilingual, and the wrappers, boxes, and card backs were printed with both English and French. This was a legal requirement, as federal legislation demanded that items produced in Canada carry both languages. This also applied to other products such as cereal boxes, etc.
OPC issued their first wackys in 1974, reprinting most of the original 1st, 2nd, 3rd, and 4th series. They also later printed the 1982 album stickers, and then the U.S. 2nd, 3rd, and 4th reissue sets of 1980 were released in Canada in 1987, 1988, and 1989.
The last wacky OPC set was in 1992, as a reprint of the 1991 U.S. set. Then the 1994 baseball strike, the 1994-95 hockey lockout, and the accompanying damage to the baseball card industry hit O-Pee-Chee particularly hard. The company first announced that it would get out of the card business and refocus its efforts on candy. But in 1996, OPC was bought out by Nestlé.
|OPC Wackys
|O-Pee-Chee Wacky Packages -- 24 Titles & Puzzle
|1974 Wacky Packages OPC 1st Series
|Click here to find Wackys on Ebay
OPC 1st Series Variations
|The OPC 1st Series stickers were printed on 2 different backings -- Tan (common) and White (rare). This is the opposite of the U.S. set, where the tan backs are rarer than the white backs.
OPC Dropped Titles
|Band-Ache, Maddie Boy, Quacker Oats, Skimpy, Weakies
|1st Series Rough Art
|Cover Ghoul (1967)
OPC 1st Series Puzzle & Checklist
|Gadzooka Puzzle
OPC Wax Wrapperwacky packages
|OPC 1st Series Wrapper
|OPC Wacky Packages Original Series
OPC 1st Series
OPC 2nd Series
|U.S. Wacky Packages Original Series
email email@example.com
See the Full List of Lost Wackys
funny pictures Wacky Packages Old School Hollywood Zombies New Webkinz


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Listing IDNEST-107118
CountyNew York
Property TypeUnit Sale
Property Sub TypeCondoCoop
"Virtual Tours of The Kent are now available. Please contact us for more information." THE KENT OFFERS ONE OF THE LAST 20-YEAR TAX ABATEMENTS AVAILABLE IN NEW YORK CITY Closings have commenced! This exceptional 5 bedroom, 4.5 bathroom residence offers 3,564 square feet of living and entertaining space. Enter this gracious residence through a formal gallery and enjoy the spacious eat-in kitchen and expansive living and dining room. Expansive south, east and west-facing exposures offer open views of the city and East River. Extell Development Company is proud to present The Kent, a tailored collection of elegantly appointed condominium residences on the Upper East Side, crafted by award-winning architects Beyer Blinder Belle and acclaimed interior designer Alexandra Champalimaud. Two-to-five bedroom gracious residences exhibit the finest finishing details, complemented by three levels of curated indoor and outdoor services and amenities. The Kent Service and Amenities: - Grand Lobby with concierge desk - 24-hour Doorman - Stroller Valet - Lobby cold storage room for fresh food and flower deliveries - The Drawing Room" Lobby Lounge with fireplace and bar - 55-foot indoor heated swimming pool - Private State-of-the-Art Fitness Center - Men's and Women's changing rooms with Finnish saunas - "The Sound Lounge" by Kravitz Design, envisioned by Lenny Kravitz - Camp Kent children's playroom designed by Williams New York - Outdoor children's play area designed by West 8 Urban Design & Landscape Architecture - "The Garden Salon" residents' lounge with fireplace, billiards table, catering kitchen - Landscaped courtyard garden designed by West 8 Urban Design & Landscape Architecture - Canine Spa - Bike Room The complete offering terms are in an offering plan available from Sponsor. File No. CD15-0238. Sponsor: 95th and Third LLC, 805 Third Avenue, Seventh Floor, New York, NY 10022. Sponsor reserves the right to make changes in accordance with the terms of the offering plan. Equal Housing Opportunity.
