Effects of atrazine on movement, metabolism and gene expression in Pelophylax nigromaculatus larvae under global warming.

Global warming and environmental pollutants both pose a threat to the behavior and physiology of animals, but research on the combined effects of the two is limited. Atrazine, a widely used herbicide, has toxic effects on organisms. In this study, the effects of environmental concentrations of atrazine exposure (100 µg/L) for seven days on the movement, metabolism and gene expression related to motility of Pelophylax nigromaculatus larvae (GS8) were investigated under global warming. The results showed that compared to the optimal growth temperature (18 °C), atrazine treatment under global warming (21 °C) significantly increased the average speed (about 11.2 times) and maximum acceleration (about 1.98 times) of P. nigromaculatus larvae, altered the relative abundance of 539 metabolites, including Formyl-5-hydroxykynurenamine, 2,4-Dihydroxybenzophenone, and FAPy-adenine, and changed the nucleotide metabolism, pyrimidine metabolism, glycerophospholipid metabolism, and purine metabolism, as well as increased the gene expression of SPLA2 (about 6.46 times) and CHK (about 3.25 times). In summary, atrazine treatment under global warming caused metabolic disorders in amphibian larvae and increased the expression of some movement-related genes in the brain, resulting in abnormally active.

Time interval between alfentanil and rocuronium administration necessary to prevent rocuronium-induced withdrawal movement.

BACKGROUND: We aimed to determine the time interval between alfentanil and rocuronium administration, at a 50% probability of preventing pain-induced withdrawal movement from rocuronium injection (TimeAR50). METHODS: A total of 64 patients scheduled for general anesthesia were enrolled in this study (33 men and 31 women). Anesthesia was induced with target-controlled infusion of propofol, at an effect-site target concentration of 3 µg/mL. Then, alfentanil 15 µg/kg was injected for 30 s. After 60 s, rocuronium 0.6 mg/kg was administered to the first patient. The Dixon's up-and-down method was used to determine the time interval for each subsequent patient (interval of 5 s). Mean arterial pressure (MAP) and heart rate (HR) were recorded at three time points: T0, pre-induction; T1, before rocuronium injection; and T2, 1 min after rocuronium injection. RESULTS: The TimeAR50 ± standard deviation (SD) was 5.6 ± 3.7 s and 21.9 ± 5.6 s in the male and female patients, respectively. Based on the probit regression, the TimeAR50 was 4.7 s (95% confidence interval [CI], 1.2-7.6 s) and 20.3 s (95% CI, 7.7-26.1 s) in the male and female patients, respectively. The TimeAR95 was 10.6 s (95% CI, 7.7-25.3 s) and 35.0 s (95% CI, 28.1-95.5 s) in the male and female patients, respectively, with significantly higher values in females than in males (P < 0.001). Compared with the T0, MAP and HR decreased significantly at T1 and T2 in both groups. CONCLUSION: The TimeAR50 required for preventing rocuronium-induced withdrawal movement were 4.7 s and 20.3 s in male and female patients, respectively. TRIAL REGISTRATION: This study was registered with the Chinese Clinical Trials Registry on April 7, 2021 (URL: http://www.chictr.org.cn . Registry number: ChiCTR2100045137 ) .

The effect of mind-body exercise on cervical spine mobility of people with neck discomfort: A systemic review and meta-analysis of randomised controlled trials.

