Abstract
Background
Common and rare variants of guanosine triphosphate cyclohydrolase 1 (
GCH1
) gene may play important roles in Parkinson’s disease (PD). However, there is a lack of comprehensive ...analysis of
GCH1
genotypes, especially in non-coding regions. The aim of this study was to explore the genetic characteristics of
GCH1
, including rare and common variants in coding and non-coding regions, in a large population of PD patients in Chinese mainland, as well as the phenotypic characteristics of
GCH1
variant carriers.
Methods
In the first cohort of this case-control study, we performed whole-exome sequencing in 1555 patients with early-onset or familial PD and 2234 healthy controls; then in the second cohort, whole-genome sequencing was performed in sporadic late-onset PD samples (1962 patients), as well as 1279 controls. Variants at target
GCH1
regions were extracted, and then genetic and detailed phenotypic data were analyzed using regression models and the sequence kernel association test. We also performed a meta-analysis to correlate deleterious
GCH1
variants with age at onset (AAO) in PD patients.
Results
For coding variants, we identified a significant burden of
GCH1
deleterious variants in early-onset or familial PD cases compared to controls (1.2% vs 0.1%,
P
< 0.0001). In the analysis of possible regulatory variants in
GCH1
non-coding regions, rs12323905 (
P
= 0.001, odds ratio = 1.19, 95%CI 1.07–1.32) was significantly associated with PD, and variant sets in untranslated regions and intron regions,
GCH1
brain-specific expression quantitative trait loci, and two possible promoter/enhancer (GH14J054857 and GH14J054880) were suggestively associated with PD. Genotype-phenotype correlation analysis revealed that the carriers of
GCH1
deleterious variants manifested younger AAO (
P
< 0.0001), and had milder motor symptoms, milder fatigue symptoms and more autonomic nervous dysfunctions. Meta-analysis of six studies demonstrated 6.4-year earlier onset in
GCH1
deleterious variant carriers (
P
= 0.0009).
Conclusions
The results highlight the importance of deleterious variants and non-coding variants of
GCH1
in PD in Chinese mainland and suggest that
GCH1
mutation can influence the PD phenotype, which may help design experimental studies to elucidate the mechanisms of
GCH1
in the pathogenesis of PD.
Background:
Recent years have witnessed an increasing number of studies indicating an essential role of the lysosomal dysfunction in Parkinson’s disease (PD) at the genetic, biochemical, and cellular ...pathway levels. In this study, we investigated the association between rare variants in lysosomal storage disorder (LSD) genes and Chinese mainland PD.
Methods:
We explored the association between rare variants of 69 LSD genes and PD in 3,879 patients and 2,931 controls from Parkinson’s Disease & Movement Disorders Multicenter Database and Collaborative Network in China (PD-MDCNC) using next-generation sequencing, which were analyzed by using the optimized sequence kernel association test.
Results:
We identified the significant burden of rare putative LSD gene variants in Chinese mainland patients with PD. This association was robust in familial or sporadic early-onset patients after excluding the
GBA
variants but not in sporadic late-onset patients. The burden analysis of variant sets in genes of LSD subgroups revealed a suggestive significant association between variant sets in genes of sphingolipidosis deficiency disorders and familial or sporadic early-onset patients. In contrast, variant sets in genes of sphingolipidoses, mucopolysaccharidoses, and post-translational modification defect disorders were suggestively associated with sporadic late-onset patients. Then,
SMPD1
and other four novel genes (i.e.,
GUSB, CLN6, PPT1
, and
SCARB2
) were suggestively associated with sporadic early-onset or familial patients, whereas
GALNS
and
NAGA
were suggestively associated with late-onset patients.
Conclusion:
Our findings supported the association between LSD genes and PD and revealed several novel risk genes in Chinese mainland patients with PD, which confirmed the importance of lysosomal mechanisms in PD pathogenesis. Moreover, we identified the genetic heterogeneity in early-onset and late-onset of patients with PD, which may provide valuable suggestions for the treatment.
Recent studies have suggested ARSA, a gene responsible for metachromatic leukodystrophy, could be a genetic modifier of Parkinson's disease (PD) pathogenesis, acting as a molecular chaperone for ...α-synuclein. To elucidate the role of ARSA variants in PD, we did a comprehensive analysis of ARSA variants by performing next-generation sequencing on 477 PD families, 1440 sporadic early-onset PD patients and 1962 sporadic late-onset PD patients and 2636 controls from Chinese mainland, as well as the association between ARSA variants and cognitive function of PD patients. We identified 2 familial PD following autosomal dominant inherence carrying rare variants of ARSA, but they had limited clinical significance. We detected a total of 81 coding variants of ARSA in our subjects but none of the identified variants were associated with either susceptibility or cognitive performance of PD, while loss-of-function variants showed slightly increased burden in late-onset PD (0.25% vs. 0%, p = 0.08). Our results suggested ARSA may not play important roles in PD of Chinese population.