Building Name THE KENT
Property Sub Type CondoCoop
Furnished no
Laundry yes
Lobby Attendance Type No
Lobby Attendant Yes
Washer and Dryer in Unit yes
Washer Dryer Allowed no
Garage no
New Development yes
Building Type High-rise
Doorman Yes
Floor Has Laundry Facility no
Pet Policy Pets allowed
Pet Policy Pets allowed
Pre-war no
REBNY Status Active
Borough Manhattan
Geographic Section 1
Neighborhood Upper East Side
Street Number And Name 200 East 95th Street
Maintenance CC Amount 4539
Maximum Financing Percent 75
Monthly Tax Amount 461
Ownership Type Condo
© 2020 Real Estate Board of New York. All rights reserved. The data relating to real estate for sale on this web site comes in part from the Internet Data Exchange Program of REBNY. Real estate listings held by IDX Brokerage firms other than Barnes New York are marked with the Internet Data Exchange logo or the Internet Data Exchange thumbnail logo and detailed information about them includes the name of the listing Brokers. Information provided is deemed reliable but not guaranteed. Data last updated: Thursday, April 9th, 2020 at 05:24:31 AM. Listing courtesy of Extell - The Kent.
Request More Information - Listing ID NEST-107118
Data services provided by IDX Broker


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25% off!*
*Offer valid online at Crocs.com. Excludes Jibbitz™ Charms, additional exclusions apply; see cart for details. Discount applied in cart. Cannot be combined with any other offer or promotion. Offer valid while supplies last. Offer not valid on previous purchases. No rain checks. Offer ends Monday, April 6th, 2020 at 11:59pm MT.
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Men's Bogota FlipItem #204971
A little more down to earth, sporting a southern latitude kind of attitude, these flips feature synthetic leather uppers and tonally matching footbeds that wouldn't look out of place with a linen suit. They're equally at home with jeans or your favorite pair of shorts, out for walks on the beach or on weekends knocking around town.
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Japan's top 3 telcos to exclude Huawei, ZTE network equipment
Japan's huge three telecoms administrators plan not to utilize organize hardware from China's Huawei Technologies Co Ltd and ZTE Corp, Kyodo News gave an account of Monday.
The arrangement applies to current hardware and also forthcoming fifth-age (5G) equip, Kyodo announced without refering to sources.
Japan intends to forbid government buys of gear from Huawei and ZTE to guarantee quality in its safeguards against knowledge spills and cyber attacks.
Delegates of the three telcos, NTT Docomo Inc, KDDI Corp,
Huawei has just been bolted out of the US market and Australia, and New Zealand have blocked it from building 5G systems in the midst of worries of conceivable connections the firm has with China's administration. Huawei has more than once demanded Beijing has no impact over it.
Markets have been reeling after the news a week ago that Canadian authorities had captured Huawei's CFO for removal to the United States, starting feelings of dread the capture would hurl another obstacle to the goals of an exchange war between the world's greatest two economies.
SoftBank, which has an involved acquaintance with Huawei and has collaborated the firm in 5G preliminaries, was the greatest decliner among the three telcos on Monday. Its offers shut down 3.5 percent in front of the Kyodo report, over worries about the effect a reaction against Huawei could have on its business.


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Technology Transfer OfficeView Profile
Yissum - Research Development Company of the Hebrew University posted this:High Speed, High Spatial Resolution Scanning Micro-ellipsometerMetrology instrument for measuring coatings properties/dimensions Keywords: measurement, device, Project ID : 14-2017-4398
R&D Manager at Biótica, Bioquímica Analítica,S.L.View Profile
Guillermo Rodríguez posted this:
R&D Manager at Biótica, Bioquímica Analítica,S.L.
UACOOPERA University of Aveiro posted this:
Technology Transfer Office at uacoopera
Scientist at Institute of Metallurgy and Materials Science, Polish Academy of SciencesView Profile
Jerzy Morgiel posted this:
Scientist at Institute of Metallurgy and Materials Science, Polish Academy of Sciences
UACOOPERA University of Aveiro posted this:
Technology Transfer Office at uacoopera
UACOOPERA University of Aveiro posted this:
Technology Transfer Office at uacoopera
Technology Transfer Office
Universidade de Santiago de Compostela posted this:New Thermal Sensing for Microcalorimetry and Microfluidics (ERC-PoC project)The prototype developed within ERC-PoC "ANTS" project, has demonstrated its sensitivity for a new concept of microcalorimeters, as well as providing advantages in microfluidics. We aim to: a) Integrate this technology within microfluidic devices or applications where size and fast response time are crucial. b) Develop a High-Throughput Calorimetry going beyond the current capabilities on ITC. > Sensing element. Ferromagnetic permalloy line 4x28 µm x 20 nm thick: affordable, miniaturization… Sensor was fabricated in a single deposition. > Temporal response. Milliseconds, to stimulus >10 microwatts; further improvements are in progress. > Easy adoption. Compatible with standard configuration of microcalorimeters. > IPR: EP, US, CN, KR, JP
Jordi Reverter posted this:
Licensing Manager at Institut Català de Nanociència i Nanotecnologia
Jordi Reverter posted this:
Licensing Manager at Institut Català de Nanociència i Nanotecnologia
Universidad de Alicante posted this:Natural hybrids nanopigments synthesis for multiple industrial applications.The Colour and Vision Research Group of the University of Alicante has been designed a new process to develop nano-structured hybrid nanopigments (from synthetic or natural dyes). These nanopigments confer improved optical, thermal, and mechanical properties when they were applied on composite materials. The nanoclays, dyes, and additives have been selected depending on the composite matrix source. Also, it has been selected the additives order in the process of synthesis, based on the material properties that would be going to improve. The parameters that could be control with this new system are: the adsorbed dye concentration, the degradation temperature of the reinforced dye, the degradation temperature of the final nanocomposite, the bending resistant modulus, and the UV-VIS colour fastness. Also, it can be controlled the optical properties as transparency and colouring power degree. It is looking for companies interested in commercial exploitation of these new colored nanomaterials.
Universidad de Alicante posted this:Novel and simple procedure for dispersing graphene derivatives in chemically curable resins.The Laboratory of Adhesion and Adhesives of the University of Alicante and the company Dental Global Training, have developed a new procedure to incorporate efficiently graphene derivatives (nanofibers, nanosheets, nanoparticles) in chemically cured resins by using an in situ polymerization technique. The method is very simple and fast, it provides an excellent dispersion of the graphene derivatives in both the solid components of the resin and in the cured polymer matrix, and is entirely friendly with the environment. The novel method does not require the use of organic solvents nor water, ultrasounds, and high pressure/temperature. The resulting resin composites show excellent mechanical properties, good wear resistance, easy manipulation and increase the insolubility in oral fluids, and therefor they have special interest in applications in odontology, traumatology and non-medical applications too (automobile, construction, civil engineering, aeronautics, space engineering, electronics and optics). It is looking for companies interested in acquiring this technology for its commercial exploitation.
uacoopera posted this:Lighting device with adjustable white light based on zirconia nanostructuresA group of researchers from a Portuguese university has developed the concept of a lighting device with adjustable white light based on zirconia nanostructures. The invention aims to control the color temperature of white light emission that is different depending on the morphology/dimension of the particles, on the surrounding environment and on excitation power. The advantage of this type of device is based on the high color quality index and the possibility of color temperature control that is relevant to the lighting technologies market. The university is looking for companies that develop this type of solution on an industrial scale. The university is looking for companies that develop this type of solution on an industrial scale for the further joint development of specific applications or technology licensing.
uacoopera posted this:Optical pressure sensor based on zirconia nanostructuresA group of researchers from a Portuguese university has developed the concept of a gas pressure gauge based on the control of the luminescence from zirconia nanostructures. The invention aims to measure the gas pressure based on the nanoparticles emission that is different depending on the amount of gas molecules surrounding the nanoparticles. Comparing with existing solutions, the advantage of this process, which operate in a pressure range of interest for various market sectors (ex. Food industry), is the absence of electrical contacts. The university is looking for companies that develop this type of solution on an industrial scale for the further joint development of specific applications or technology licensing.
Universidad de Alicante posted this:New process for the manufacture of electrodes from superporous nanostructured carbon materialsSpanish University have developed a process for the manufacture of electrodes from superporous nanostructured carbon materials. The process uses electrospraying technique to deposit a suspension of a carbon material over a collector. This method facilitates processing superporous nanostructured carbon materials due to its high efficiency and less complexities compared to conventional techniques. The electrodes obtained can be used in energy storage or analytical sensors in commercial devices.