BACKGROUND: Long-term and high-intensity work can lead to considerable discomfort in people's cervical spines. OBJECTIVES: This study sought to explore the effect of mind-body exercise intervention on the cervical spine mobility of people with neck discomfort through meta-analysis. METHODS: This study's researchers were searched a total of five research databases for data retrieval: China National Knowledge Infrastructure (from 1979), Web of Science (from 1950), PubMed (from 1965), Cochrane (from 1991), and EBSCO (from 1949) (Date of retrieval: March 10, 2021). Two authors independently searched literature records, scanned titles, abstracts, and full texts, collected data, and assessed materials for risk of bias. Stata14.0 software was used for the data analysis (Registration number: INPLASY202140126). RESULTS: Four articles were finally included with a total of 208 participants, and their age range was 18-65 years old. (1) Mind-body exercise intervention had a significant improving effect on Cervical extension, effect size of [SMD = 0.51 (95% CI 0.13 to 0.88), p <0.01; I2 = 45.2%], there was moderate heterogeneity; Mind-body exercise intervention had a significant improving effect on Cervical flexion, effect size of [SMD = 0.61 (95% CI 0.32 to 0.90), p <0.01; I2 = 5.7%], no heterogeneity; (2) Mind-body exercise intervention was no effect on the other four cervical range of motions; (3) The difference in participant's neck discomfort was the source of heterogeneity, and all results had the potential risk of publication bias. CONCLUSION: This study showed that mind-body exercise had a positive effect on the extension and flexion of people with neck discomfort. However, further research and more reliable evidence were needed to prove that mind-body exercise could be used for the treatment of neck discomfort.

The role of ambra1 in Pb-induced developmental neurotoxicity in zebrafish.

Lead is a highly toxic metal that displays developmental neurotoxicity. Ambra1 plays a crucial role in embryonic neural development. At present, the role of Ambra1 in lead-induced developmental neurotoxicity remains unknown. In this study, we investigated the mechanism of Ambra1 concerning its role in lead-induced neurotoxicity. Zebrafish (Danio rerio) embryos were exposed to 0.1, 1, or 10 µM Pb until 5 days post-fertilization, and their locomotor activity was significantly impaired by the 10 µM treatment. Meanwhile, Pb reduced the expression of ambra1a and ambra1b in the brain at 48 and 72 h post-fertilization. Overexpression of ambra1a or ambra1b reversed Pb-induced alterations in locomotor activity, and decreased the apoptotic cell numbers in the brains of Pb-treated zebrafish. Our data reveal a novel protective role of Ambra1 against Pb-induced neural damage in the developing zebrafish.

Blockade of adenosine A2A receptors inhibits Tremulous Jaw Movements as well as expression of zif-268 and GAD65 mRNAs in brain motor structures.

Tremor is one of the motor symptoms of Parkinson's disease (PD), present also in neuroleptic-induced parkinsonism. Tremulous Jaw Movements (TJMs) are suggested to be a well-validated rodent model of PD resting tremor. TJMs can be induced by typical antipsychotics and are known to be reduced by different drugs, including adenosine A2A receptor antagonists. The aim of the present study was to search for brain structures involved in the tremorolytic action of SCH58261, a selective A2A receptor antagonist, in TJMs induced by subchronic pimozide. Besides TJMs, we evaluated in the same animals the expression of zif-268 mRNA (neuronal responsiveness marker), and mRNA levels for glutamic acid decarboxylase 65-kDa isoform (GAD65) and vesicular glutamate transporters 1 and 2 (vGluT1/2) in selected brain structures, as markers of GABAergic and glutamatergic neurons, respectively. We found that SCH58261 reduced the pimozide-induced TJMs. Pimozide increased the zif-268 mRNA level in the striatum, nucleus accumbens (NAc) core, and substantia nigra pars reticulata (SNr). Additionally, it increased GAD65 mRNA in the striatum and SNr, and vGluT2 mRNA levels in the subthalamic nucleus (STN). A positive correlation between zif-268, GAD65 and vGluT2 mRNAs and TJMs was found. SCH58261 reversed the pimozide-increased zif-268 mRNA in the striatum and NAc core and GAD65 mRNA in the striatum and SNr. In contrast, SCH58261 did not influence vGluT2 mRNA in STN. The present study suggests an importance of the striato-subthalamo-nigro-thalamic circuit in neuroleptic-induced TJMs. The tremorolytic effect of A2A receptor blockade seems to involve this circuit bypassing, however, STN.

Forehead Movement Discrepancies After Botulinum Toxin Injections: A Review of Etiology, Correction, and Prevention.

BACKGROUND: Forehead rhytides are a popular target for botulinum toxin injections, but neuromodulation of the frontalis can be fraught with complications because of its anatomic complexity and integral role in brow position and expressivity. OBJECTIVE: This article explores common forehead movement discrepancies that can occur after neuromodulation of the frontalis, as well as how to correct and prevent them. METHODS: A review of the literature was conducted and combined with clinical experience to examine underlying forehead anatomy, etiology and correction of forehead movement discrepancies, and important factors to consider before injecting the frontalis with botulinum toxin. RESULTS AND CONCLUSION: Variable anatomy from person to person necessitates an individualized treatment approach to achieve the best cosmetic results and prevent the occurrence of forehead movement discrepancies.

Effects of lanthanum nitrate on behavioral disorder, neuronal damage and gene expression in different developmental stages of Caenorhabditis elegans.

Rare earth elements (REEs) are widely used in the industry, agriculture, biomedicine, aerospace, etc, and have been shown to pose toxic effects on animals, as such, studies focusing on their biomedical properties are gaining wide attention. However, environmental and population health risks of REEs are still not very clear. Also, the REEs damage to the nervous system and related molecular mechanisms needs further research. In this study, the L1 and L4 stages of the model organism Caenorhabditis elegans were used to evaluate the effects and possible neurotoxic mechanism of lanthanum(III) nitrate hexahydrate (La(NO3)3·6H2O). For the L1 and L4 stage worms, the 48-h median lethal concentrations (LC50s) of La(NO3)3·6H2O were 93.163 and 648.0 mg/L respectively. Our results show that La(NO3)3·6H2O induces growth inhibition and defects in behavior such as body length, body width, body bending frequency, head thrashing frequency and pharyngeal pumping frequency at the L1 and L4 stages in C. elegans. The L1 stage is more sensitive to the toxicity of lanthanum than the L4 stage worms. Using transgenic strains (BZ555, EG1285 and NL5901), we found that La(NO3)3·6H2O caused the loss or break of soma and dendrite neurons in L1 and L4 stages; and α-synuclein aggregation in L1 stage, indicating that Lanthanum can cause toxic damage to dopaminergic and GABAergic neurons. Mechanistically, La(NO3)3·6H2O exposure inhibited or activated the neurotransmitter transporters and receptors (glutamate, serotonin and dopamine) in C. elegans, which regulate behavior and movement functions. Furthermore, significant increase in the production of reactive oxygen species (ROS) was found in the L4 stage C. elegans exposed to La(NO3)3·6H2O. Altogether, our data show that exposure to lanthanum can cause neuronal toxic damage and behavioral defects in C. elegans, and provide basic information for understanding the neurotoxic effect mechanism and environmental health risks of rare earth elements.

Improvement effects of tanshinone on the impaired cognition and motor function in MCAO mice with ischemic penumbra.

This study aims to investigate the effects of tanshinone on improving the impaired cognition and motor function in MCAO model mice with ischemic penumbra. MWM test was carried out to evaluate the spatial learning and memory performance and the cognitive function of mice. The area of cerebral infarction was analyzed by immunohistochemistry. The TUNEL apoptosis detection kit was used to detect neuronal apoptosis. On the 25th day, the induction model group had lower body weight than the control group and the tanshinone treatment group; the induction model group had decreased walking deficiency and correct area escape times than the other two groups; while, tanshinone treatment group had higher movement distance, movement speed, periphery entry frequency, grooming rate, decreased center entry frequency, infarction area, apoptotic neuron number, latent escape time than induction model group; additionally, the control group had increased periphery and corner entry frequency, but decreased center entry frequency and latent escape time than the other two groups. Tanshinone can reduce neuronal damage in the ischemic penumbra after stroke, improve the integrity of white and gray matter, and restore connectivity in motor and cognitive functions, thereby supporting recovery from ischemic stroke.

Roflupram protects against rotenone-induced neurotoxicity and facilitates α-synuclein degradation in Parkinson's disease models.

