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Background Anaplastic thyroid carcinoma (ATC) is one of the most aggressive tumours. We previously confirmed that apatinib has potential therapeutic effects on ATC via regulated cell death (RCD). As a newly identified RCD, pyroptosis demonstrates direct antitumour activity different from apoptosis or autophagy. Therefore, the clinical significance, regulatory role and underlying mechanisms of pyroptosis in ATC were focused on in this study. Methods In a phase II trial, patients with anaplastic or poorly differentiated thyroid carcinoma received apatinib 500 mg once daily. Multiple assays were implemented to evaluate the antitumour efficacy of apatinib and/or melittin in vitro and in vivo. High‐throughput sequencing was applied to analyse differential mRNAs expression in ATC cells treated by apatinib with or without melittin. In situ Hoechst 33342/PI double‐staining, LDH release assay and enzyme‐linked immunosorbent assay (ELISA) were employed to determine pyroptosis. In mechanism exploration, quantitative RT‐PCR, Western blotting and si‐RNA knocking down were executed. Results Seventeen patients were evaluable. Apatinib showed a promising therapeutic effect by a disease control rate (DCR) of 88.2%; however, treatment was terminated in 23.5% of patients due to intolerable toxicity. To reduce adverse events, a pyroptosis‐mediated synergistic antitumour effect of apatinib and melittin was identified in treatment of ATC in vitro and in vivo. The caspase‐1–gasdermin D (GSDMD) axis‐mediated pyroptosis was the key to extra antitumour effect of the combination of apatinib and melittin. Moreover, caspase‐3–gasdermin E (GSDME) pyroptosis pathway also functioned importantly in addition to caspase‐1–GSDMD pathway. Evidenced by in vitro and in vivo study, a two‐way positive feedback interaction was innovatively confirmed between caspase‐1–GSDMD and caspase‐3–GSDME axes. Conclusions Through pyroptosis mediated by caspase‐1–GSDMD and caspase‐3–GSDME axes synchronically, low‐dosage apatinib and melittin could synergistically achieve a comparable therapeutic potential with reduced AEs. More importantly, a two‐way positive feedback interaction is innovatively proposed between these two axes, which provide a new prospect of targeted therapy. Apatinib and melittin could synergistically achieve a comparable therapeutic potential, which could reduce adverse events. A novel antitumour effect of pyroptosis induced by combination of apatinib and melittin in anaplastic thyroid carcinoma (ATC) was identified. Both caspase‐1–GSDMD and caspase‐3–GSDME pyroptosis pathways were the key to this extra antitumour effect. A two‐way positive feedback regulation was innovatively proposed between caspase‐1–GSDMD and caspase‐3–GSDME axes.

We conducted behavioral and functional magnetic resonance imaging (fMRI) research to investigate the effects of two types of achievement goals--mastery goals and performance-approach goals--on challenge seeking and feedback processing. The results of the behavioral experiment indicated that mastery goals were associated with a tendency to seek challenge, both before and after experiencing difficulty during task performance, whereas performance-approach goals were related to a tendency to avoid challenge after encountering difficulty during task performance. The fMRI experiment uncovered a significant decrease in ventral striatal activity when participants received negative feedback for any task type and both forms of achievement goals. During the processing of negative feedback for the rule-finding task, performance-approach-oriented participants showed a substantial reduction in activity in the dorsolateral prefrontal cortex (DLPFC) and the frontopolar cortex, whereas mastery-oriented participants showed little change. These results suggest that performance-approach-oriented participants are less likely to either recruit control processes in response to negative feedback or focus on task-relevant information provided alongside the negative feedback. In contrast, mastery-oriented participants are more likely to modulate aversive valuations to negative feedback and focus on the constructive elements of feedback in order to attain their task goals. We conclude that performance-approach goals lead to a reluctant stance towards difficulty, while mastery goals encourage a proactive stance.

To promote motor learning, robotic devices have been used to improve subjects’ performance by guiding desired movements (haptic guidance—HG) or by artificially increasing movement errors to foster a more rapid learning (error amplification—EA). To better understand the neurophysiological basis of motor learning, a few studies have evaluated brain regions activated during EA/HG, but none has compared both approaches. The goal of this study was to investigate using fMRI which brain networks were activated during a single training session of HG/EA in healthy adults learning to play a computerized pinball-like timing task. Subjects had to trigger a robotic device by flexing their wrist at the correct timing to activate a virtual flipper and hit a falling ball towards randomly positioned targets. During training with HG/EA, subjects’ timing errors were decreased/increased, respectively, by the robotic device to delay or accelerate their wrist movement. The results showed that at the beginning of the training period with HG/EA, an error-detection network, including cerebellum and angular gyrus, was activated, consistent with subjects recognizing discrepancies between their intended actions and the actual movement timing. At the end of the training period, an error-detection network was still present for EA, while a memory consolidation/automatization network (caudate head and parahippocampal gyrus) was activated for HG. The results indicate that training movement with various kinds of robotic input relies on different brain networks. Better understanding the neurophysiological underpinnings of brain processes during HG/EA could prove useful for optimizing rehabilitative movement training for people with different patterns of brain damage.

