Sut-6/NIPP1 modulates tau toxicity.

Neurodegenerative diseases exhibiting the pathological accumulation of tau such as Alzheimer's disease and related disorders still have no disease-modifying treatments and the molecular mechanisms of neurodegeneration remain unclear. To discover additional suppressor of tauopathy (sut) genes that mediate or modulate the toxicity of pathological tau, we performed a classical genetic screen using a tau transgenic Caenorhabditis elegans model. From this screen, we identified the suppressing mutation W292X in sut-6, the C. elegans homolog of human NIPP1, which truncates the C-terminal RNA-binding domain. Using CRISPR-based genome editing approaches, we generated null and additional C-terminally truncated alleles in sut-6 and found that loss of sut-6 or sut-6(W292X) suppresses tau-induced behavioral locomotor deficits, tau protein accumulation and neuron loss. The sut-6(W292X) mutation showed stronger and semi-dominant suppression of tau toxicity while sut-6 deletion acted recessively. Neuronal overexpression of SUT-6 protein did not significantly alter tau toxicity, but neuronal overexpression of SUT-6 W292X mutant protein reduced tau-mediated deficits. Epistasis studies showed tauopathy suppression by sut-6 occurs independent of other known nuclear speckle-localized suppressors of tau such as sut-2, aly-1/aly-3 and spop-1. In summary, we have shown that sut-6/NIPP1 modulates tau toxicity and found a dominant mutation in the RNA-binding domain of sut-6 which strongly suppresses tau toxicity. This suggests that altering RNA-related functions of SUT-6/NIPP1 instead of complete loss of SUT-6/NIPP1 will provide the strongest suppression of tau.

The influence of cadence and power output on force application and in-shoe pressure distribution during cycling by competitive and recreational cyclists.

The aim of this study was to determine the response of cyclists to manipulations of cadence and power output in terms of force application and plantar pressure distribution. Two groups of cyclists, 17 recreational and 12 competitive, rode at three nominal cadences (60, 80, 100 rev x min(-1)) and four power outputs (100, 200, 300, 400 W) while simultaneous force and in-shoe pressure data were collected. Two piezoelectric triaxial force transducers mounted in the right pedal measured components of the pedal force and orientation, and a discrete transducer system with 12 transducers recorded the in-shoe pressures. Force application was characterized by calculating peak resultant and peak effective pedal forces and positive and negative impulses. In-shoe pressures were analysed as peak pressures and as the percent relative load. The force data showed no significant group effect but there was a cadence and power main effect. The impulse data showed a significant three-way interaction. Increased cadence resulted in a decreased positive impulse, while increased power output resulted in an increased impulse. The competitive group produced less positive impulse but the difference became less at higher cadences. Few between-group differences were found in pressure, notable only in the pressure under the first metatarsal region. This showed a consistent pattern of in-shoe pressure distribution, where the primary loading structures were the first metatarsal and hallux. There was no indication that pressure at specific sites influenced the pedal force application. The absence of group differences indicated that pressure distribution was not the result of training, but reflected the intrinsic relationship between the foot, the shoe and the pedal.

Effects of three-dimensional assessment on surgical correction and on hook strategies in multi-hook instrumentation for adolescent idiopathic scoliosis.

STUDY DESIGN: A prospective study using intraoperative stereophotogrammetry to analyze change during the correction of scoliosis. OBJECTIVE: To examine the relation between the number of hooks used during segmental instrumentation and the amount of correction achieved. SUMMARY OF BACKGROUND DATA: An intraoperative stereophotogrammetric technique was developed at our center. Vertebral translations and rotations can be measured at several stages during scoliosis surgery. METHODS: Thirty-two patients with right thoracic adolescent idiopathic scoliosis were studied using our stereophotogrammetry technique during surgical correction. Correlations were determined between apical vertebral movements and the hook ratio (number of vertebrae/number of hooks used). RESULTS: Mean curve Cobb angle correction was 66%. Correction occurred in all three planes but primarily along the x and y axes. Scoliotic deformity was corrected by translation of the vertebra along the y axis and rotation about the x; physiologic kyphosis was restored by translation along the x axis and rotation about the y. The plane of maximum deformity as compared with the sagittal plane of the patient corrected from 57 degrees to 25 degrees as an indication of detorsion of the scoliotic deformity. CONCLUSIONS: Increasing the number of hooks per vertebral segment significantly enhances the correction of the coronal scoliotic deformity and enhances the z axis derotation, but does not significantly change the reestablishment of the kyphosis, nor does it result in significant elongation of the spine.