The complete description of a continuous-wave light field includes its four fundamental properties: wavelength, polarization, phase and amplitude. However, the simultaneous measurement of a ...multi-dimensional light field of such four degrees of freedom is challenging in conventional optical systems requiring a cascade of dispersive and polarization elements. In this work, we demonstrate a disordered-photonics-assisted intelligent four-dimensional light field sensor. This is achieved by discovering that the speckle patterns, generated from light scattering in a disordered medium, are intrinsically sensitive to a high-dimension light field given their high structural degrees of freedom. Further, the multi-task-learning deep neural network is leveraged to process the single-shot light-field-encoded speckle images free from any prior knowledge of the complex disordered structures and realizes the high-accuracy recognition of full-Stokes vector, multiple orbital angular momentum (OAM), wavelength and power. The proof-of-concept study shows that the states space of four-dimensional light field spanning as high as 1680=4 (multiple-OAM)
×
2 (OAM power spectra)
×
15 (multiple-wavelength)
×
14 (polarizations) can be well recognized with high accuracy in the chip-integrated sensor. Our work provides a novel paradigm for the design of optical sensors for high-dimension light fields, which can be widely applied in optical communication, holography, and imaging.
A variety of microbially mediated metabolic pathways impact biogeochemical cycling in terrestrial subsurface environments. However, the role that viruses have in influencing microbial mortality and ...microbial community structure is poorly understood. Here we investigated the production of viruses and change in microbial community structure within shallow alluvial aquifer sediment slurries amended with (13)C-labeled acetate and nitrate. Biostimulation resulted in production of viruses concurrent with acetate oxidation, (13)CO2 production and nitrate reduction. Interestingly, change in viral abundance was positively correlated to acetate consumption (r(2)=0.6252, P<0.05) and (13)CO2 production (r(2)=0.6572, P<0.05); whereas change in cell abundance was not correlated to acetate consumption or (13)CO2 production. Viral-mediated cell lysis has implications for microbial community structure. Betaproteobacteria predominated microbial community composition (62% of paired-end reads) upon inoculation but decreased in relative abundance and was negatively correlated to changes in viral abundance (r(2)=0.5036, P<0.05). As members of the Betaproteobacteria decreased, Gammaproteobacteria, specifically Pseudomonas spp., increased in relative abundance (82% of paired-end reads) and was positively correlated with the change in viral abundance (r(2)=0.5368, P<0.05). A nitrate-reducing bacterium, Pseudomonas sp. strain Alda10, was isolated from these sediments and produced viral-like particles with a filamentous morphology that did not result in cell lysis. Together, these results indicate that viruses are linked to carbon biogeochemistry and community structure in terrestrial subsurface sediments. The subsequent cell lysis has the potential to alter available carbon pools in subsurface environments, additionally controlling microbial community structure from the bottom-up.
Introduction: In paediatric practice, healthcare professionals are required to connect with the child and interact at his/her level. However, it can be very difficult for medical students to put ...themselves in the shoes of the young child, to empathize and understand how a child actually feels while being treated. The Teddy Bear Hospital (TBH) can serve as a platform for medical students to learn how to communicate and empathise with children. Additionally, virtual reality (VR) can be used to portray a child’s viewpoint. This study aims to assess how TBH and VR can improve learning outcomes for medical students. Methods: A cohort study was conducted on 20 first-year medical students taking part in TBH sessions. The medical students did a Pre-, Post- and 1-year Post-intervention Jefferson Scale of Empathy to assess their empathy levels. They also completed a 1-year Post-intervention quantitative and qualitative survey on their experience. Results: There was a significant increase in Jefferson score compared to Pre-intervention (116.95 ± 8.19) for both Post-intervention (121.65 ± 11.03) and 1-year Post-intervention (123.31 ± 8.86). More than 80% believed that participating in TBH improved their confidence and ability to interact with children, while 50% felt that VR scenarios helped prepare them for the TBH. Thematic analysis of qualitative responses described (1) Personal development, (2) Insights into interacting with children, and (3) Structure and curriculum. Conclusion: TBH improved empathy and communication with children among pre-clinical medical students and the use of VR can be used to augment sessions.
Approximate dynamic programming is an effective optimal control method. This article researches a data-driven approximate dynamic programming. The method is extended to a nonlinear multi-input ...multi-output form. Using the data from a unique 4JB1-T weifu accumulator pump system (WAPS) engine, the developed approximate dynamic programming controller is trained to achieve its optimal trade-off emission control between the nitrogen oxides and particulate matter. The convergent proof of this method is given. The second-order training algorithm is introduced to promote the robust and convergent performance. The control objective is to let the WAPS engine pass the China State-IV emission test under the New European Drive Cycle. The bench test shows that an excellent control transient performance and significant promotion have been achieved. This article presents a new approach for the engine control and calibration. In addition, it also adds another dimension to the existing literature on the data-driven nonlinear multi-input multi-output trade-off emission control of the WAPS engine.
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