Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer

Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4’s hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

Memorisation and implicit perceptual learning are enhanced for preferred musical intervals and chords

Is it true that we learn better what we like? Current neuroaesthetic and neurocomputational models of aesthetic appreciation postulate the existence of a correlation between aesthetic appreciation and learning. However, even though aesthetic appreciation has been associated with attentional enhancements, systematic evidence demonstrating its influence on learning processes is still lacking. Here, in two experiments, we investigated the relationship between aesthetic preferences for consonance versus dissonance and the memorisation of musical intervals and chords. In Experiment 1, 60 participants were first asked to memorise and evaluate arpeggiated triad chords (memorisation phase), then, following a distraction task, chords’ memorisation accuracy was measured (recognition phase). Memorisation resulted to be significantly enhanced for subjectively preferred as compared with non-preferred chords. To explore the possible neural mechanisms underlying these results, we performed an EEG study, directed to investigate implicit perceptual learning dynamics (Experiment 2). Through an auditory mismatch detection paradigm, electrophysiological responses to standard/deviant intervals were recorded, while participants were asked to evaluate the beauty of the intervals. We found a significant trial-by-trial correlation between subjective aesthetic judgements and single trial amplitude fluctuations of the ERP attention-related N1 component. Moreover, implicit perceptual learning, expressed by larger mismatch detection responses, was enhanced for more appreciated intervals. Altogether, our results showed the existence of a relationship between aesthetic appreciation and implicit learning dynamics as well as higher-order learning processes, such as memorisation. This finding might suggest possible future applications in different research domains such as teaching and rehabilitation of memory and attentional deficits.

Effectiveness of massage therapy on fatigue and pain in patients with multiple sclerosis: A systematic review and meta-analysis

Background Fatigue and pain are prevalent symptoms of multiple sclerosis (MS) and frequent complaint in MS patients, which reduce their quality of life. This study aimed to assess the effect of massage therapy on pain and fatigue in MS Patients. Method The original and Persian databases were searched included PubMed, web of science, embase, ovid, scopus, and the Cochrane Library, SID, and Iranedex from inception to November 2020. Studies that reported the effect of massage on fatigue and pain were included. Two investigators extracted all relevant data, independently. For deriving analysis, mean difference (MD) and standardized mean difference (SMD) were used. Result Ten studies were eligible acoording criteria. The effect of massage on fatigue showed significant improvement (−1.62; 95% CL −2.40, −0.83; p < .00001), also results of the systematic review showed a significant reduction in pain severity. Conclusion Massage as a complementary and non-pharmacological therapy might have been associated with alleviating fatigue and pain in M.S. patients. Based on the current study, massage intervention for MS patients could have possible clinical value for palliating pain and fatigue and improving quality of life; however, this matter needs further and more significant trial studies.

Noninvasive neuromagnetic single-trial analysis of human neocortical population spikes

Neuronal spiking is commonly recorded by invasive sharp microelectrodes, whereas standard noninvasive macroapproaches (e.g., electroencephalography [EEG] and magnetoencephalography [MEG]) predominantly represent mass postsynaptic potentials. A notable exception are low-amplitude high-frequency (∼600 Hz) somatosensory EEG/MEG responses that can represent population spikes when averaged over hundreds of trials to raise the signal-to-noise ratio. Here, a recent leap in MEG technology—featuring a factor 10 reduction in white noise level compared with standard systems—is leveraged to establish an effective single-trial portrayal of evoked cortical population spike bursts in healthy human subjects. This time-resolved approach proved instrumental in revealing a significant trial-to-trial variability of burst amplitudes as well as time-correlated (∼10 s) fluctuations of burst response latencies. Thus, ultralow-noise MEG enables noninvasive single-trial analyses of human cortical population spikes concurrent with low-frequency mass postsynaptic activity and thereby could comprehensively characterize cortical processing, potentially also in diseases not amenable to invasive microelectrode recordings.

