Abstract A recent study identified a missense mutation in coiled-coil-helix-coiled-coil-helix domain–containing 2 ( CHCHD2 ) gene, p.Thr61Ile, in a Japanese multigenerational family with autosomal ...dominant Parkinson's disease (PD). Subsequent analyses identified several genetic variants in this gene that contributed to increased risk of sporadic PD, making CHCHD2 a novel candidate gene associated with PD. However, independent studies are warranted to confirm the role of CHCHD2 in PD. Among 1433 participated subjects, we sequenced all exons and exon-intron boundaries of CHCHD2 from 137 probands with familial PD and 129 age/sex-matched controls. An additional 586 sporadic PD patients and another 581 independent controls were later screened to validate possible risk substitutions. We found no CHCHD2 mutations, but we observed 5 genetic variants, including p.Pro2Leu (rs142444896), a risk variant for sporadic PD in Japanese populations. However, we did not find any significant associations between p.Pro2Leu (rs142444896) and risk of PD in our study cohort (0.86% vs. 1.20%, p = 0.20). Our data suggest that genetic variants of CHCHD2 do not play a major role in our Taiwanese PD population.
Mutations in transmembrane protein 230 (TMEM230) have recently been reported to be associated with Parkinson's disease (PD) in a North American population. A highly prevalent mutation, ...c.550_552delTAGinsCCCGGG (p.*184ProGlyext*5) was found in 3.1% of Chinese familial PD patients. However, subsequent studies failed to replicate these findings in different populations. Our objective was to confirm the role of this gene in a large number of PD patients and controls in a Taiwanese population. Among 1,672 participants, we sequenced all coding exons and exon–intron boundary junctions of the TMEM230 gene in 180 probands with familial PD. We also genotyped the potential pathogenic variants identified and the previously reported mutations (p.Arg141Leu, p.Tyr92Cys, p.*184Trpext*5, and p.*184ProGlyext*5) in an additional cohort of 500 patients with sporadic PD, and 992 age and gender‐matched neurologically normal control subjects. We did not find any of the previously reported mutations, but we observed one novel missense exonic variant, c.G68A (p.Arg23Gln), in one patient with familial PD, and two patients with sporadic PD in a heterozygous state. However, subsequent analysis of this variant in 992 controls did not find any significant associations between p.Arg23Gln and the risk of PD (0.44% vs. 0.30%, p = 0.22). Our findings suggest that genetic variants of TMEM230 do not play a major role in PD in our Taiwanese population. Further experimental studies are warranted to confirm the pathogenicity of this gene in PD disease process.
Abstract Introduction Leucine-rich repeat kinase 2 ( LRRK2 ) mutations are the most common genetic cause of Parkinson's disease (PD). However, only few cases carrying LRRK2 mutations have been ...reported in Taiwanese PD patients. Methods We used targeted next generation sequencing (NGS), covering 24 candidate genes involved in neurodegenerative disorders, to analyze 40 probands with familial PD, and 10 patients with mixed neurodegenerative disorders. Sanger sequencing of the identified mutation in the first set of the study was performed in additional 270 PD patients, including 139 familial PD and 131 early-onset PD (onset age less than 50 years old), and 300 age/gender matched control subjects. Results We found a missense variant, p.I2012T, in the LRRK2 gene in one sporadic patient having early-onset frontotemporal dementia with parkinsonism and dystonia. Sanger sequencing this substitution in additional 270 PD patients in the second set of the study revealed two additional variant carriers: one having autosomal-dominant familial PD, and one with sporadic PD. The p.I2012T substitution was absent in 300 normal control subjects. Analyzing family members of the proband with p.I2012T revealed co-segregation of the variant and parkinsonism. Clinical presentations, levodopa responses, andTc99m TRODAT-SPECT imaging findings of this index family were similar to idiopathic PD. Conclusions Our results revealed clinical heterogeneity of the LRRK2 p.I2012T substitution, and demonstrated the use of targeted NGS for genetic diagnosis in multiplex families with PD or mixed neurodegenerative disorders.