We have previously shown that roflupram (ROF) protects against MPP+-induced neuronal damage in models of Parkinson's disease (PD). Since impaired degradation of α-synuclein (α-syn) is one of the key factors that lead to PD, here we investigated whether and how ROF affects the degradation of α-syn in rotenone (ROT)-induced PD models in vivo and in vitro. We showed that pretreatment with ROF (10 µM) significantly attenuated cell apoptosis and reduced the level of α-syn in ROT-treated SH-SY5Y cells. Furthermore, ROF significantly enhanced the lysosomal function, as evidenced by the increased levels of mature cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1) through increasing NAD+/NADH and the expression of sirtuin 1 (SIRT1). Pretreatment with an SIRT1 inhibitor selisistat (SELI, 10 µM) attenuated the neuroprotection of ROF, ROF-reduced expression of α-syn, and ROF-increased expression levels of LAMP1 and mature CTSD. Moreover, inhibition of CTSD by pepstatin A (20 µM) attenuated ROF-reduced expression of α-syn. In vivo study was conducted in mice exposed to ROT (10 mg·kg-1·d-1, i.g.) for 6 weeks; then, ROT-treated mice received ROF (0.5, 1, or 2 mg·kg-1·d-1; i.g.) for four weeks. ROF significantly ameliorated motor deficits, which was accompanied by increased expression levels of tyrosine hydroxylase, SIRT1, mature CTSD, and LAMP1, and a reduced level of α-syn in the substantia nigra pars compacta. Taken together, these results demonstrate that ROF exerts a neuroprotective action and reduces the α-syn level in PD models. The mechanisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.

TCMacro: A Simple and Robust ImageJ-Based Method for Automated Measurement of Tail Coiling Activity in Zebrafish.

Tail coiling is a reflection response in fish embryos that can be used as a model for neurotoxic analysis. The previous method to analyze fish tail coiling is largely based on third-party software. In this study, we aim to develop a simple and cost-effective method called TCMacro by using ImageJ macro to reduce the operational complexity. The basic principle of the current method is based on the dynamic change of pixel intensity in the region of interest (ROI). When the fish tail is moving, the average intensity is increasing. In time when the fish freeze, the peak of mean intensity is maintaining at a relatively low level. By using the optimized macro settings and excel VBA scripts, all the tail coiling measurement processes can be archived with few operation steps with high precision. Three major endpoints of tail coiling counts, tail coiling duration and tail coiling intervals can be obtained in batch. To validate this established method, we tested the potential neurotoxic activity of Tricaine (methanesulfonate, MS-222) and psychoactive compound of caffeine. Zebrafish embryos after Tricaine exposure displayed significantly less tail coiling activity in a dose-dependent manner, and were comparable to manual counting through the Wilcoxon test and Pearson correlation double validation. Zebrafish embryos after caffeine exposure displayed significantly high tail coiling activity. In conclusion, the TCMacro method presented in this study provides a simple and robust method that is able to measure the relative tail coiling activities in zebrafish embryos in a high-throughput manner.

Lumbriculus variegatus: A novel organism for in vivo pharmacology education.

Pharmacology graduates require an understanding of both in vitro and in vivo drug responses but there has been a decline in animal use in pharmacology education over the last 30 years. To address this, we present the novel invertebrate model, Lumbriculus variegatus, for in vivo testing of drugs in a teaching environment. We have developed two novel behavioral assays: the stereotypical movement assay, which measures the effect of drugs on the ability of L. variegatus to perform stereotypical movements following tactile stimulation, and the free locomotion assay, which measures drug effects on unstimulated movement. We report the effects of compounds with diverse pharmacodynamic properties on L. variegatus using these assays. The ryanodine receptor antagonist, dantrolene, altered the unstimulated movement of L. variegatus at 5 µM, whereas stimulated movement was inhibited at ≥25 µM. Lidocaine, a voltage-gated sodium channel blocker, and quinine, a nonselective sodium and potassium channel blocker, reduced both stimulated and unstimulated L. variegatus movement at ≥0.5 mM. Inhibitory effects of quinine persisted for up to 24 h after drug removal, whereas lidocaine effects were reduced 10 min after drug removal. Herein, we provide proof-of-concept utilization of L. variegatus as an organism for use in in vivo pharmacology education but without regulatory constraints or the need for specialized equipment and training.

