Impaired value-based decision-making in Parkinson's disease apathy.

Apathy is a common and disabling complication of Parkinson's disease characterized by reduced goal-directed behaviour. Several studies have reported dysfunction within prefrontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision-making. Specifically, these neuromodulators have overlapping contributions to encoding the value of decisions, and influence whether to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal. Building upon this work, we hypothesized that apathy in Parkinson's disease should be associated with an impairment in value-based learning. Using a four-armed restless bandit reinforcement learning task, we studied decision-making in 75 volunteers; 53 patients with Parkinson's disease, with and without clinical apathy, and 22 age-matched healthy control subjects. Patients with apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient's apathy severity measured using the Lille Apathy Rating Scale (R = -0.46, P < 0.001). Computational modelling of the patient's choices confirmed the apathy group made decisions that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration, which also correlated with apathy scores (R = -0.5, P < 0.001). We went on to acquire functional MRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age-matched controls performing the Restless Bandit Task. Analysis of the functional MRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson's disease, which was more marked in apathy, but not predictive of their individual apathy severity. Using a model-based categorization of choice type, decisions to explore lower value bandits in the apathy group activated prefrontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson's patients without apathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula. Given that task performance in patients without apathy was no different to the age-matched control subjects, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson's disease.

Transferrin-Bearing, Zein-Based Hybrid Lipid Nanoparticles for Drug and Gene Delivery to Prostate Cancer Cells.

Gene therapy holds great promise for treating prostate cancer unresponsive to conventional therapies. However, the lack of delivery systems that can transport therapeutic DNA and drugs while targeting tumors without harming healthy tissues presents a significant challenge. This study aimed to explore the potential of novel hybrid lipid nanoparticles, composed of biocompatible zein and conjugated to the cancer-targeting ligand transferrin. These nanoparticles were designed to entrap the anti-cancer drug docetaxel and carry plasmid DNA, with the objective of improving the delivery of therapeutic payloads to prostate cancer cells, thereby enhancing their anti-proliferative efficacy and gene expression levels. These transferrin-bearing, zein-based hybrid lipid nanoparticles efficiently entrapped docetaxel, leading to increased uptake by PC-3 and LNCaP cancer cells and significantly enhancing anti-proliferative efficacy at docetaxel concentrations exceeding 1 µg/mL. Furthermore, they demonstrated proficient DNA condensation, exceeding 80% at polymer-DNA weight ratios of 1500:1 and 2000:1. This resulted in increased gene expression across all tested cell lines, with the highest transfection levels up to 11-fold higher than those observed with controls, in LNCaP cells. These novel transferrin-bearing, zein-based hybrid lipid nanoparticles therefore exhibit promising potential as drug and gene delivery systems for prostate cancer therapy.

Depression, anxiety, stress symptoms and their determinants among secondary students with vision impairment in rural Northwestern China during the COVID-19 pandemic.

Objective: The measures implemented to control the spread of Coronavirus disease 2019 (COVID-19) could affect children's mental and vision health. Youth particularly from minority and socioeconomically disadvantaged backgrounds were more likely to be impacted by these measures. This study aimed to examine the mental health of children with vision impairment and associated factors in North-western China during the COVID-19 pandemic. Methods: A cross-sectional study was conducted among 2,036 secondary school children living in Ningxia Hui Autonomous Region. Participants completed a survey on sociodemographic and lifestyle information and answered the Chinese version of the 21-item Depression Anxiety Stress Scales (DASS-21) questionnaire. Presenting visual acuity was measured by a trained enumerator. Multivariate logistic regression analysis was used to identify potential risk factors for mental health problems. Results: Responses from 1,992 (97.8%) children were included in the analysis after excluding those with incomplete mental health outcome data. The prevalence of depression, anxiety and stress symptoms within the dataset were 28.9, 46.4, and 22.3%, respectively. The distribution of children with different stress levels differed significantly between those with and without vision impairment (p = 0.03). Multivariable logistic regression analyses revealed that depression symptoms decreased with higher parental education (OR, 0.76, 95% confidence intervals (CI):0.63-0.96), longer sleep duration (OR, 0.90, 95% CI: 0.81-0.97) and longer study time (OR, 0.82, 95% CI: 0.74-0.91), whereas they increased with higher recreational screen time (OR, 1.19, 95% CI: 1.08-1.32). Anxiety symptoms decreased with higher parental education (OR, 0.80, 95% CI: 0.66-0.96) and increased with higher recreational screen time (OR, 1.15, 95% CI: 1.04-1.27) and being a left-behind child (OR, 1.26, 95% CI: 1.04-1.54). In addition, stress symptoms decreased with longer sleep duration (OR, 0.92, 95%CI: 0.85-0.99) and increased with higher number of siblings (OR, 1.10, 95% CI: 1.01-1.19), higher recreational screen time (OR, 1.15, 95% CI: 1.04-1.28) and older age (OR,1.12, 95% CI: 1.004-1.24). Conclusion: A considerable proportion of our sample experienced mental health problems during the pandemic. Healthcare planners in China should consider interventions such as reducing recreational screen time, ensuring sufficient sleep, and timely detection of mental health symptoms among socioeconomically disadvantaged groups.

Preparation of Zein-Based Nanoparticles: Nanoprecipitation versus Microfluidic-Assisted Manufacture, Effects of PEGylation on Nanoparticle Characteristics and Cellular Uptake by Melanoma Cells.

Background: The manufacture of nanoparticles using manual methods is hampered by its challenging scale-up and poor reproducibility. To overcome this issue, the production of zein nanoparticles entrapping a lipophilic drug model, coumarin-6, by using a microfluidic system was assessed in this study. The influence of PEG density and chain length on zein nanoparticle characteristics, as well as their uptake efficacy in melanoma cancer cells, was also evaluated. Methods: Zein nanoparticles were prepared by both manual and microfluidic approaches to allow comparison between the two processes. PEGylated zein nanoparticles with various PEG densities and chain lengths were produced by nanoprecipitation and characterized. Their cellular uptake was evaluated on B16F10 melanoma cancer cells in vitro. Results: Zein nanoparticles have successfully been produced by both manual and microfluidic approaches. Parameters such as total flow rate and flow rate ratio of the aqueous and organic phases in microfluidic process, as well as the method preparation and aqueous to organic phase volume ratio during nanoprecipitation, have been shown to strongly influence the characteristics of the resulting nanoparticles. Continuous microfluidics led to the production of nanoparticles with low yield and drug entrapment, unlike nanoprecipitation, which resulted in zein nanoparticles with an appropriate size and an optimal drug entrapment efficiency of 64%. The surface modification of the nanoparticles produced by nanoprecipitation, with lower PEG density and shorter PEG chain length made mPEG5K-zein (0.5:1) the most favorable formulation in our study, resulting in enhanced stability and higher coumarin-6 uptake by melanoma cancer cells. Conclusion: mPEG5K-zein (0.5:1) nanoparticles prepared by nanoprecipitation were the most promising formulation in our study, exhibiting increased stability and enhancing coumarin-6 uptake by melanoma cancer cells.