Abstract Whole-exome sequencing recently identified a homozygous truncating mutation in Synaptojanin 1 ( SYNJ1 , PARK20 ), p.Arg258Gln, in 2 independent families with autosomal recessive young-onset ...parkinsonism with seizures and cognitive decline. This mutation's role in typical Parkinson's disease (PD) is unclear. We sequenced all coding exons and exon-intron boundaries of SYNJ1 gene in a total of 700 participants: 250 early-onset PD patients, 100 familial PD patients with family history, and 350 age/sex-matched controls from Taiwan. No patients harbored homozygous or compound heterozygous mutations of SYNJ1 gene in our study population. We observed 1 novel missense substitution, p.Ala551Val, in a single heterozygous state in 1 early-onset PD patient. This variant was not observed in controls with total 700 normal alleles. The clinical phenotype of this genetic variant carrier is similar to that seen in idiopathic PD, with motor fluctuation after 11 years of PD diagnosis and comorbidity with dementia after 13 years of motor symptoms. Our results suggest that mutations in SYNJ1 gene do not play a major role in early-onset or familial PD in our population.
Abstract A recent collaborative study that combined linkage analysis with whole-genome sequencing of family members of multiplex families with multiple system atrophy (MSA) has identified COQ2 gene ...as a causative gene for MSA. The common variant, c.T1178C (p.V393A, rs148156462), in the COQ2 gene was found to be associated with an increased risk of sporadic MSA. There is overlapping clinical characteristics between MSA and Parkinson's disease (PD), and the pathologic hallmark of both diseases is α-synucleinopathy. We therefore aim to analyze the COQ2 p.V393A variant in a large Taiwanese cohort with PD patients. We genotyped COQ2 p.V393A variant in a total of 1005 participants, comprising 500 patients with PD and 505 age/gender-matched control subjects. The frequency of TC/CC genotype was comparable between PD patients and control subjects (odds ratio: 0.81, 95% confidence interval: 0.42–1.56, p = 0.53). COQ2 p.V393A variant is not a genetic risk factor for PD, suggesting its specificity in disease susceptibility to MSA.
The forest ecosystem plays a pivotal role in contributing greenhouse gases to the atmosphere.In order to characterize the temporal pattern of nitrous oxide（N2O） emissions and identify the key factors ...affecting N2O emissions from a Masson pine forest in a hilly red-soil region in subtropical central China,we measured the N2O emissions in Jinjing of Hunan Province using the static chambergas chromatographic method for 3 years（2010-2012） and analyzed the relationships between the N2O fluxes and the environmental variables.Our results revealed that the N2O fluxes over the 3 years varied from-36.0 to 296.7 μg N m^-2 h^-1,averaging 18.4±5.6 μg N m^-2 h^-1（n=3）.The average annual N2O emissions were estimated to be 1.6±0.3 kg N ha^-1 year^-1.The N2O fluxes exhibited clear intra-annual（seasonal） variations as they were higher in summers and lower in winters.Compared with other forest observations in the subtropics,N2O emissions at our site were relatively high,possibly due to the high local dry/wet N deposition,and were mostly sensitive to variations in precipitation and soil ammonium N content.In this work,a multiple linear regression model was developed to determine the influence of environmental factors on N2O emissions,in which a category predictor of ＂Season＂ was intentionally used to account for the seasonal variation of the N2O fluxes.Such a model explained almost 40%of the total variation in daily N2O emissions from the Masson pine forest soil studied（P〈0.001）.
