Parkinson's Disease Is Associated with Impaired Gut-Blood Barrier for Short-Chain Fatty Acids.

BACKGROUND: Short-chain fatty acids (SCFAs) produced by gut microbiota are reduced in feces but paradoxically increased in plasma of patients with Parkinson's disease (PD), which may stem from intestinal wall leakage. Gut function should be taken into consideration when conducting microbial-metabolite research. OBJECTIVE: The objective was to investigate synchronous changes of SCFAs in feces and plasma of patients with PD, taking constipation as a confounder to better disentangle the SCFA metabolism exclusively associated with PD. METHODS: The concentrations of fecal and plasma SCFAs in 33 healthy control subjects and 95 patients with PD were measured using liquid and gas chromatography mass spectrometry, respectively. Patients with PD were divided into patients with PD without constipation (n = 35) and patients with PD with constipation (n = 60). Gut-blood barrier (GBB) permeability was assessed by plasma/fecal ratio of SCFA concentrations and fecal α1-antitrypsin concentration. RESULTS: Patients with PD displayed decreased concentrations of fecal acetic, propionic, and butyric acid and increased concentrations of plasma acetic and propionic acid. Fecal acetic, isobutyric, and isovaleric acid were lower and plasma acetic and propionic acid were higher in patients with PD with constipation than in patients with PD without constipation. Constipation aggravated GBB permeability in patients with PD. Combined fecal and plasma SCFAs could discriminate patients with PD from healthy control subjects. Fecal SCFAs, except propionic acid, were negatively correlated with disease severity, while plasma acetic, propionic, and valeric acid showed a positive correlation. CONCLUSIONS: Our study showed alterations of fecal and plasma SCFAs in patients with PD that were associated with an impaired GBB and might be aggravated by constipation. © 2022 International Parkinson and Movement Disorder Society.

Exploring impacts of COVID-19 on city-wide taxi and ride-sourcing markets: Evidence from Ningbo, China.

The outbreak of the COVID-19 epidemic has brought enormous impacts and changes to human mobility. To better understand and quantify the impacts of COVID-19 on city-wide ride-sourcing and taxi markets, we present exploratory evidence on the factors such as coronavirus cases related attributes, policy-related attributes, operational status of transportation, socio-economic status related variables, demographics related variables, and other factors. Based on 5-month real-world ride-sourcing and taxi datasets in Ningbo, China, including 37-million trips, we study the temporal variations of drivers' working characteristics and productivity of ride-sourcing and taxi fleets. The spatial heterogeneity of the impacts of COVID-19 on taxi and ride-sourcing trips is demonstrated in terms of traffic analysis zones (TAZs). Regression models are established to examine the impacts of a variety of explanatory variables, including COVID-19 related variables, on the district-level productivity of taxi and ride-sourcing services. The results show that the accumulated cured coronavirus cases, policy of closed management, operational status of mass transit, and average fee spent on transportation per capita significantly impact the productivity of the taxi and ride-sourcing fleets. This paper empirically reveals the influence of the epidemic on ride-sourcing and taxi markets and the temporal and spatial variations. The findings can support decision-making to restore the ride-sourcing and taxi markets and benefit other COVID-19 related research efforts.

LncRNA HOXA-AS2 regulates microglial polarization via recruitment of PRC2 and epigenetic modification of PGC-1α expression.