The Role of the Medial Septum-Associated Networks in Controlling Locomotion and Motivation to Move.

The Medial Septum and diagonal Band of Broca (MSDB) was initially studied for its role in locomotion. However, the last several decades were focussed on its intriguing function in theta rhythm generation. Early studies relied on electrical stimulation, lesions and pharmacological manipulation, and reported an inconclusive picture regarding the role of the MSDB circuits. Recent studies using more specific methodologies have started to elucidate the differential role of the MSDB's specific cell populations in controlling both theta rhythm and behaviour. In particular, a novel theory is emerging showing that different MSDB's cell populations project to different brain regions and control distinct aspects of behaviour. While the majority of these behaviours involve movement, increasing evidence suggests that MSDB-related networks govern the motivational aspect of actions, rather than locomotion per se. Here, we review the literature that links MSDB, theta activity, and locomotion and propose open questions, future directions, and methods that could be employed to elucidate the diverse roles of the MSDB-associated networks.

Antinociceptive Efficacy of the µ-Opioid/Nociceptin Peptide-Based Hybrid KGNOP1 in Inflammatory Pain without Rewarding Effects in Mice: An Experimental Assessment and Molecular Docking.

Opioids are the most effective analgesics, with most clinically available opioids being agonists to the µ-opioid receptor (MOR). The MOR is also responsible for their unwanted effects, including reward and opioid misuse leading to the current public health crisis. The imperative need for safer, non-addictive pain therapies drives the search for novel leads and new treatment strategies. In this study, the recently discovered MOR/nociceptin (NOP) receptor peptide hybrid KGNOP1 (H-Dmt-D-Arg-Aba-ß-Ala-Arg-Tyr-Tyr-Arg-Ile-Lys-NH2) was evaluated following subcutaneous administration in mouse models of acute (formalin test) and chronic inflammatory pain (Complete Freund's adjuvant-induced paw hyperalgesia), liabilities of spontaneous locomotion, conditioned place preference, and the withdrawal syndrome. KGNOP1 demonstrated dose-dependent antinociceptive effects in the formalin test, and efficacy in attenuating thermal hyperalgesia with prolonged duration of action. Antinociceptive effects of KGNOP1 were reversed by naltrexone and SB-612111, indicating the involvement of both MOR and NOP receptor agonism. In comparison with morphine, KGNOP1 was more potent and effective in mouse models of inflammatory pain. Unlike morphine, KGNOP1 displayed reduced detrimental liabilities, as no locomotor impairment nor rewarding and withdrawal effects were observed. Docking of KGNOP1 to the MOR and NOP receptors and subsequent 3D interaction pattern analyses provided valuable insights into its binding mode. The mixed MOR/NOP receptor peptide KGNOP1 holds promise in the effort to develop new analgesics for the treatment of various pain states with fewer MOR-mediated side effects, particularly abuse and dependence liabilities.

Distinct patterns of dyskinetic and dystonic features following D1 or D2 receptor stimulation in a mouse model of parkinsonism.

L-DOPA-induced dyskinesia (LID) is a significant complication of dopamine replacement therapy in Parkinson's disease (PD), and the specific role of different dopamine receptors in this disorder is poorly understood. We set out to compare patterns of dyskinetic behaviours induced by the systemic administration of L-DOPA and D1 or D2 receptor (D1R, D2R) agonists in mice with unilateral 6-hydroxydopamine lesions. Mice were divided in four groups to receive increasing doses of L-DOPA, a D1R agonist (SKF38393), a D2/3 agonist (quinpirole), or a selective D2R agonist (sumanirole). Axial, limb and orofacial abnormal involuntary movements (AIMs) were rated using a well-established method, while dystonic features were quantified in different body segments using a new rating scale. Measures of abnormal limb and trunk posturing were extracted from high-speed videos using a software for markerless pose estimation (DeepLabCut). While L-DOPA induced the full spectrum of dyskinesias already described in this mouse model, SKF38393 induced mostly orofacial and limb AIMs. By contrast, both of the D2-class agonists (quinpirole, sumanirole) induced predominantly axial AIMs. Dystonia ratings revealed that these agonists elicited marked dystonic features in trunk/neck, forelimbs, and hindlimbs, which were overall more severe in sumanirole-treated mice. Accordingly, sumanirole induced pronounced axial bending and hindlimb divergence in the automated video analysis. In animals treated with SKF38393, the only appreciable dystonic-like reaction consisted in sustained tail dorsiflexion and stiffness. We next compared the effects of D1R or D2R selective antagonists in L-DOPA-treated mice, where only the D2R antagonist had a significant effect on dystonic features. Taken together these results indicate that the dystonic components of LID are predominantly mediated by the D2R.

Analyzing the Effect of Strigolactones on the Motility Behavior of Rhizobia.

In the Rhizobium-legume symbiosis, strigolactones (SLs) promote root nodule formation; however, the exact mechanism underlying this positive effect remains unknown. The recent finding that an SL receptor legume mutant shows a wild-type nodulation phenotype suggests that SLs influence the symbiosis by acting on the bacterial partner. In agreement with this, the application of the synthetic SL analog GR24 on the alfalfa symbiont Sinorhizobium (Ensifer) meliloti has been shown to stimulate swarming, a specialized bacterial surface motility, which could influence infection of legumes by Rhizobia. Surface motility assays for many bacteria, and particularly for Rhizobia, are challenging. The establishment of protocols to study bacterial surface motility is key to decipher the role of SLs as rhizosphere cues for rhizobacteria. In this chapter, we describe a set of protocols implemented to study the different types of motility exhibited by S. meliloti.

Sublethal concentration of insecticide amplifies interference competition in a tortrix moth.

Insecticides are extensively used worldwide to kill insect pests, yet organisms are most often exposed to insecticides at sublethal concentrations. Our understanding of sublethal effects on life histories is needed to predict the impact of insecticides on population dynamics and improve insecticide use and pest control. Sublethal concentrations can impact life histories directly and indirectly through changes in the intraspecific competition. Yet, few studies have evaluated the sublethal effects on intraspecific competition and these do not disentangle the insecticide effects on interference competition versus exploitative competition. As such, sublethal effects on the relative contribution of each pathways in shaping life histories are largely unknown, despite the fact that this can impact population dynamics. In this study, we focused on the neurotoxic insecticide spinosad and investigated its sublethal effects on interference among the aggressive larvae of the tortrix moth Adoxophyes honmai and the consequences for life histories. We conducted a set of paired experiments to disentangle the insecticide effects on interference from the ones on exploitation. Spinosad was found to amplify interference with most effects on mortality which lets us suggest that the insecticide likely increases the level of aggressive interactions resulting in more conspecific killings (e.g. cannibalism). Spinosad exposure was found to impair movement ability. Less movements may increase susceptibility to conspecific attacks and or increase aggresivity for better defence, two plausible mechanisms that could explain the increase in interference with insecticide. This study shows that insecticide at sublethal concentration can impact life histories by altering the strength of interference competition. Many organisms (pest and non-target species) compete through interference and theory predicts that a change in interference can substantially change dynamics. Our finding therefore reveals the importance of assessing the effect of insecticides on the mechanisms of competition when predicting their impact on populations.

Escherichia coli Swimming back Toward Stiffer Polyetheylene Glycol Coatings, Increasing Contact in Flow.

