A Comprehensive Analysis of the Association Between SNCA Polymorphisms and the Risk of Parkinson's Disease

Background: Various studies have reported associations between synuclein alpha (SNCA) polymorphisms and Parkinson's disease (PD) risk. However, the results are inconsistent. We conducted a comprehensive meta-analysis of the associations between SNCA single-nucleotide polymorphisms (SNPs) and PD risk in overall populations and subpopulations by ethnicity.Methods: Standard meta-analysis was conducted according to our protocol with a cutoff point of p < 0.05. To find the most relevant SNCA SNPs, we used a cutoff point of p < 1 × 10−5 in an analysis based on the allele model. In the subgroup analysis by ethnicity, we divided the overall populations into five ethnic groups. We conducted further analysis on the most relevant SNPs using dominant and recessive models to identify the contributions of heterozygotes and homozygotes regarding each SNP.Results: In our comprehensive meta-analysis, 24,075 cases and 22,877 controls from 36 articles were included. We included 16 variants in the meta-analysis and found 12 statistically significant variants with p < 0.05. After narrowing down the variants using the p < 1 × 10−5 cutoff, in overall populations, seven SNPs increased the risk of PD (rs2736990, rs356220, rs356165, rs181489, rs356219, rs11931074, and rs2737029, with odds ratios [ORs] of 1.22–1.38) and one SNP decreased the risk (rs356186, with an OR of 0.77). In the East Asian group, rs2736990 and rs11931074 increased the risk (with ORs of 1.22–1.34). In the European group, five SNPs increased the risk (rs356219, rs181489, rs2737029, rs356165, and rs11931074, with ORs of 1.26–1.37) while one SNP decreased the risk (rs356186, with an OR of 0.77). The heterozygotes and homozygotes contributed differently depending on the variant.Conclusions: In summary, we found eight SNCA SNPs associated with PD risk, which had obvious differences between ethnicities. Seven SNPs increased the risk of PD and one SNP decreased the risk in the overall populations. In the East Asian group, rs2736990 and rs11931074 increased the risk. In the European group, rs356219, rs181489, rs2737029, rs356165, and rs11931074 increased the risk while rs356186 decreased the risk. Variants with the highest ORs and allele frequencies in our analysis should be given priority when carrying out genetic screening

Recent Advances in Biomarkers for Parkinson’s Disease

Parkinson’s disease (PD) is one of the common progressive neurodegenerative disorders with several motor and non-motor symptoms. Most of the motor symptoms may appear at a late stage where most of the dopaminergic neurons have been already damaged. In order to provide better clinical intervention and treatment at the onset of disease, it is imperative to find accurate biomarkers for early diagnosis, including prodromal diagnosis and preclinical diagnosis. At the same time, these reliable biomarkers can also be utilized to monitor the progress of the disease. In this review article, we will discuss recent advances in the development of PD biomarkers from different aspects, including clinical, biochemical, neuroimaging and genetic aspects. Although various biomarkers for PD have been developed so far, their specificity and sensitivity are not ideal when applied individually. So, the combination of multimodal biomarkers will greatly improve the diagnostic accuracy and facilitate the implementation of personalized medicine

The Effects of SNCA rs894278 on Resting-State Brain Activity in Parkinson’s Disease

The pathogenesis of Parkinson’s disease (PD) is not well established. The rs894278 polymorphism of SNCA has been associated with PD. We performed this study to investigate the relationship between rs894278 and PD status on resting-state brain activity, by analyzing the amplitude of low-frequency fluctuation (ALFF). A total of 81 PD patients and 64 healthy controls were recruited. Disease severity and PD stage were evaluated in PD patients using the unified Parkinson’s disease rating scale (UPDRS) and the Hoehn and Yahr (HY) scale, while the cognitive function of all participants was assessed using the mini-mental state examination (MMSE). All participants were genotyped for the rs894278 SNP and underwent a resting state functional magnetic resonance imaging scan. We found that the ALFF values of PD patients in the lingual gyrus and left caudate were lower than those of HCs; and the ALFF values for the right fusiform of participants with G allele were lower than those of participants without G allele. And we further revealed higher ALFF values in bilateral fusiform in rs894278-G carriers than in rs894278-G non-carriers in the PD group and lower ALFF values in bilateral fusiform in rs894278-G carriers than in rs894278-G non-carriers in the HC group. Our findings show that rs894278 and PD status interactively affect the brain activity of PD patients and HCs, and changes in the brain connectomes may play a key role in the pathogenesis of PD. Thus, our work sheds light on the mechanism underlying PD pathogenesis