Acute effects of plyometric warm-up with different box heights on sprint and agility performance in national-level field hockey athletes

BACKGROUND: Postactivation potentiation (PAP) is an acute and temporary enhancement of muscular performance resulting from previous muscular contraction. Extensive research exists examining the PAP effect after a heavy resistance exercise but there is limited research examining the PAP effect after a plyometric stimulus to the pre-competition practices (e.g., warm-up) of well-trained athletes. OBJECTIVE: The purpose of this study was to investigate the acute effects of plyometric warm-up with different box heights on sprint and agility performance in national-level field hockey athletes at recovery time of immediately, 5 minutes and 10 minutes. METHODS: In a randomized crossover design, ten male national-level field hockey athletes performed 30-m sprint (with 10-m split) and agility test at baseline, immediately (∼ 15 sec), 5 minutes and 10 minutes after a high-intensity plyometric warm-up (HIPW), a low-intensity plyometric warm-up (LIPW) and a control trial (CT). RESULTS: Mean 10-m sprint times, 30-m sprint times and agility times were similar between trials at baseline (p> 0.05). Significant trial x time interactions (p⩽ 0.05) were observed for 10-m sprint time, 30-m sprint time and agility time. 10-m sprint times were significantly decreased after HIPW at all time-points and LIPW at immediately time-point, relative to baseline (p⩽ 0.05). HIPW 10-m sprint times were faster at all time-points and LIPW sprint time was faster at 10 minutes when compared with CT (p⩽ 0.05). Thirty-meter sprint times were significantly decreased after HIPW and LIPW at all time-points, relative to baseline (p⩽ 0.05). HIPW 30-m sprint times at all time-points and LIPW at both the 5 and 10 minute time-points were faster than CT (p⩽ 0.05). Agility times were significantly decreased after HIPW at all time-points and LIPW at both the immediately and 5 minutes time-points, relative to baseline (p⩽ 0.05). HIPW and LIPW agility times were faster than CT, at all time-points (p⩽ 0.05). CONCLUSIONS: Both HIPW and LIPW may be effective in enhancing the pre-training or pre-competition practices in off-season for national-level field hockey athletes. However, the individualization of HIPW is highly recommended in order to maintain PAP effects for 10-m sprint times, 30-m sprint times and agility times throughout the 10 minutes when compared to LIPW.

Understanding the Role of Linguistic Complexity in Famous Trial Outcomes

Famous trials not only generate immense popularity and intrigue, they also have the power to change history. Surprisingly, little research examines the use of complex language during these culturally-significant trial outcomes. In the present study, we helped fill in this gap by evaluating the relationship between attorneys’ use of integratively complex language and trial outcomes. Using the well-validated Automated Integrative Complexity scoring system, we analyzed the complexity of language in the opening and closing statements of famous trials. We found that higher levels of integrative complexity led to a significant increase in winning outcomes, but only for the prosecution. Further, this effect was driven by elaborative forms of complexity and not dialectical forms of complexity. Taken together, these results fill a large gap in our understanding of how language might influence the outcomes of culturally-significant legal proceedings.

Water immersion methods do not alter muscle damage and inflammation biomarkers after high-intensity sprinting and jumping exercise

Purpose The aim of this study was to compare the efficacy of three water immersion interventions performed after active recovery compared to active recovery only on the resolution of inflammation and markers of muscle damage post-exercise. Methods Nine physically active men (n = 9; age 20‒35 years) performed an intensive loading protocol, including maximal jumps and sprinting on four occasions. After each trial, one of three recovery interventions (10 min duration) was used in a random order: cold-water immersion (CWI, 10 °C), thermoneutral water immersion (TWI, 24 °C), contrast water therapy (CWT, alternately 10 °C and 38 °C). All of these methods were performed after an active recovery (10 min bicycle ergometer), and were compared to active recovery only (ACT). 5 min, 1, 24, 48, and 96 h after exercise bouts, immune response and recovery were assessed through leukocyte subsets, monocyte chemoattractant protein-1, myoglobin and high-sensitivity C-reactive protein concentrations. Results Significant changes in all blood markers occurred at post-loading (p < 0.05), but there were no significant differences observed in the recovery between methods. However, retrospective analysis revealed significant trial-order effects for myoglobin and neutrophils (p < 0.01). Only lymphocytes displayed satisfactory reliability in the exercise response, with intraclass correlation coefficient > 0.5. Conclusions The recovery methods did not affect the resolution of inflammatory and immune responses after high-intensity sprinting and jumping exercise. It is notable that the biomarker responses were variable within individuals. Thus, the lack of differences between recovery methods may have been influenced by the reliability of exercise-induced biomarker responses.

