Cerebrospinal fluid neurofilament dynamic profiles predict cognitive progression in individuals with de novo Parkinson’s disease

BackgroundNeurofilament light chain protein (NfL) in cerebrospinal fluid (CSF) reflects the severity of neurodegeneration, with its altered concentrations discovered in Parkinson’s disease (PD) and Parkinson’s disease dementia (PD-D).ObjectiveTo determine whether CSF NfL, a promising biomarker of neuronal/axonal damage, can be used to monitor cognitive progression in de novo Parkinson’s disease and predict future cognitive decline.MethodsA total of 259 people were recruited in this study, including 85 healthy controls (HC) and 174 neonatal PD patients from the Parkinson’s Progression Markers Initiative (PPMI). Multiple linear regression and linear mixed effects models were used to examine the associations of baseline/longitudinal CSF NfL with cognitive decline and other CSF biomarkers. Kaplan–Meier analysis and log-rank test were used to compare the cumulative probability risk of cognition progression during the follow-up. Multivariate cox regression was used to detect cognitive progression in de novo PD.ResultsWe found PD patients with mild cognitive impairment (PD-MCI) was higher than with normal cognition (PD-NC) in terms of CSF NfL baseline levels (p = 0.003) and longitudinal increase rate (p = 0.034). Both baseline CSF NfL and its rate of change predicted measurable cognitive decline in de novo PD (MoCA, β = −0.010, p = 0.011; β = −0.0002, p < 0.001, respectively). The predictive effects in de novo PD patients aged >65, male, ill-educated (<13 years) and without carrying Apolipoprotein E ε4 (APOE ε4) seemed to be more obvious and reflected in more domains investigated. We also observed that CSF NfL levels predicted progression in de novo PD patients with different cognitive diagnosis and amyloid status. After an average follow-up of 6.66 ± 2.54 years, higher concentration above the median of baseline CSF NfL was associated with a future high risk of PD with dementia (adjusted HR 2.82, 95% CI: 1.11–7.20, p = 0.030).ConclusionOur results indicated that CSF NfL is a promising prognostic predictor of PD, and its concentration and dynamics can monitor the severity and progression of cognitive decline in de novo PD patients

ART1 induces aberrant methylation of uPA promoter: a preliminary study

Colorectal carcinoma remains one of the most prevalent cancers with high morbidity and mortality. Arginine ADP-ribosyltransferase 1 (ART1) is one of the major mono-ADP-ribose transferases and has been shown to be involved importantly in many biological processes. DNA methylation is an important epigenetic mechanism in tumorgenesis.However, the influence of ART1 on DNA methylation contributing to this function in colorectal carcinoma cells remains unclear. The expression and activity of DNA methyltransferase 1 (DNMT1) was detected by western blotting. The binding between ART1 and DNMT1 was assessed by co-immunoprecipitation. The methylation status of uPA gene was determined by bisulfite sequencing PCR. DNMT1 expression and activity were increased as ART1 was silenced, and decreased as ART1 was over-expressed in CT26 colorectal carcinoma cells. The expression of DNMT1 decreased and uPA increased, respectively, following the treatment with 5-aza-2’deoxycytidine in GFP-shART1 group. Invasion and metastasis were enhanced in GFP-shART1 group treated with 5-aza-dC. Similar regulation of expression of DNMT1 and uPA were confirmed in Balb/c mice. This study revealed that silencing of ART1 induced hypermethylation of uPA gene and over-expression causes hypomethylation. It probably relates to the feedback mechanism of NF-κB to PARP1 thus mediating the expression and activity of DNMT1. The relationship between ART1 and DNA methylation might offer a new therapeutic target for the improved treatment of this major cancer

Chemical Composition and Antimicrobial Activity of the Essential Oil of Kumquat (Fortunella crassifolia Swingle) Peel