Damage to the superior and/or inferior parietal lobules (SPL, IPL) (Sirigu et al., 1996) or cerebellum (Grealy and Lee, 2011) can selectively disrupt motor imagery, motivating the hypothesis that these regions participate in predictive (i.e., feedforward) control. If so, then the SPL, IPL, and cerebellum should show greater activity as the demands on feedforward control increase from visually-guided execution (closed-loop) to execution without visual feedback (open-loop) to motor imagery. Using fMRI and a Fitts' reciprocal aiming task with tools directed at targets in far space, we found that the SPL and cerebellum exhibited greater activity during closed-loop control. Conversely, open-loop and imagery conditions were associated with increased activity within the IPL and prefrontal areas. These results are consistent with a superior-to-inferior gradient in the representation of feedback-to-feedforward control within the posterior parietal cortex. Additionally, the anterior SPL displayed greater activity when aiming movements were performed with a stick vs. laser pointer. This may suggest that it is involved in the remapping of far into near (reachable) space (Maravita and Iriki, 2004), or in distalization of the end-effector from hand to stick (Arbib et al., 2009). [Display omitted] •Closed-loop, open-loop, and imagined tool-use, in far space, obey Fitts' law.•Reduced influence of reciprocal aiming task difficulty during motor imagery•Superior-to-inferior gradient of feedback-to-feedforward control within the PPC•Mechanisms involved in motor imagery and open-loop control overlap substantially.•Anterior SPL supports dynamic representations of reachable as opposed to near space.

Rucci, JA and Tomporowski, PD. Three types of kinematic feedback and the execution of the hang power clean. J Strength Cond Res 24(3)771-778, 2010-The type and quality of feedback provided during instruction influences motor skill learning. The purpose of the study is to gain a better understanding of how altering feedback can impact discrete dynamic movements that are integral to strength training programs. The effects of 3 types of feedback on the execution hang power clean (4 sets of 4 repetitions at 75% of 1 repetition maximum) were evaluated over 6 training sessions. Nine different movement indices of the hang power clean were assessed using Dartfish video analysis software and comparisons among groups were made for each individually. Participantsʼ performance was predicted to benefit more from a combination of visual and verbal feedback cues than from visual feedback alone or verbal feedback alone. Results showed that 5 of the movement indices yielded a statistically significant interaction (p < 0.05). Analyses of movement form indicated that with training participants in both the video + cues group and the verbal-only group improved, whereas individuals in the video-only group did not. These results have implications for instructors seeking efficient methods of improving the way in which to teach female athletes to perform complex, dynamic, and technical movements through altering the type of feedback given.

Objective To determine whether the provision of comparative performance feedback during 4 km track cycling affects completion time. Design Five highly trained male cyclists first performed a baseline (BL) 4-km time trial (TT) on a velodrome track, followed by two further randomised 4-km TT, during which riders received either correct (COR) or non-contingent (FAL) feedback based on their BL performance. Results Participants completed the COR TT in a significantly faster time (t4=−3.10, p<0.05) than the FAL TT (341 (8) s vs 350 (12) s). Over the TT, a significant difference in mean speed was apparent between the two conditions (F15,60=1.95, p<0.05) on the second (t4=4.71, p<0.05), 15th (t4=3.45, p<0.05) and final lap (t4=3.30, p<0.05). Conclusion The significant difference in completion time and pacing strategy between the two conditions suggests that accurate, comparative performance feedback is beneficial to performance, especially during the start and end of an exercise bout. The results support the previously unfounded assumption that performance feedback is advantageous during exercise and highlights the importance of an athlete's support team during an event.

Epidural electrical stimulation (EES) of the spinal cord restores locomotion in animal models of spinal cord injury but is less effective in humans. Here we hypothesized that this interspecies discrepancy is due to interference between EES and proprioceptive information in humans. Computational simulations and preclinical and clinical experiments reveal that EES blocks a significant amount of proprioceptive input in humans, but not in rats. This transient deafferentation prevents modulation of reciprocal inhibitory networks involved in locomotion and reduces or abolishes the conscious perception of leg position. Consequently, continuous EES can only facilitate locomotion within a narrow range of stimulation parameters and is unable to provide meaningful locomotor improvements in humans without rehabilitation. Simulations showed that burst stimulation and spatiotemporal stimulation profiles mitigate the cancellation of proprioceptive information, enabling robust control over motor neuron activity. This demonstrates the importance of stimulation protocols that preserve proprioceptive information to facilitate walking with EES.