A single injection of vitamin D3 improves insulin sensitivity and β-cell function but not muscle damage or the inflammatory and cardiovascular responses to an acute bout of resistance exercise in vitamin D-deficient resistance-trained males

Vitamin D deficiency is now a recognised problem affecting multiple physiological functions. The aim of the present study was to evaluate the effect of a single dose of vitamin D3 injection on the inflammatory, muscular damage, metabolic and cardiovascular responses to an acute bout of resistance exercise (RE) in vitamin D-deficient resistance-trained males. Blood samples from fourteen vitamin D-deficient resistance-trained males were obtained during two separate trials: lower vitamin D (LVD) and higher vitamin D (HVD, after vitamin D3 injection). Metabolic, inflammatory, muscle damage and cardiovascular markers were evaluated at baseline, immediately and 1 h after RE. There were significant trial-by-time interactions for insulin and homeostatic model assessment of insulin resistance (HOMA-IR) which significantly (P < 0·05) declined for 1 h after RE in the HVD trial compared with the LVD trial. Homeostasis model assessment of β-cell function (HOMA-β) declines at 1 h post-RE in the HVD trial. There was also a time effect for blood sugar which significantly (P < 0·05) decreased and for creatine kinase, lactate dehydrogenase and IL-6 which increased significantly 1 h post-RE in both trials. There were no significant changes in other inflammatory and cardiovascular markers following both trials. A single injection of vitamin D3 improved insulin resistance and β-cell function following RE in previously vitamin D-deficient resistance-trained males. Conversely, the injection did not change muscle damage and the inflammatory response to acute RE. Intramuscular vitamin D replacement may have key implications for the promotion of glucose metabolism and lowering the risk of diabetes in vitamin D-deficient individuals.

Neuronal thresholds and correlations in the peripheral vestibular system during rotation discrimination

ABSTRACTNeuronal and behavioral thresholds were measured simultaneously as trained male macaques performed a yaw rotation discrimination task in darkness. When corrected to account for variations in neuronal direction preferences, neurons in the vestibular nuclei and semicircular canal afferents had discrimination thresholds that were only two-fold smaller than behavioral thresholds. There was no significant trial-by-trial correlation between neuronal activity and perceptual decisions, despite the presence of significant pair-wise noise correlations. The lack of choice-related activity during rotation discrimination contrasts with the robust correlations observed previously between brainstem neurons and choices during translation perception. These results suggest task-dependent differences in subcortical processing of vestibular signals, as well as how signals related to perceptual decisions may propagate back to early stages of sensory processing.SIGNIFICANCE STATEMENTThis is the first ever simultaneous recordings of neural and behavioral thresholds during rotation discrimination. Its importance lies on the fact that the vestibular system provides an excellent model to probe origins of perception because directional selectivity signals are similar at many levels of processing, from afferents to cortex. The findings of similar neuronal and behavioral discrimination thresholds, significant inter-neuronal correlations, but lack of correlations between behavior and neuronal activity of both afferents and central brainstem neurons are intriguing and suggest task-dependent organization of early sensory areas.

Prior Exercise Does Not Reduce Postprandial Lipemia Following a Mixed Glucose Meal When Compared with a Mixed Fructose Meal

This study examined the effect of prior exercise on postprandial lipemia (PPL) concentration following a mixed meal (MM) made with either glucose or fructose. Sedentary women completed four trials in random order: 1) Rest-Fructose: RF, 2) Rest-Glucose: RG, 3) Exercise-Fructose: EF, 4) Exercise-Glucose: EG. Exercise expended 500 kcal while walking at 70%VO2max. Rest was 60 min of sitting. The morning after each trial, a fasting (12 hr) blood sample was collected followed by consumption of the MM. The MM was blended with whole milk and ice cream plus a glucose or fructose powder. Glucose and fructose powder accounted for 30% of the total kcal within the MM. Blood was collected periodically for 6 hr post-MM and analyzed for PPL. Magnitude of PPL over the 6 hr postmeal was quantified using the triglyceride incremental area under the curve (TG AUCI). Significant differences (p < .05) between trials were determined using repeated-measures ANOVA and Bonferroni post hoc test. There was no significant difference in the TG AUCI between the four trials (p > .05). A significant trial by time interaction for TG concentration was reported (p < .05). Despite lack of change in the AUCI with prior exercise, the lower TG concentration at multiple time points in the EG trial does indicate that prior exercise has some desirable effect on PPL. This study suggests that replacing fructose with glucose sugars and incorporating exercise may minimize PPL following a mixed meal but exercise will need to elicit greater energy expenditure.