BACKGROUND: Microglia-mediated neuroinflammation plays an important role in Parkinson's disease (PD), and it exerts proinflammatory or anti-inflammatory effects depending on the M1/M2 polarization phenotype. Hence, promoting microglia toward the anti-inflammatory M2 phenotype is a potential therapeutic approach for PD. Long noncoding RNAs (lncRNAs) are crucial in the progression of neurodegenerative diseases, but little is known about their role in microglial polarization in PD. METHODS: In our study, we profiled the expression of lncRNAs in the peripheral blood mononuclear cells (PBMCs) of PD patients using a microarray. RT-qPCR was used to evaluate the lncRNA levels and mRNA levels of cytokines and microglial cell markers both in vitro and in vivo. RIP and ChIP assays were analyzed for the underlying mechanism of lncRNA regulating microglial polarization. RESULTS: We found that HOXA-AS2 was upregulated in the PBMCs of PD patients and negatively associated with peroxisome proliferator-activated receptor gamma coactivator-1a (PGC-1α) expression. Moreover, HOXA-AS2 knockdown significantly repressed microglial M1 polarization and promoted M2 polarization by regulating PGC-1α expression. Mechanistic investigations demonstrated that HOXA-AS2 could directly interact with polycomb repressive complex 2 (PRC2) and modulate the histone methylation of the promoter of PGC-1α. CONCLUSIONS: Our findings identify the upregulated lncRNA HOXA-AS2 promotes neuroinflammation by regulating microglial polarization through interacts with the PRC2 complex and epigenetically silencing PGC-1α. HOXA-AS2 may be a potential therapeutic target for microglia-mediated neuroinflammation in patients with PD.

Gut metagenomics-derived genes as potential biomarkers of Parkinson's disease.

Identification of the gut microbiome compositions associated with disease has become a research focus worldwide. Emerging evidence has revealed the presence of gut microbiota dysbiosis in Parkinson's disease. In this study, we aimed to identify the gut microbiome associated with Parkinson's disease and subsequently to screen and to validate potential diagnostic biomarkers of Parkinson's disease. This case-control study investigated gut microbial genes in faeces from 40 volunteer Chinese patients with Parkinson's disease and their healthy spouses using shotgun metagenomic sequencing. Furthermore, the identified specific gut microbial gene markers were validated with real-time PCR in an independent Chinese cohort of 78 Parkinson's disease patients, 75 control subjects, 40 patients with multiple system atrophy and 25 patients with Alzheimer's disease. We developed the first gut microbial gene catalogue associated with Parkinson's disease. Twenty-five gene markers were identified that distinguished Parkinson's disease patients from healthy control subjects, achieving an area under the receiver operating characteristic curve (AUC) of 0.896 (95% confidence interval: 83.1-96.1%). A highly accurate Parkinson's disease index, which was not influenced by disease severity or Parkinson's disease medications, was created. Testing these gene markers using quantitative PCR distinguished Parkinson's disease patients from healthy controls not only in the 40 couples (AUC = 0.922, 95% confidence interval: 86.4-98.0%), but also in an independent group of 78 patients with Parkinson's disease and 75 healthy control subjects (AUC = 0.905, 95% confidence interval: 86.0-95.1%). This classifier also performed a differential diagnosis power in discriminating these 78 patients with Parkinson's disease from a cohort of 40 patients with multiple system atrophy and 25 patients with Alzheimer's disease based on the panel of 25 biomarkers. Based on our results, the identified Parkinson's disease index based on the gene set from the gut microbiome may be a potential diagnostic biomarker of Parkinson's disease.

Parkinson's disease-related DJ-1 modulates the expression of uncoupling protein 4 against oxidative stress.

Loss of function mutations of DJ-1 (PARK7) have been linked to the pathogenesis of Parkinson's disease. Antioxidative stress is one of the multi-protective functions of DJ-1, and oxidation of cysteine 106 has been proposed to regulate the protective activity of DJ-1. Uncoupling protein 4 (UCP4) is located in the inner membrane of mitochondria and functions to protect against oxidative stress. In this study, we used neuronal (SH-SY5Y) cells and DJ-1 knockout mice to elucidate whether DJ-1 regulated oxidative stress via modulating the expression of UCP4, and the underlying mechanism. The downstream products of oxidative stress, mitochondrial membrane potential (ΔΨm) and cell viability were also investigated. We found that UCP4 was up-regulated upon 1-methyl-4-phenylpyridinium (MPP+ ) stimulation in SH-SY5Y cells, which was enhanced by wild type DJ-1 and alleviated by DJ-1 knockdown. Expression of UCP4 in DJ-1 knockout mice was lower compared with wild-type mice. In addition, up-regulation of UCP4 was alleviated by inhibition of oxidized DJ-1, and enhanced by increase in oxidized DJ-1 under conditions of oxidative stress using western blot analysis. Moreover, over-expression of UCP4 in DJ-1 knockdown cells partially reversed the decrease in cell viability, ΔΨm, as well as the increase in products of oxidative stress upon MPP+ stimulation. Furthermore analysis showed that DJ-1 regulated transcriptional activity of UCP4 partially via Nuclear factor-kappa B (NF-κB) pathway in the presence of MPP+ . Together, our results suggested DJ-1 might regulate the expression of UCP4 by oxidation of DJ-1 and partially via NF-κB pathway in its protective response to oxidative stress.