Objective: To study the effect of pedometer-based gait training on changing gait parameters in children with spastic hemiparetic cerebral palsy.Design: Two group randomized controlled trial with pre-treatment and posttreatment measures.Setting: Rehabilitation clinics.Subjects: Thirty spastic hemiparetic children with cerebral palsy of both sexes (13 females and 17 males) ranging in age from six to eight years old with mean age 7.05 ± 0.78 years.Interventions: Children were randomized equally to receive pedometer-based gait training or a traditional gait training programme three times per week for three successive months.Main measures: Assessment was done before and after three months of treatment application using 3D motion analysis system with six pro-reflex cameras to evaluate spatiotemporal gait parameters. The primary outcome measure was the walking velocity while the secondary outcome measures were stride length, cadence and cycle duration.Results: There was a high statistically significant improvement in favour of the study group more than the control group concerning all the measured gait parameters. T-test results showed that velocity was 0.68 ± 0.09 m/sec (0.26 ± 0.07 change score) for study group and 0.42 ± 0.11 m/sec (0.06 ± 0.05 change score) for control group (t = 6.2) (P<0.0001) while cadence was much less significant 124.3 ± 4.3 step/min (-5.8 ± 2.1 change score) for study group and 128.7 ± 4.1 step/min (-0.86 ± 0.05 change score) for control group (t = 2.8) (P<0.008).Conclusion: Pedometer-based gait training is a useful tool that can be used in improving gait parameters in children with spastic hemiparetic cerebral palsy.

Key Points Circadian rhythms are endogenous oscillations in organisms of ∼24 hours in length that exist in virtually all cells. The number of circulating leukocytes in the blood oscillates in a manner according to the phase of physical activity of the organism. Generally, the peak occurs during the resting phase. In contrast to the peak number of circulating leukocytes, leukocyte recruitment to tissues occurs preferentially during the active phase of the organism. It is mediated by the in-phase expression of cell adhesion molecules and chemokines. The response of an organism to acute inflammatory insults exhibits circadian oscillations. This is probably due to the circadian regulation of leukocyte trafficking, of the expression of pathogen-sensitive receptors and of the phagocytic activity of leukocytes. Chronic diseases exhibit circadian exacerbations in their symptoms or presentations, which has been linked to an exaggeration of the circadian expression of pro-inflammatory mediators. Circadian rhythms should be taken into account when harvesting human tissue samples and in experimental settings using preclinical animal models. In addition, chronopharmacology holds great promise to provide benefits for clinical care in the future. Here, the authors discuss recent evidence indicating that components of the immune system are under the control of circadian rhythms. The circadian oscillations of immune mediators may allow the host to anticipate threats more efficiently but may also contribute to circadian exacerbations of chronic diseases. In addition, these circadian rhythms should be considered in the design of preclinical animal models, when harvesting human tissue samples and in vaccine administration. Circadian rhythms, which have long been known to play crucial roles in physiology, are emerging as important regulators of specific immune functions. Circadian oscillations of immune mediators coincide with the activity of the immune system, possibly allowing the host to anticipate and handle microbial threats more efficiently. These oscillations may also help to promote tissue recovery and the clearance of potentially harmful cellular elements from the circulation. This Review summarizes the current knowledge of circadian rhythms in the immune system and provides an outlook on potential future implications.

Large-scale cell death is commonly observed during organismal development and in human pathologies 1 , 2 , 3 , 4 – 5 . These cell death events extend over great distances to eliminate large populations of cells, raising the question of how cell death can be coordinated in space and time. One mechanism that enables long-range signal transmission is trigger waves 6 , but how this mechanism might be used for death events in cell populations remains unclear. Here we demonstrate that ferroptosis, an iron- and lipid-peroxidation-dependent form of cell death, can propagate across human cells over long distances (≥5 mm) at constant speeds (around 5.5 μm min −1 ) through trigger waves of reactive oxygen species (ROS). Chemical and genetic perturbations indicate a primary role of ROS feedback loops (Fenton reaction, NADPH oxidase signalling and glutathione synthesis) in controlling the progression of ferroptotic trigger waves. We show that introducing ferroptotic stress through suppression of cystine uptake activates these ROS feedback loops, converting cellular redox systems from being monostable to being bistable and thereby priming cell populations to become bistable media over which ROS propagate. Furthermore, we demonstrate that ferroptosis and its propagation accompany the massive, yet spatially restricted, cell death events during muscle remodelling of the embryonic avian limb, substantiating its use as a tissue-sculpting strategy during embryogenesis. Our findings highlight the role of ferroptosis in coordinating global cell death events, providing a paradigm for investigating large-scale cell death in embryonic development and human pathologies. Ferroptosis can propagate across human cells over long distances (≥5 mm) at constant speeds (around 5.5 μm per minute) through self-regenerating waves of reactive oxygen species; such waves facilitate large-scale cell death in the developing avian limb.