The aim of this study was to determine the main constituents of the essential oil isolated from Fortunella crassifolia Swingle peel by hydro-distillation, and to test the efficacy of the essential oil on antimicrobial activity. Twenty-five components, representing 92.36% of the total oil, were identified by GC-MS analysis. The essential oil showed potent antimicrobial activity against both Gram-negative (E. coli and S. typhimurium) and Gram-positive (S. aureus, B. cereus, B. subtilis, L. bulgaricus, and B. laterosporus) bacteria, together with a remarkable antifungal activity against C. albicans. In a food model of beef extract, the essential oil was observed to possess an effective capacity to control the total counts of viable bacteria. Furthermore, the essential oil showed strongly detrimental effects on the growth and morphological structure of the tested bacteria. It was suggested that the essential oil from Fortunella crassifolia Swingle peel might be used as a natural food preservative against bacteria or fungus in the food industry

Altered Behaviors and Impaired Synaptic Function in a Novel Rat Model With a Complete Shank3 Deletion

Mutations within the Shank3 gene, which encodes a key postsynaptic density (PSD) protein at glutamatergic synapses, contribute to the genetic etiology of defined autism spectrum disorders (ASDs), including Phelan-McDermid syndrome (PMS) and intellectual disabilities (ID). Although there are a series of genetic mouse models to study Shank3 gene in ASDs, there are few rat models with species-specific advantages. In this study, we established and characterized a novel rat model with a deletion spanning exons 11–21 of Shank3, leading to a complete loss of the major SHANK3 isoforms. Synaptic function and plasticity of Shank3-deficient rats were impaired detected by biochemical and electrophysiological analyses. Shank3-depleted rats showed impaired social memory but not impaired social interaction behaviors. In addition, impaired learning and memory, increased anxiety-like behavior, increased mechanical pain threshold and decreased thermal sensation were observed in Shank3-deficient rats. It is worth to note that Shank3-deficient rats had nearly normal levels of the endogenous social neurohormones oxytocin (OXT) and arginine-vasopressin (AVP). This new rat model will help to further investigate the etiology and assess potential therapeutic target and strategy for Shank3-related neurodevelopmental disorders

Suppress HBV by therapeutic vaccine

乙肝预防性疫苗显著减少了乙肝新发感染，但目前全球仍有约2.5亿慢性乙肝感染者，若未得到有效治疗，可能发展为肝癌、肝硬化等终末期肝病并导致死亡。夏宁邵教授团队研究发展了一种新型的B细胞表位嵌合型类病毒颗粒乙肝治疗性疫苗（治疗性蛋白），在多种模型中证实了其对慢性乙肝感染的治疗潜力，为研发治疗慢性乙肝的原创药物提供了新思路。 我校博士后张天英、博士生郭雪染和博士生巫洋涛为该论文共同第一作者，夏宁邵教授、袁权副教授、张军教授为该论文的共同通讯作者。【Abstract】Objective: This study aimed to develop a novel therapeutic vaccine based on a unique B cell epitope and investigate its therapeutic potential against chronic hepatitis B (CHB) in animal models. Methods: A series of peptides and carrier proteins were evaluated in HBV-tolerant mice to obtain an optimized therapeutic molecule. The immunogenicity,therapeutic efficacy and mechanism of the candidate were investigated systematically. Results: Among the HBsAg-aa119-125-containing peptides evaluated in this study, HBsAg-aa113-135 (SEQ13) exhibited the most striking therapeutic effects. A novel immuno-enhanced virus-like particle carrier (CR-T3) derived from the roundleaf bat HBV core antigen (RBHBcAg) was created and used to display SEQ13, forming candidate molecule CR-T3-SEQ13. Multiple copies of SEQ13 displayed on the surface of this particulate antigen promote the induction of a potent anti-HBs antibody response in mice, rabbits and cynomolgus monkeys. Sera and purified polyclonal IgG from the immunized animals neutralized HBV infection in vitro and mediated efficient HBV/HBsAg clearance in the mice. CR-T3-SEQ13-based vaccination induced long-term suppression of HBsAg and HBV DNA in HBV transgenic mice and eradicated the virus completely in hydrodynamic-based HBV carrier mice. The suppressive effects on HBsAg were strongly correlated with the anti-HBs level after vaccination, suggesting that the main mechanism of CR-T3-SEQ13 vaccination therapy was the induction of a SEQ13-specific antibody response that mediated HBV/HBsAg clearance. Conclusions: The novel particulate protein CR-T3-SEQ13 suppressed HBsAg effectively through induction of a humoral immune response in HBV-tolerant mice. This B cell epitope-based therapeutic vaccine may provide a novel immunotherapeutic agent against chronic HBV infection in humans.This work was supported by the National Scientific and Technological Major project (2017ZX10202203-001), the National Natural Science Foundation of China (31730029, 81672023, 81871316 and 81702006) and the Xiamen University President Fund Project (20720160063). 该研究获得了“艾滋病和病毒性肝炎等重大传染病防治”科技重大专项、国家自然科学基金等资助