Factors Associated With Dyskinesia in Parkinson's Disease in Mainland China

Background and Objectives: Studies examining the risk factors for dyskinesia in Parkinson's disease (PD) have been inconsistent, and racial differences exist. Since there have been no systematic studies of the characteristics of dyskinesia in the Mainland Chinese population, we sought to elucidate the risk factors for dyskinesia.Methods: A total of 1974 PD patients from Mainland China were systematically investigated by univariable and multivariable analyses. PD patients with and without dyskinesia were stratified into 4 groups according to levodopa equivalent daily dose (LEDD) and analyzed by a Cox proportional hazards model. A longitudinal study of 87 patients with dyskinesia was classified into 3 groups according to the duration from onset of PD to the initiation of levodopa, and comparisons among groups were analyzed by the Mann-Whitney test.Results: Early age of onset, long disease duration, being female, high LEDD, low UPDRS III scores (ON-state) and high Hoehn-Yahr stage (ON-state) were predictors of dyskinesia. Dyskinesia was levodopa dosage-dependent, and the incidence increased remarkably when LEDD exceeded 300 mg/d (p < 0.05). The emergence of dyskinesia had no association with the initiation time of levodopa, and if the latter was more than 4 years, the duration of time on chronic levodopa free of motor complications was significantly shortened.Conclusions: We found risk factors for the prediction of dyskinesia. Our data shows that physicians should be cautious if the LEDD exceeds 300 mg/d. The development of dyskinesia was not correlated with the time of levodopa initiation

QualitySNP: a pipeline for detecting single nucleotide polymorphisms and insertions/deletions in EST data from diploid and polyploid species

BACKGROUND: Single nucleotide polymorphisms (SNPs) are important tools in studying complex genetic traits and genome evolution. Computational strategies for SNP discovery make use of the large number of sequences present in public databases (in most cases as expressed sequence tags (ESTs)) and are considered to be faster and more cost-effective than experimental procedures. A major challenge in computational SNP discovery is distinguishing allelic variation from sequence variation between paralogous sequences, in addition to recognizing sequencing errors. For the majority of the public EST sequences, trace or quality files are lacking which makes detection of reliable SNPs even more difficult because it has to rely on sequence comparisons only. RESULTS: We have developed a new algorithm to detect reliable SNPs and insertions/deletions (indels) in EST data, both with and without quality files. Implemented in a pipeline called QualitySNP, it uses three filters for the identification of reliable SNPs. Filter 1 screens for all potential SNPs and identifies variation between or within genotypes. Filter 2 is the core filter that uses a haplotype-based strategy to detect reliable SNPs. Clusters with potential paralogs as well as false SNPs caused by sequencing errors are identified. Filter 3 screens SNPs by calculating a confidence score, based upon sequence redundancy and quality. Non-synonymous SNPs are subsequently identified by detecting open reading frames of consensus sequences (contigs) with SNPs. The pipeline includes a data storage and retrieval system for haplotypes, SNPs and alignments. QualitySNP's versatility is demonstrated by the identification of SNPs in EST datasets from potato, chicken and humans. CONCLUSION: QualitySNP is an efficient tool for SNP detection, storage and retrieval in diploid as well as polyploid species. It is available for running on Linux or UNIX systems. The program, test data, and user manual are available at and as Additional files

Constructing prediction models for excessive daytime sleepiness by nomogram and machine learning: A large Chinese multicenter cohort study

ObjectiveAlthough risk factors for excessive daytime sleepiness (EDS) have been reported, there are still few cohort-based predictive models for EDS in Parkinson’s disease (PD). This 1-year longitudinal study aimed to develop a predictive model of EDS in patients with PD using a nomogram and machine learning (ML).Materials and methodsA total of 995 patients with PD without EDS were included, and clinical data during the baseline period were recorded, which included basic information as well as motor and non-motor symptoms. One year later, the presence of EDS in this population was re-evaluated. First, the baseline characteristics of patients with PD with or without EDS were analyzed. Furthermore, a Cox proportional risk regression model and XGBoost ML were used to construct a prediction model of EDS in PD.ResultsAt the 1-year follow-up, EDS occurred in 260 of 995 patients with PD (26.13%). Baseline features analysis showed that EDS correlated significantly with age, age of onset (AOO), hypertension, freezing of gait (FOG). In the Cox proportional risk regression model, we included high body mass index (BMI), late AOO, low motor score on the 39-item Parkinson’s Disease Questionnaire (PDQ-39), low orientation score on the Mini-Mental State Examination (MMSE), and absence of FOG. Kaplan–Meier survival curves showed that the survival prognosis of patients with PD in the high-risk group was significantly worse than that in the low-risk group. XGBoost demonstrated that BMI, AOO, PDQ-39 motor score, MMSE orientation score, and FOG contributed to the model to different degrees, in decreasing order of importance, and the overall accuracy of the model was 71.86% after testing.ConclusionIn this study, we showed that risk factors for EDS in patients with PD include high BMI, late AOO, a low motor score of PDQ-39, low orientation score of MMSE, and lack of FOG, and their importance decreased in turn. Our model can predict EDS in PD with relative effectivity and accuracy