Purinergic receptor P2Y6 contributes to 1-methyl-4-phenylpyridinium-induced oxidative stress and cell death in neuronal SH-SY5Y cells.

Oxidative stress and neural degeneration have been shown to be involved in the pathogenesis of Parkinson's disease (PD). The P2Y6 purinergic receptor (P2Y6R) has been shown to participate in the activation of microglia and the production of pro-inflammatory factors induced by lipopolysaccharide to cause neuronal loss. However, the function of P2Y6R during oxidative stress in neurons is unclear. In the present study, 1-methyl-4-phenylpyridinium (MPP+ ) treatment increased the level of UDP/P2Y6R on neuronal SH-SY5Y cells. Importantly, pharmacological inhibition of P2Y6R or knockdown of P2Y6R using a siRNA exerted an increased protective effect by preventing MPP+ -induced increases in the levels of reactive oxygen species (ROS), superoxide anion, inducible nitric oxide synthase (iNOS), and malondialdehyde (MDA) and down-regulation of superoxide dismutase 1 (SOD1) expression. UDP, an agonist of P2Y6R, enhanced the effects of MPP+ , which was also inhibited by apyrase or MRS2578. Additionally, P2Y6R knockdown also significantly reversed both the loss of cell viability and the increase in the levels of phosphorylated extracellular signal-regulated protein kinase (p-ERK1/2) and p38 (p-p38) caused by MPP+ stimulation. However, the inhibition of the ERK1/2 and p38 kinase signaling pathways had no effect on P2Y6R expression. Taken together, these results support the hypothesis that P2Y6R expressed on neuronal SH-SY5Y cell is associated with the progression of oxidative stress and cell death induced by MPP+ , suggesting that P2Y6R may play an important role in the pathogenesis of PD.

Alteration of the fecal microbiota in Chinese patients with Parkinson's disease.

Emerging evidences suggest that gut microbiota dysbiosis plays a role in Parkinson's disease (PD). However, the alterations in fecal microbiome in Chinese PD patients remains unknown. This case-control study was conducted to explore fecal microbiota compositions in Chinese PD patients. Microbiota communities in the feces of 45 patients and their healthy spouses were investigated using high-throughput Illumina Miseq sequencing targeting the V3-V4 region of 16S ribosomal RNA (rRNA) gene. The relationships between fecal microbiota and PD clinical characteristics were analyzed. The structure and richness of the fecal microbiota differed between PD patients and healthy controls. Genera Clostridium IV, Aquabacterium, Holdemania, Sphingomonas, Clostridium XVIII, Butyricicoccus and Anaerotruncus were enriched in the feces of PD patients after adjusting for age, gender, body mass index (BMI), and constipation. Furthermore, genera Escherichia/Shigella were negatively associated with disease duration. Genera Dorea and Phascolarctobacterium were negatively associated with levodopa equivalent doses (LED). Among the non-motor symptoms (NMSs), genera Butyricicoccus and Clostridium XlVb were associated with cognitive impairment. Overall, we confirmed that gut microbiota dysbiosis occurs in Chinese patients with PD. A well-controlled population involved was beneficial for the identification of microbiota associated with diseases. Additionally, the fecal microbiota was closely related to PD clinical characteristics. Elucidating these differences in the fecal microbiome will provide a foundation to improve our understanding the pathogenesis of PD and to support the potentially therapeutic options modifying the gut microbiota.

Microglia P2Y6 receptor is related to Parkinson's disease through neuroinflammatory process.

BACKGROUND: Microglia in the central nervous system (CNS) were reported to play crucial role in neurodegeneration. Previous studies showed that P2Y6 receptor (P2Y6R) mainly contributed to microglia activation and phagocytosis in CNS. However, the level of P2Y6R in Parkinson's disease (PD) patients is unclear. Therefore, we measured the level of P2Y6R in PD patients and speculated whether it could be a potential biomarker for PD. Given on the basis that P2Y6R was higher in PD patients, we further explored the mechanisms underlying P2Y6R in the pathogenesis of PD. METHODS: We tested the expression level of P2Y6R in the peripheral blood mononuclear cells (PBMCs) among 145 PD patients, 170 healthy controls, and 30 multiple system atrophy (MSA) patients. We also used a lipopolysaccharide (LPS)-stimulated microglial cell culture model to investigate (i) the effects of LPS on P2Y6R expression with western blot and RT-PCR, (ii) the effects of LPS on UDP expression using HPLC, (iii) the effects of UDP/P2Y6R signaling on cytokine expression using western blot, RT-PCR, and ELISA, and (iv) the signaling pathways activated by the P2Y6R involved in the neuroinflammation. RESULTS: Expression levels of P2Y6R in PD patients were higher than healthy controls and MSA patients. P2Y6R could be a good biomarker of PD. P2Y6R was also upregulated in LPS-treated BV-2 cells and involved in proinflammatory cytokine release through an autocrine loop based on LPS-triggered UDP secretion and accelerated neuroinflammatory responses through the ERK1/2 pathway. Importantly, blocking UDP/P2Y6R signaling could reverse these pathological processes. CONCLUSIONS: P2Y6R may be a potential clinical biomarker of PD. Blocking P2Y6R may be a potential therapeutic approach to the treatment of PD patients through inhibition of microglia-activated neuroinflammation.

Resveratrol regulates microglia M1/M2 polarization via PGC-1α in conditions of neuroinflammatory injury.

Microglia are the primary cells that exert immune function in the central nervous system (CNS), and accumulating evidence suggests that microglia act as key players in the initiation of neurodegenerative diseases. It is now well recognized that microglia have functional plasticity and dual phenotypes, proinflammatory M1 and anti-inflammatory M2 phenotypes. Inhibiting the M1 phenotype while stimulating the M2 phenotype has been suggested as a potential therapeutic approach for the treatment of neuroinflammation-related diseases. Resveratrol has been demonstrated to exert anti-inflammatory effects by suppressing M1 microglia activation. However, the role of resveratrol in regulating microglia polarization and the molecular mechanisms involved have not been fully clarified. In this study, we tested whether resveratrol could suppress microglia activation by promoting microglia polarization toward the M2 phenotype via PGC-1α by measuring M1 and M2 markers in vitro and in vivo. Our study demonstrated that resveratrol reduced inflammatory damage and promoted microglia polarization to the M2 phenotype in LPS-induced neuroinflammation. In addition, resveratrol ameliorated LPS-induced sickness behavior in mice. The promoting effects of resveratrol on M2 polarization were attenuated by knocking down PGC-1α. PGC-1α not only suppressed LPS-evoked M1 marker expression by inhibition of NF-κB activity but also increased M2 marker expression by coactivation of the STAT6 and STAT3 pathways. We propose that overexpression PGC-1α by resveratrol could be a potential therapeutic approach to suppress neuroinflammation by regulating microglia polarization.

KLF9 regulates osteogenic differentiation of mesenchymal stem cells.

Osteoporosis is a progressive skeletal disease which is characterized by reduced bone mass and degradation of bone microstructure. Mesenchymal stem cells (MSCs) have the potential to inhibit osteoporosis since they are multipotent stem cells that can differentiate into multiple types of cells including osteoblasts. Hence the mechanism of osteogenic differentiation of MSCs deserves comprehensive study. Here we report that KLF9 is a novel regulator in osteogenic differentiation of MSCs. We observed that depletion of KLF9 can largely compromise the osteogenic differentiation ability of MSCs. In addition, we revealed that inhibition of the PI3K-Akt pathway could also affect osteogenic differentiation since KLF9 depletion inhibits PI3K expression. Finally, we discovered that KLF9 expression can be induced by dexamethasone which is an essential component in osteogenic induction medium. Taken together, our study provides new insights into the regulatory role of KLF9 in osteogenic differentiation of MSCs.

POZ/BTB and AT hook containing zinc finger 1 (PATZ1) suppresses differentiation and regulates metabolism in human embryonic stem cells.

Human embryonic stem cells (hESCs) can proliferate infinitely (self-renewal) and give rise to almost all types of somatic cells (pluripotency). Hence, understanding the molecular mechanism of pluripotency regulation is important for applications of hESCs in regenerative medicine. Here we report that PATZ1 is a key factor that regulates pluripotency and metabolism in hESCs. We found that depletion of PATZ1 is associated with rapid downregulation of master pluripotency genes and prominent deceleration of cell growth. We also revealed that PATZ1 regulates hESC pluripotency though binding the regulatory regions of OCT4 and NANOG. In addition, we demonstrated PATZ1 is a key node in the OCT4/NANOG transcriptional network. We further revealed that PATZ1 is essential for cell growth in hESCs. Importantly, we discovered that depletion of PATZ1 drives hESCs to exploit glycolysis which energetically compensates for the mitochondrial dysfunction. Overall, our study establishes the fundamental role of PATZ1 in regulating pluripotency in hESCs. Moreover, PATZ1 is essential for maintaining a steady metabolic homeostasis to refine the stemness of hESCs.

Synthetic minority over-sampling technique-enhanced machine learning models for predicting recurrence of postoperative chronic subdural hematoma.

Objective: Chronic subdural hematoma (CSDH) is a neurological condition with high recurrence rates, primarily observed in the elderly population. Although several risk factors have been identified, predicting CSDH recurrence remains a challenge. Given the potential of machine learning (ML) to extract meaningful insights from complex data sets, our study aims to develop and validate ML models capable of accurately predicting postoperative CSDH recurrence. Methods: Data from 447 CSDH patients treated with consecutive burr-hole irrigations at Wenzhou Medical University's First Affiliated Hospital (December 2014-April 2019) were studied. 312 patients formed the development cohort, while 135 comprised the test cohort. The Least Absolute Shrinkage and Selection Operator (LASSO) method was employed to select crucial features associated with recurrence. Eight machine learning algorithms were used to construct prediction models for hematoma recurrence, using demographic, laboratory, and radiological features. The Border-line Synthetic Minority Over-sampling Technique (SMOTE) was applied to address data imbalance, and Shapley Additive Explanation (SHAP) analysis was utilized to improve model visualization and interpretability. Model performance was assessed using metrics such as AUROC, sensitivity, specificity, F1 score, calibration plots, and decision curve analysis (DCA). Results: Our optimized ML models exhibited prediction accuracies ranging from 61.0% to 86.2% for hematoma recurrence in the validation set. Notably, the Random Forest (RF) model surpassed other algorithms, achieving an accuracy of 86.2%. SHAP analysis confirmed these results, highlighting key clinical predictors for CSDH recurrence risk, including age, alanine aminotransferase level, fibrinogen level, thrombin time, and maximum hematoma diameter. The RF model yielded an accuracy of 92.6% with an AUC value of 0.834 in the test dataset. Conclusion: Our findings underscore the efficacy of machine learning algorithms, notably the integration of the RF model with SMOTE, in forecasting the recurrence of postoperative chronic subdural hematoma. Leveraging the RF model, we devised an online calculator that may serve as a pivotal instrument in tailoring therapeutic strategies and implementing timely preventive interventions for high-risk patients.

Association between Fecal Bile Acids and Levodopa Response in Patients with Parkinson's Disease.

Levodopa is the mainstay of treatments for Parkinson's disease (PD), but large heterogeneity exists in patient response. Increasing evidence implicates bile acids (BAs) involved in the pathogenesis of PD. Furthermore, BAs have also participated in drug bioavailability. However, the impact of BAs on levodopa response (LR) has not been investigated. This study evaluated the association between fecal BAs and LR. Levodopa challenge test (LCT) was conducted in 92 PD patients to assess LR. A total of 36 fecal BAs and plasma levodopa concentrations were detected using LC-MS/MS. The difference of BAs between subgroups with bottom and top 30% LR were analyzed and fecal samples from the two groups were collected for metagenomic shotgun analysis. No fecal BAs were significantly correlated with LR, except for chenodeoxycholic acid-3-ß-D-glucuronide (CDCA-3-ß-glucuronide, R = -0.228, p-value = 0.039). We found no significant difference in BAs between subgroups with bottom and top 30% LR. What is more, no significant changes in bacterial species composition related to bile acids metabolism or in the proportional representation of genes encoding known bile acids enzymes were observed between the groups. Overall, our data do not support an association between fecal BAs and levodopa response in PD patients. More precise macro-metabolomic approaches are needed to reveal the potential association between gut microbial interactions and the treatment effect of levodopa.

Sodium butyrate ameliorates gut dysfunction and motor deficits in a mouse model of Parkinson's disease by regulating gut microbiota.

Background: A growing body of evidence showed that gut microbiota dysbiosis might be associated with the pathogenesis of Parkinson's disease (PD). Microbiota-targeted interventions could play a protective role in PD by regulating the gut microbiota-gut-brain axis. Sodium butyrate (NaB) could improve gut microbiota dysbiosis in PD and other neuropsychiatric disorders. However, the potential mechanism associated with the complex interaction between NaB and gut microbiota-gut-brain communication in PD needs further investigation. Methods: C57BL/6 mice were subjected to a rotenone-induced PD model and were treated intragastrically with NaB for 4 weeks. The gut function and motor function were evaluated. The α-synuclein expression in colon and substantia nigra were detected by western blotting. Tyrosine hydroxylase (TH)-positive neurons in substantia nigra were measured by immunofluorescence. Moreover, gut microbiota composition was analyzed by 16S rRNA sequencing. Fecal short chain fatty acids (SCFAs) levels were determined by liquid chromatography tandem mass spectrometry (LC-MS). The levels of glucagon like peptide-1 (GLP-1) in tissues and serum were evaluated using enzyme-linked immunosorbent assay (ELISA). Results: NaB ameliorated gut dysfunction and motor deficits in rotenone-induced mice. Meanwhile, NaB protected against rotenone-induced α-synuclein expression in colon and substantia nigra, and prevented the loss of TH-positive neurons. In addition, NaB could remodel gut microbiota composition, and regulate gut SCFAs metabolism, and restore GLP-1 levels in colon, serum, and substantia nigra in PD mice. Conclusion: NaB could ameliorate gut dysfunction and motor deficits in rotenone-induced PD mice, and the mechanism might be associated with the regulation of gut microbiota dysbiosis.

Effect of Lacticaseibacillus paracasei strain Shirota supplementation on clinical responses and gut microbiome in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor issues and a range of non-motor symptoms. Microbial therapy may be a useful approach for the treatment of PD. However, comprehensive analyses of the impact of probiotic supplementation on motor and non-motor symptoms are still lacking and the mechanisms whereby the treatment works remain unclear. This study investigated Lacticaseibacillus paracasei strain Shirota (LcS) supplementation on clinical responses, gut microbiota and faecal metabolites in PD patients. Patients (n = 128) were randomised to receive either probiotics (LcS-fermented milk, containing 1 × 1010 living LcS cells) or placebo for 12 weeks. All participants were examined and the basic clinical features were recorded using questionnaires. Fecal and blood samples were collected at the baseline and after 12 weeks for further omics analysis. We found that LcS intervention significantly alleviated patients' constipation-related symptoms and non-motor symptoms. We found no significant shifts in the composition of gut microbiota or faecal metabolites. Several taxa were differentially abundant between the groups, especially with regard to LcS intake, which increased the abundance of the genus Lacticaseibacillus in the probiotic group compared with those at the baseline and in the placebo group. The faecal concentration of L-tyrosine was significantly decreased and the plasma concentration of L-tyrosine was increased in the probiotic group compared with the placebo group. Our study demonstrated that although supplementation with LcS did not induce major changes in the global gut microbiome, the probiotic had favorable effects in managing constipation and other non-motor symptoms in PD patients. This study was registered at the Chinese Clinical Trial Registry: ChiCTR1800016795.

Effectiveness of a government-led, multiarm intervention on early childhood development and caregiver mental health: a study protocol for a factorial cluster-randomised trial in rural China.

INTRODUCTION: The high incidences of both the developmental delay among young children and the mental health problems of their caregivers are major threats to public health in low-income and middle-income countries. Parental training interventions during early childhood have been shown to benefit early development, yet evidence on strategies to promote caregiver mental health remains limited. In addition, evidence on the optimal design of scalable interventions that integrate early child development and maternal mental health components is scarce. METHODS AND ANALYSIS: We design a single-blind, factorial, cluster-randomised controlled, superiority trial that will be delivered and supervised by local agents of the All China Women's Federation (ACWF), the nationwide, government-sponsored social protection organisation that aims to safeguard the rights and interests of women and children. We randomise 125 villages in rural China into four arms: (1) a parenting stimulation arm; (2) a caregiver mental health arm; (3) a combined parenting stimulation and caregiver mental health arm and (4) a pure control arm. Caregivers and their children (aged 6-24 months at the time of baseline data collection) are selected and invited to participate in the 12-month-long study. The parenting stimulation intervention consists of weekly, one-on-one training sessions that follow a loose adaptation of the Reach Up and Learn curriculum. The caregiver mental health intervention is comprised of fortnightly group activities based on an adaptation of the Thinking Healthy curriculum from the WHO. Primary outcomes include measures of child development and caregiver mental health. Secondary outcomes include a comprehensive set of physical, psychological and behavioural outcomes. This protocol describes the design and evaluation plan for this programme. ETHICS AND DISSEMINATION: This study received approval from the Institutional Review Board of Stanford University (IRB Protocol #63680) and the Institutional Review Board of the Southwestern University of Finance and Economics in Chengdu, Sichuan, China. Informed oral consent will be obtained from all caregivers for their own and their child's participation in the study. The full protocol will be publicly available in an open-access format. The study findings will be published in economics, medical and public health journals, as well as Chinese or English policy briefs. TRIAL REGISTRATION NUMBER: AEA RCT Registry (AEARCTR-0010078) and ISRCTN registry (ISRCTN84864201).

The Role of Self-Esteem in the Academic Performance of Rural Students in China.

The self-esteem of students may be significantly associated with their academic performance. However, past research in developing contexts on this issue is limited, particularly among early adolescents. Using a sample of 3101 students from rural primary and junior high schools in China, this study measured their self-esteem by the Rosenberg Self-Esteem Scale (RSES) and explored its association with academic performance. Our findings indicate that students in rural China had both significantly lower self-esteem and a higher prevalence of low self-esteem when compared to past studies of similarly aged students both from urban China and internationally. Furthermore, there was a strong positive correlation between a student's self-esteem and academic performance. A one-SD increase in RSES score (indicating better self-esteem) was associated with an increase of 0.12 SD in standardized math scores (p < 0.001), and students with low self-esteem (RSES score < 25) scored lower on math tests by 0.14 SD (p < 0.001), which were robust and consistent when employing the propensity score matching method. Our study expands the growing body of empirical evidence on the link between self-esteem and academic performance among rural youth in developing countries and emphasizes the need to improve their self-esteem with the aim of helping them achieve academically.

Analysis of serum levels of organochlorine pesticides and related factors in Parkinson's disease.