Operant conditioning and discrimination of alpha: some methodological limitations inherent in response-discrimination experiments.

Studies on the operant conditioning of central nervous system activity have produced results interpreted as demonstrating that responses, certain properties of responses, or response-produced stimuli can function as discriminative stimuli. It is assumed that the feedback stimulus in biofeedback makes the subject aware of the internal response and that by becoming aware of the response, the subject can acquire voluntary control over it. In this context, awareness is operationally defined as the ability to use the response as a discriminative stimulus. Since direct evidence for the assumed relationship between control and discrimination is lacking, an attempt was made to test the hypothesis that discrimination of a response automatically leads to control over that response. The discriminative stimuli were the presence and absence of occipital alpha electroencephalograph (EEG) activity. Data from two experiments are reported. The first study, employing naive subjects, was designed to answer the following questions: (a) Since pilot data indicated that subjects seemed to match their responses to the more probable type of trial, would increases in the probability of a correct response result when the probabilities of alpha and nonalpha trials were held near .50? (b) If correct responding does increase, would performance of these subjects in an alpha feedback task be enhanced relative to that of subjects not previously given discrimination training? and (c) If subjects could not learn the discrimination task, would feedback training enhance their performance in a subsequent discrimination task? Results from this study indicate that holding the probabilities of alpha and nonalpha discrimination trials near .50 results in an absence of learning curves, but leaves open the possibility that sophisticated subjects are capable of discriminating alpha and nonalpha activity. The second study deals with two questions: (a) Can sophisticated subjects learn to discriminate occipital alpha activity from nonalpha activity? and (b) Does the procedure of providing subjects with salient stimuli, contingent on the presence and absence of alpha activity, establish stimulus control of the presence and absence of alpha activity? Results indicate that it is not possible to conclude that subjects can learn to discriminate alpha and nonalpha activity. However, learning to increase percent-time nonalpha or decrease percent-time alpha with respect to baseline levels by means of EEG-contingent stimulation provides subjects with the ability to suppress percent-time alpha in the absence of feedback. Information gained in both studies through subject interviews indicates that subjects most often acquired their control of alpha activity during feedback by a specific strategy and then used the strategy during the stimulus-control tests.

Reducing epileptic seizures through operant conditioning of central nervous system activity: procedural variables.

Operant conditioning of the sensorimotor rhythm of the human electroencephalogram with time-outs contingent on epileptiform activity reduces epileptic seizure rates in patients whose seizures are not well controlled by medication. A comparison of this procedure with time-out training alone demonstrates that operant conditioning of the sensorimotor rhythm is neither necessary nor sufficient for seizure reduction.

Single unit and lesion experiments on the sensory inputs to the hippocampal cognitive map.

The hippocampal cognitive map theory states that the hippocampus calculates the animal's location in an environment and also the locations of objects such as rewards and threats. In this paper we report single cell experiments which explored how sensory inputs are used by the hippocampus to calculate spatial information and behavioural experiments which tested the sensory capabilities of fornix-lesioned rats. Both sets of experiments were done in cue-controlled enclosures which contained only a few distant cues by which the rat could locate itself and the goal. Other cues were eliminated by rotating the constellation of cues and the goal from trial to trial. The results of the single cell experiment show that the place fields of hippocampal cells recorded in this environment are related to the controlled cues and, further, that some of these place cells maintain their fields after the removal of any two of four controlled cues. The lesion studies show that rats with damaged fornices can learn to approach distant cues behind and below the level of the goal but not ones behind and above the goal. A second study showed that the addition of redundant distant cues to the enclosure impairs the learning ability of the lesioned, but not the normal, animals.

Transfer following operant conditioning in the curarized dog.

Dogs were trained to press a pedal to avoid shock. They were then operantly reinforced for making or for refraining from making a series of electromyographic responses while almost completely curarized. Tests after recovery from curarization showed that operant conditioning under curare influenced the original pedal-press response.