Rank Optimization for MIMO systems with RIS: Simulation and Measurement

Reconfigurable intelligent surface (RIS) is a promising technology that can reshape the electromagnetic environment in wireless networks, offering various possibilities for enhancing wireless channels. Motivated by this, we investigate the channel optimization for multiple-input multiple-output (MIMO) systems assisted by RIS. In this paper, an efficient RIS optimization method is proposed to enhance the effective rank of the MIMO channel for achievable rate improvement. Numerical results are presented to verify the effectiveness of RIS in improving MIMO channels. Additionally, we construct a 2$\times$2 RIS-assisted MIMO prototype to perform experimental measurements and validate the performance of our proposed algorithm. The results reveal a significant increase in effective rank and achievable rate for the RIS-assisted MIMO channel compared to the MIMO channel without RIS

Characteristics of buried paleo-channels in the Western South Yellow Sea during the Late Last Glaciation

Istraživanja o evoluciji paleolitskih korita u obalnim područjima važna su za konstrukcije podmorskog inženjerstva i za otkrivanje promjena u globalnom paleolitskom okruženju. Stoga je za istraživanje značajki paleo-korita tijekom kasnog posljednjeg ledenog doba u zapadnom Južnom Žutom moru primijenjena digitalna metoda analize terena i ArcGis funkcija porijekla rijeke, analizirani su plitki stratigrafski seizmički profili visoke rezolucije i osnovni podaci, a rabljene su empirijske formule rijeke za određivanje riječnih svojstava i struktura. Rezultati pokazuju da je drevni riječni sustav tijekom kasnog posljednjeg ledenog doba grebena Južnog Žutog mora podijeljen na paleo-Žutu (Huanghe) i paleo-Yangtze (Changjiang) rijeku. Paleo-korita blizu 33°N pripadaju paleo-Yangtze rijeci i uglavnom teku od istoka do sjeveroistoka. Paleo-korita oko 35°N i 123,5°E dio su paleo-Žute rijeke. U usporedbi s paleo-Žutom rijekom, paleo-Yangtze rijeka inklinira horizontalnom premiještanju, ima veću prodornu moć i veću količinu vode. Na temelju metode širine nagiba sustav paleo-Žute rijeke može se smatrati uglavnom krivudavim dok je sustav paleo-Yangtze rijeke uglavnom sustav račvaste (braided) rijeke. Pronađene su značajne razlike između paleo-Yangtze rijeke i paleo-Žute rijeke. Značajke podzemnih paleo-korita tijekom kasnog posljednjeg ledenog doba mogu biti korisne u predviđanju popratne moguće opasnosti kod podvodnih konstrukcija i otkrivanju promjena paleookruženja u grebenu Južnog Žutog mora.Studies on the evolution of paleo-channels in coastal areas are important for submarine engineering construction and to reveal changes in the global paleoenvironment. Thus, to explore the characteristics of paleo-channels during the late Last Glaciation in the western South Yellow Sea, digital terrain analysis method and ArcGis river extraction function were employed, high-resolution shallow stratigraphic seismic profiles and core data were analysed, and river empirical formulas were used to determine river properties and river patterns. Results indicate that the ancient river system during the late Last Glaciation of the South Yellow Sea shelf is divided into paleo-Yellow (Huanghe) and paleo-Yangtze (Changjiang) Rivers. The paleo-channels near 33°N belong to the paleo-Yangtze River, and generally flow from east to northeast. The paleo-channels around 35°N and 123,5°E are part of the paleo-Yellow River. Compared with the paleo-Yellow River, the paleo-Yangtze River is prone to horizontal migration and has higher penetration depths and discharge. Based on the slope-width method, the paleo-Yellow River system can be considered mainly as a meandering river, whereas the paleo-Yangtze River system is largely a braided river. Remarkable differences are found between the paleo-Yangtze River and the paleo-Yellow River. The characteristics of buried paleo-channels during the late Last Glaciation can be useful in predicting the incident potential hazard of submarine engineering and in revealing the paleoenvironment changes in the South Yellow Sea shelf