Technology Transfer Office
RAMOT at Tel Aviv University Ltd. posted this:Harnessing inhibitory RNA based- nanoparticles for therapeutic intervention in blood cancersModulating T cells functions by down regulating specific genes using RNA interference (RNAi) holds tremendous potential in advancing targeted therapies in many immune related disorders including cancer, inflammation, autoimmunity and viral infections. Hematopoietic cells, in general, and primary T lymphocytes, in particular, are notoriously hard to transfect with small interfering RNAs (siRNAs). Herein, we describe a novel strategy to specifically deliver siRNAs to murine CD4+ T cells using targeted lipid nanoparticles (tLNPs). To increase the efficacy of siRNA delivery, these tLNPs have been formulated with several lipids designed to improve the stability and efficacy of siRNA delivery. The tLNPs were surface functionalized with anti-CD4 monoclonal antibody (mAb) to permit delivery of the siRNAs specifically to CD4+ T lymphocytes. Ex vivo, tLNPs demonstrated specificity by targeting only primary CD4+ T lymphocytes and no other cell types. Systemic intravenous administration of these particles led to efficient binding and uptake into CD4+ T lymphocytes in several anatomical sites including the spleen, inguinal lymph nodes, blood and the bone marrow. Silencing by tLNPs occur in a subset of circulating and resting CD4+ T lymphocytes. Interestingly, we show that tLNPs internalization and not endosome escape is a fundamental event that takes place as early as one hour after systemic administration that determine tLNPs efficacy. Taken together, these results suggest that tLNPs may open new avenues for the manipulation of T cell functionality and may help to establish RNAi as a therapeutic modality in leukocyte-associated diseases. Project ID : 10-2016-962


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?Our aim is for this iconic building to regain and maintain its position as a living cultural space in the centre of Athens,? Athens Mayor George Kaminis said on Thursday, during a press conference held at the Foyer of the Olympia Theatre that formerly housed the Greek National Opera.
Left vacant after the GNO relocated to its new stage at the Stavros Niarchos Foundation Cultural Centre in March 2017, the theatre will now reopen its doors to the public after a total refurbishment carried out by the City of Athens. Renamed the "Olympia Municipal Musical Theatre Maria Callas" (MMTMC) it will house the City of Athens' new initiative, a municipal opera. As a tribute to the great Greek opera singer, in the Foyer of the theatre several personal objects of Maria Callas will be put on display in a space dedicated to her memory .
During the press conference, conductor Loukas Karytinos and member of the MMTMC artistic committee presented the program for the coming period, which will open on December 3 with Felix Mendelssohn's ?A Midsummer Night's Dream?, directed by Vassilis Nikolaides. On the opening night, entrance will be free upon presentation of one of the vouchers the Olympia box office will distribute at 18:30 on the same day.
Speaking to the Athens-Macedonian News Agency (ANA), Kaminis referred to the new MMTMC as ?a source of light in the dark,? and added that he would like to see more central Athens shops and entertainment venues "keep their lights on during the night."


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The burden and aetiology of type 2 diabetes (T2D) and its microvascular complications may be influenced by varying behavioural and lifestyle environments as well as by genetic susceptibility. These aspects of the epidemiology of T2D have not been reliably clarified in sub-Saharan Africa (SSA), highlighting the need for context-specific epidemiological studies with the statistical resolution to inform potential preventative and therapeutic strategies. Therefore, as part of the Human Heredity and Health in Africa (H3Africa) initiative, we designed a multi-site study comprising case collections and population-based surveys at 11 sites in eight countries across SSA. The goal is to recruit up to 6000 T2D participants and 6000 control participants. We will collect questionnaire data, biophysical measurements and biological samples for chronic disease traits, risk factors and genetic data on all study participants. Through integrating epidemiological and genomic techniques, the study provides a framework for assessing the burden, spectrum and environmental and genetic risk factors for T2D and its complications across SSA. With established mechanisms for fieldwork, data and sample collection and management, data-sharing and consent for re-approaching participants, the study will be a resource for future research studies, including longitudinal studies, prospective case ascertainment of incident disease and interventional studies.
With the changing distribution of infectious diseases, and an increase in the burden of non-communicable diseases, low- and middle-income countries, including those in Africa, will need to expand their health care capacities to effectively respond to these epidemiological transitions. The interrelated risk factors for chronic infectious and non-communicable diseases and the need for long-term disease management, argue for combined strategies to understand their underlying causes and to design strategies for effective prevention and long-term care. Through multidisciplinary research and implementation partnerships, we advocate an integrated approach for research and healthcare for chronic diseases in Africa.
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