Background Type 2 diabetes mellitus （T2DM） results from the complex association of insulin resistance and pancreatic β-cell failure. Recent studies have shown that patients diagnosed with T2DM ...present with a significant decrease in β-cell function, which can be further compromised during the progression of the disease. Several mechanisms have been shown to play a role in this process such as glucotoxicity and lipotoxicity, which contribute to accelerating insulin secretion. In this regard, Chinese medicine has a certain advantage. This experiment was performed to observe the effect of a Chinese medicine named Kaiyuqingre formula （KYQRF） on β-cell function and its mechanisms of action therein. Methods High glucose was used to set up a model of β-cell function failure. At the same time, medicated serum of KYQRF with different doses were administered to the cells. Rosiglitazone was taken as a control to observe the changes in insulin secretion, ATP-sensitive K＋ channels （KATP channel） and uncoupling protein-2 （UCP-2） in each group. Results KYQRF had some effects on the insulin secretion. In a low glucose environment, no effective change in insulin secretion was observed （P 〉0.05）. However, insulin levels increased significantly when INS-1 cells were exposed to a high glucose environment （P 〈0.05）. KYQRF could also enhance cell viability （P 〈0.05） in an effect similar to rosiglitazone. Although KYQRF had no effect on inwardly rectifying potassium channels （Kir6.2） （P 〉0.05）, it could decrease the overexpression of both UCP-2 and sulfonylurea receptor 1 （P〈0.05）. Conclusion KYQRF can protect islet function by decreasing UCP-2 and sulfonylurea receptor 1.
Background Acute kidney injury （AKI） has been recognized as a major healthcare problem affecting millions of patients worldwide.However,epidemiologic data concerning AKI in China are still ...lacking.The objectives of this study were to characterize AKI defined by RIFLE criteria,assess the association with hospital mortality,and evaluate the impact of AKI in the context of other risk factors.Methods This prospective multicenter observational study enrolled 3,063 consecutive patients from 1 July 2009 to 31 August 2009 in 22 ICUs across mainland China.We excluded patients who were admitted for less than 24 hours （n=1623）,younger than 18 years （n=127）,receiving chronic hemodialysis （n=29）,receiving renal transplantation （n=1） and unknown reasons （n=28）.There were 1255 patients in the final analysis.AKI was diagnosed and classified according to RIFLE criteria.Results There were 396 patients （31.6％） who had AKI,with RIFLE maximum class R,I,and F in 126 （10.0％）,91 （7.3％）,and 179 （14.3％） patients,respectively.Renal function deteriorated in 206 patients （16.4％）.In comparison with non AKI patients,patients in the risk class on ICU admission were more likely to progress to the injury class （odds ratio （OR） 3.564,95％ confidence interval （CI） 1.706-7.443,P =0.001,while patients in the risk class （OR 5.215,95％ CI 2.798-9.719,P ＜0.001） and injury class （OR 13.316,95％ CI 7.507-23.622,P ＜0.001） had a significantly higher probability of deteriorating into failure class.The adjusted hazard ratios for 90-day mortality were 1.884 for the risk group,3.401 for the injury group,and 5.306 for the failure group.Conclusions The prevalence of AKI was high among critically ill patients in Chinese ICUs.In comparison with non-AKI patients,patients with RIFLE class R or class I on ICU admission were more susceptibility to progression to class I or class F.The RIFLE criteria were robust and correlated well with clinical deterioration and mortality.
The flow behavior of delta-processed Inconel 718 was studied in temperature range of 900-1 060℃ and strain rate range of 0.001-0.5s-1.The effects of friction and temperature on the compressive ...deformation behavior were investigated,and the flow stress-strain error caused by friction was revised.The results showed that the effect of the friction was obvious with increasing strain rate and decreasing deformation temperature.The revised flow stress is decreased by increasing temperature and decreasing strain rate and exhibits a typical dynamic recrystallization behavior.The constitutive model has been developed through a hyperbolic-sine Arrhenius type equation to relate the flow stress,strain rate and temperature.The influence of strain has also been incorporated by considering the variation of material constants as a function of strain.The prediction accuracy of developed constitutive model has been assessed using standard statistical formulae.According to the analysis results,the proposed deformation constitutive equation gives an accurate and precise estimate of flow stress of delta-processed Inconel 718 alloy.
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