Bacterial swimming in flow near surfaces is critical to the spread of infection and device colonization. Understanding how material properties affect flagella- and motility-dependent bacteria-surface interactions is a first step in designing new medical devices that mitigate the risk of infection. We report that, on biomaterial coatings such as polyethylene glycol (PEG) hydrogels and end-tethered layers that prevent adhesive bacteria accumulation, the coating mechanics and hydration control the near-surface travel and dynamic surface contact of E. coli cells in gentle shear flow (order 10 s-1). Along relatively stiff (order 1 MPa) PEG hydrogels or end-tethered layers of PEG chains of similar polymer correlation length, run-and-tumble E. coli travel nanometrically close to the coating's surface in the flow direction in distinguishable runs or "engagements" that persist for several seconds, after which cells leave the interface. The duration of these engagements was greater along stiff hydrogels and end-tethered layers compared with softer, more-hydrated hydrogels. Swimming cells that left stiff hydrogels or end-tethered layers proceeded out to distances of a few microns and then returned to engage the surface again and again, while cells engaging the soft hydrogel tended not to return after leaving. As a result of differences in the duration of engagements and tendency to return to stiff hydrogel and end-tethered layers, swimming E. coli experienced 3 times the integrated dynamic surface contact with stiff coatings compared with softer hydrogels. The striking similarity of swimming behaviors near 16-nm-thick end-tethered layers and 100-µm-thick stiff hydrogels argues that only the outermost several nanometers of a highly hydrated coating influence cell travel. The range of material stiffnesses, cell-surface distance during travel, and time scales of travel compared with run-and-tumble time scales suggests the influence of the coating derives from its interactions with flagella and its potential to alter flagellar bundling. Given that restriction of flagellar rotation is known to trigger increased virulence, bacteria influenced by surfaces in one region may become predisposed to form a biofilm downstream.

Dyskinesia estimation during activities of daily living using wearable motion sensors and deep recurrent networks.

Levodopa-induced dyskinesias are abnormal involuntary movements experienced by the majority of persons with Parkinson's disease (PwP) at some point over the course of the disease. Choreiform as the most common phenomenology of levodopa-induced dyskinesias can be managed by adjusting the dose/frequency of PD medication(s) based on a PwP's motor fluctuations over a typical day. We developed a sensor-based assessment system to provide such information. We used movement data collected from the upper and lower extremities of 15 PwPs along with a deep recurrent model to estimate dyskinesia severity as they perform different activities of daily living (ADL). Subjects performed a variety of ADLs during a 4-h period while their dyskinesia severity was rated by the movement disorder experts. The estimated dyskinesia severity scores from our model correlated highly with the expert-rated scores (r = 0.87 (p < 0.001)), which was higher than the performance of linear regression that is commonly used for dyskinesia estimation (r = 0.81 (p < 0.001)). Our model provided consistent performance at different ADLs with minimum r = 0.70 (during walking) to maximum r = 0.84 (drinking) in comparison to linear regression with r = 0.00 (walking) to r = 0.76 (cutting food). These findings suggest that when our model is applied to at-home sensor data, it can provide an accurate picture of changes of dyskinesia severity facilitating effective medication adjustments.

Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect.

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D2, D3, 5-HT1A, 5-HT2A and H3, a moderate affinity for 5-HT6, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT2C, adrenergic α1 and H1). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.

Shaping the gradients driving phoretic micro-swimmers: influence of swimming speed, budget of carbonic acid and environment.

pH gradient-driven modular micro-swimmers are investigated as a model for a large variety of quasi-two-dimensional chemi-phoretic self-propelled entities. Using three-channel micro-photometry, we obtain a precise large field mapping of pH at a spatial resolution of a few microns and a pH resolution of [Formula: see text] units for swimmers of different velocities propelling on two differently charged substrates. We model our results in terms of solutions of the three-dimensional advection-diffusion equation for a 1:1 electrolyte, i.e. carbonic acid, which is produced by ion exchange and consumed by equilibration with dissolved [Formula: see text]. We demonstrate the dependence of gradient shape and steepness on swimmer speed, diffusivity of chemicals, as well as the fuel budget. Moreover, we experimentally observe a subtle, but significant feedback of the swimmer's immediate environment in terms of a substrate charge-mediated solvent convection. We discuss our findings in view of different recent results from other micro-fluidic or active matter investigations. We anticipate that they are relevant for quantitative modelling and targeted applications of diffusio-phoretic flows in general and artificial micro-swimmers in particular.