Endothelium- targeted overexpression of Krüppel- like factor 11 protects the blood- brain barrier function after ischemic brain injury

Microvascular endothelial cell (EC) injury and the subsequent blood- brain barrier (BBB) breakdown are frequently seen in many neurological disorders, including stroke. We have previously documented that peroxisome proliferator- activated receptor gamma (PPARγ)- mediated cerebral protection during ischemic insults needs Krüppel- like factor 11 (KLF11) as a critical coactivator. However, the role of endothelial KLF11 in cerebrovascular function and stroke outcome is unclear. This study is aimed at investigating the regulatory role of endothelial KLF11 in BBB preservation and neurovascular protection after ischemic stroke. EC- targeted overexpression of KLF11 significantly mitigated BBB leakage in ischemic brains, evidenced by significantly reduced extravasation of BBB tracers and infiltration of peripheral immune cells, and less brain water content. Endothelial cell- selective KLF11 transgenic (EC- KLF11 Tg) mice also exhibited smaller brain infarct and improved neurological function in response to ischemic insults. Furthermore, EC- targeted transgenic overexpression of KLF11 preserved cerebral tight junction (TJ) levels and attenuated the expression of pro- inflammatory factors in mice after ischemic stroke. Mechanistically, we demonstrated that KLF11 directly binds to the promoter of major endothelial TJ proteins including occludin and ZO- 1 to promote their activities. Our data indicate that KLF11 functions at the EC level to preserve BBB structural and functional integrity, and therefore, confers brain protection in ischemic stroke. KLF11 may be a novel therapeutic target for the treatment of ischemic stroke and other neurological conditions involving BBB breakdown and neuroinflammation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155919/1/bpa12831_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155919/2/bpa12831.pd

Large-scale identification of polymorphic microsatellites using an in silico approach

<p>Abstract</p> <p>Background</p> <p>Simple Sequence Repeat (SSR) or microsatellite markers are valuable for genetic research. Experimental methods to develop SSR markers are laborious, time consuming and expensive. <it>In silico </it>approaches have become a practicable and relatively inexpensive alternative during the last decade, although testing putative SSR markers still is time consuming and expensive. In many species only a relatively small percentage of SSR markers turn out to be polymorphic. This is particularly true for markers derived from expressed sequence tags (ESTs). In EST databases a large redundancy of sequences is present, which may contain information on length-polymorphisms in the SSR they contain, and whether they have been derived from heterozygotes or from different genotypes. Up to now, although a number of programs have been developed to identify SSRs in EST sequences, no software can detect putatively polymorphic SSRs.</p> <p>Results</p> <p>We have developed PolySSR, a new pipeline to identify polymorphic SSRs rather than just SSRs. Sequence information is obtained from public EST databases derived from heterozygous individuals and/or at least two different genotypes. The pipeline includes PCR-primer design for the putatively polymorphic SSR markers, taking into account Single Nucleotide Polymorphisms (SNPs) in the flanking regions, thereby improving the success rate of the potential markers. A large number of polymorphic SSRs were identified using publicly available EST sequences of potato, tomato, rice, <it>Arabidopsis</it>, <it>Brassica </it>and chicken.</p> <p>The SSRs obtained were divided into long and short based on the number of times the motif was repeated. Surprisingly, the frequency of polymorphic SSRs was much higher in the short SSRs.</p> <p>Conclusion</p> <p>PolySSR is a very effective tool to identify polymorphic SSRs. Using PolySSR, several hundred putative markers were developed and stored in a searchable database. Validation experiments showed that almost all markers that were indicated as putatively polymorphic by polySSR were indeed polymorphic. This greatly improves the efficiency of marker development, especially in species where there are low levels of polymorphism, like tomato. When combined with the new sequencing technologies PolySSR will have a big impact on the development of polymorphic SSRs in any species.</p> <p>PolySSR and the polymorphic SSR marker database are available from <url>http://www.bioinformatics.nl/tools/polyssr/</url>.</p