BACKGROUND: There is evidence that environmental factors contribute to the onset and progression of Parkinson's disease (PD). Pesticides are a class of environmental toxins that are linked to increased risk of developing PD. However, few studies have investigated the association between specific pesticides and PD, especially in China, which was one of the first countries to adopt the use of pesticides. METHODS: In this study, serum levels of 19 pesticides were measured in 90 patients with PD and 90 healthy spouse controls. We also analyzed the interaction between specific pesticides and PD. In addition, the association between pesticides and clinical features of PD was also investigated. Finally, we investigated the underlying mechanism of the association between pesticides and PD. RESULTS: Serum levels of organochlorine pesticides, which included α-hexachlorocyclohexane (HCH), ß-HCH, γ-HCH, δ-HCH, propanil, heptachlor, dieldrin, hexachlorobenzene, p,p'-dichlorodiphenyltrichloroethane and o,p'-dichloro-diphenyl-trichloroethane were higher in PD patients than controls. Moreover, α-HCH and propanil levels were associated with PD. Serum levels of dieldrin were associated with Hamilton Depression Scale and Montreal Cognitive Assessment scores in PD patients. In SH-SY5Y cells, α-HCH and propanil increased level of reactive oxygen species and decreased mitochondrial membrane potential. Furthermore, propanil, but not α-HCH, induced the aggregation of α-synuclein. CONCLUSIONS: This study revealed that elevated serum levels of α-HCH and propanil were associated with PD. Serum levels of dieldrin were associated with depression and cognitive function in PD patients. Moreover, propanil, but not α-HCH, induced the aggregation of α-synuclein. Further research is needed to fully elucidate the effects of pesticides on PD.

Sodium butyrate attenuates rotenone-induced toxicity by activation of autophagy through epigenetically regulating PGC-1α expression in PC12 cells.

Short-chain fatty acids (SCFAs) are considered the key molecular link between gut microbiota and pathogenesis of Parkinson's disease (PD). However, the role of SCFAs in PD pathogenesis is controversial. Autophagy is important for the degradation of α-synuclein, which is critical to the development of PD. However, whether SCFAs can regulate autophagy in PD remains unknown. We aimed to investigate the role of SCFAs and explore the potential mechanisms in rat dopaminergic PC12 cells treated with rotenone. Expression levels of α-synuclein, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and microtubule-associated protein 1 light chain 3 beta (LC3B)-II were detected by Western blot. Histone acetylation levels at PGC-1α promoter region were measured using chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). Among the three SCFAs, sodium butyrate (NaB) protected against rotenone-induced toxicity. NaB activated autophagy pathway and reduced rotenone-induced α-synuclein expression through the activation of autophagy. Notably, NaB activated autophagy pathway through upregulating PGC-1α expression. More importantly, NaB promoted the levels of histone 3 lysine 9 acetylation (H3K9Ac) and histone 3 lysine 27 acetylation (H3K27Ac) at PGC-1α promoter region, indicating that NaB promotes PGC-1α expression via histone acetylation modification. In conclusion, NaB can protect against rotenone-induced toxicity through activation of the autophagy pathway by upregulating PGC-1α expression via epigenetic modification.

Plasma branched-chain and aromatic amino acids correlate with the gut microbiota and severity of Parkinson's disease.

Disturbances of circulating amino acids have been demonstrated in patients with Parkinson's disease (PD). However, there have been no consistent results for branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs), and related factors have not been explored. We aimed to explore plasma BCAA and AAA profiles in PD patients, and identify their correlations with clinical characteristics and the gut microbiota. Plasma BCAA (leucine, isoleucine, and valine) and AAA (tyrosine and phenylalanine) levels were measured in 106 PD patients and 114 controls. Fecal samples were collected from PD patients for microbiota sequencing and functional analysis. We found that plasma BCAAs and tyrosine were decreased in PD patients. BCAAs and AAAs were correlated with clinical characteristics and microbial taxa, and, in particular, they were negatively correlated with the Hoehn and Yahr stage. Compared with early PD patients, BCAA and AAA levels were even lower, and microbial composition was altered in advanced PD patients. Predictive functional analysis indicated that predicted genes numbers involved in BCAA biosynthesis were lower in advanced PD patients. What's more, the fecal abundances of critical genes (ilvB, ilvC, ilvD, and ilvN) involved in BCAA biosynthesis were reduced and fecal BCAA concentrations were lower in advanced PD patients. In conclusion, the disturbances of plasma BCAAs and AAAs in PD patients may be related to the gut microbiota and exacerbated with PD severity. The microbial amino acid metabolism may serve as a potential mechanistic link.