Uncaria rhynchophylla Ameliorates Parkinson’s Disease by Inhibiting HSP90 Expression: Insights from Quantitative Proteomics

Background/Aims: Uncaria rhynchophylla, known as “Gou-teng”, is a traditional Chinese medicine (TCM) used to extinguish wind, clear heat, arrest convulsions, and pacify the liver. Although U. rhynchophylla has a long history of being often used to treat central nervous system (CNS) diseases, its efficacy and potential mechanism are still uncertain. This study investigated neuroprotective effect and the underlying mechanism of U. rhynchophylla extract (URE) in MPP+-induced SH-SY5Y cells and MPTP-induced mice. Methods: MPP+-induced SH-SY5Y cells and MPTP-induced mice were used to established Parkinson’s disease (PD) models. Quantitative proteomics and bioinformatics were used to uncover proteomics changes of URE. Western blotting was used to validate main differentially expressed proteins and test HSP90 client proteins (apoptosis-related, autophagy-related, MAPKs, PI3K, and AKT proteins). Flow cytometry and JC-1 staining assay were further used to confirm the effect of URE on MPP+-induced apoptosis in SH-SY5Y cells. Gait analysis was used to detect the behavioral changes in MPTP-induced mice. The levels of dopamine (DA) and their metabolites were examined in striatum (STR) by HPLC-EC. The positive expression of tyrosine hydroxylase (TH) was detected by immunohischemical staining and Western blotting. Results: URE dose-dependently increased the cell viability in MPP+-induced SH-SY5Y cells. Quantitative proteomics and bioinformatics results confirmed that HSP90 was an important differentially expressed protein of URE. URE inhibited the expression of HSP90, which further reversed MPP+-induced cell apoptosis and autophagy by increasing the expressions of Bcl-2, Cyclin D1, p-ERK, p-PI3K p85, PI3K p110α, p-AKT, and LC3-I and decreasing cleaved caspase 3, Bax, p-JNK, p-p38, and LC3-II. URE also markedly decreased the apoptotic ratio and elevated mitochondrial transmembrane potential (DΨm). Furthermore, URE treatment ameliorated behavioral impairments, increased the contents of DA and its metabolites and elevated the positive expressions of TH in SN and STR as well as the TH protein. Conclusions: URE possessed the neuroprotective effect in vivo and in vitro, regulated MAPK and PI3K-AKT signal pathways, and inhibited the expression of HSP90. U. rhynchophylla has potentials as therapeutic agent in PD treatment

Phylogenomic analyses provide insights into primate evolution

Comparative analysis of primate genomes within a phylogenetic context is essential for understanding the evolution of human genetic architecture and primate diversity. We present such a study of 50 primate species spanning 38 genera and 14 families, including 27 genomes first reported here, with many from previously less well represented groups, the New World monkeys and the Strepsirrhini. Our analyses reveal heterogeneous rates of genomic rearrangement and gene evolution across primate lineages. Thousands of genes under positive selection in different lineages play roles in the nervous, skeletal, and digestive systems and may have contributed to primate innovations and adaptations. Our study reveals that many key genomic innovations occurred in the Simiiformes ancestral node and may have had an impact on the adaptive radiation of the Simiiformes and human evolution

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe