Differentially Expressed miR-511-3p in Stroke Patients Predicts the Presence of Post-Stroke Cognitive Impairment.

INTRODUCTION: Stroke is common cerebrovascular disease in the elderly, which is characterized by neurological defects caused by cerebral vessels. Multiple studies have shown that miRNAs play important roles in stroke. In addition, a large number of evidence suggest that stroke increases the risk and severity of cognitive impairments. METHODS: miR-511-3p expression levels were detected by real-time PCR. Receiver operating characteristic (ROC) curve analysis was used to evaluate the diagnostic value of miR-511-3p in distinguishing stroke patients from healthy controls and to assess risk of post-stroke cognitive impairment (PSCI) in stroke patients. Pearson correlation coefficient was used to determine the relationship between miR-511-3p expression level and Montreal Cognitive Assessment Scale (MoCA) scores. RESULTS: Serum miR-511-3p expression levels were decreased in stroke patients, and the decrease was more significant in PSCI patients. ROC curve results showed that miR-511-3p had high diagnostic accuracy in distinguishing healthy controls from stroke patients. Moreover, the expression level of miR-511-3p can be used as an independent predictor for the occurrence of PSCI and is positively correlated with MoCA scores of PSCI patients. CONCLUSION: miR-511-3p may be involved in the occurrence and development of stroke. In addition, miR-511-3p may be a novel biomarker for predicting PSCI occurred in stroke patients. These results may help improve the quality of prognosis of stroke.

Discovery of Partial Differential Equations from Highly Noisy and Sparse Data with Physics-Informed Information Criterion.

Data-driven discovery of partial differential equations (PDEs) has recently made tremendous progress, and many canonical PDEs have been discovered successfully for proof of concept. However, determining the most proper PDE without prior references remains challenging in terms of practical applications. In this work, a physics-informed information criterion (PIC) is proposed to measure the parsimony and precision of the discovered PDE synthetically. The proposed PIC achieves satisfactory robustness to highly noisy and sparse data on 7 canonical PDEs from different physical scenes, which confirms its ability to handle difficult situations. The PIC is also employed to discover unrevealed macroscale governing equations from microscopic simulation data in an actual physical scene. The results show that the discovered macroscale PDE is precise and parsimonious and satisfies underlying symmetries, which facilitates understanding and simulation of the physical process. The proposition of the PIC enables practical applications of PDE discovery in discovering unrevealed governing equations in broader physical scenes.

PRRT2 frameshift mutation reduces its mRNA stability resulting loss of function in paroxysmal kinesigenic dyskinesia.

A heterozygous frameshift PRRT2 mutation (c.649_650InsC) has been identified as the major causative mutation in several paroxysmal disorders, including paroxysmal kinesigenic dyskinesia (PKD). Since PKD is an autosomal dominant disorder and since the frameshift mutations of PRRT2 may create a truncated protein, it remains unclear whether this mutation causes toxic gain of function or loss of function. By generating Prrt2 knock-in (KI) mice that express human PRRT2 with the c.649_650InsC mutation and by comparing the phenotypes of Prrt2 KI mice with knockout (KO) mice, we find that both KI and KO mice show the same extents of impaired rotarod and balance beam performance as well as the same sensitivity to seizure induction. Both KI and KO mice show altered formation of SNARE complex and number of synaptic vesicles. In addition, western blotting of KI mouse brain tissues could not detect truncated PRRT2 protein that might be generated by the c.649_650InsC mutation. Moreover, the level of PRRT2 mRNA in KI mice is significantly decreased, recapitulating the reduction of PRRT2 mRNA reported in PKD patients. Furthermore, mutant PRRT2 mRNA is unstable and showed shortened half-life than wild-type PRRT2 mRNA. Our studies suggest that PRRT2 frameshift mutation leads to the loss of function by affecting its mRNA stability, a mechanism that is different from haploinsufficiency due to dysfunctional protein or gain of function caused by truncated protein.

C9ORF72 repeat expansion is not detected in sporadic ataxia patients in mainland China.

Expansion of a GGGGCC hexanucleotide repeat in the gene C9ORF72 is a common pathogenic mutation in families with autosomal dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In order to understand whether pathogenic GGGGCC expansions of C9ORF72 are associated with spinocerebellar ataxia (SCA) in mainland China, we performed an experiment to determine the prevalence of pathogenic hexanucleotide expansions of C9ORF72 in a large cohort of Chinese Han patients with SCA. 411 sporadic patients with SCA and 314 healthy controls were screened for pathogenic hexanucleotide expansions of C9ORF72 utilizing a repeat primed polymerase chain reaction assay. However, no pathological repeat expansion of C9ORF72 was detected in either patients or controls. We therefore conclude that an expansion in C9ORF72 may not play a significant role in SCA in our cohort. However, more studies are needed to draw conclusions for the general population.

Spinocerebellar ataxia type 21 exists in the Chinese Han population.

Recently, mutations in transmembrane protein 240 (TMEM240) were identified as the cause of spinocerebellar ataxia type 21 (SCA21) in several French families. Clinically, SCA21 is characterized as an early-onset, slowly progressive cerebellar syndrome typically associated with cognitive impairment. To date, molecular screening of SCA21 has not been reported among patients of other ethnic origins or in other areas. Here we used Sanger sequencing to detect mutations in exons of TMEM240 in 340 unrelated probands with spinocerebellar ataxia for whom commonly known causative mutations have been excluded (96 probands of autosomal dominant spinocerebellar ataxia families and 244 patients with sporadic spinocerebellar ataxia). As a result, a de novo missense mutation (c.509C > T/p.P170L) was identified in one sporadic SCA patient. The condition manifested as early-onset (30 years old), slowly progressive cerebellar ataxia accompanied by mild early evidenced mental retardation, mild frontal behavior disorders and intentional hand tremors. Although rare, a SCA21 case was identified and described in mainland China, thus broadening the ethnic distribution of SCA21 beyond French families.

SCA38 is rare in Mainland China.

Spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative disorders distributed worldwide. Nearly 35 SCAs have been localized and 28 genes have been identified. Recently, mutations in the elongation of a very long chain fatty acids-5 gene (ELOVL5) were reported to cause a SCA38 subtype. To describe the epidemiology of SCA38 in Mainland China, we analyzed the coding sequence of ELOVL5 in 346 patients diagnosed as SCAs. Finally, we did not observe any disease-related gene mutations in ELOVL5. This suggests that the SCA38 subtype is very rare in Mainland China.

[Transglutaminase and neurodegenerative diseases].

Transglutaminase (TG) is a kind of calcium-dependent enzymes. The TGase family found in rodents and human contains 9 types, including TG1-7, blood coagulation factor XIIIa and erythrocyte membrane protein 4.2, with the former 8 types possessing catalytic activity. TG catalyzes various conversion reactions of glutamine, including transamination, deamination and esterification, and participates in post-transcriptional modification of proteins such as cross-linking peptides glutamine residue and lysyl-residue, stabilizing protein structure and catalyzing formation of protein aggregates. TGase has been found to contribute to a variety of important physiological and pathological processes and play a role in the pathogenesis of multiple diseases. Notably, neurodegenerative diseases such as Huntington's disease, spinocerebellar ataxia, Alzheimer's disease and Parkinson's disease, have a close connection with TGase's role in the human body.

Friedreich's Ataxia (FRDA) is an extremely rare cause of autosomal recessive ataxia in Chinese Han population.

Friedreich's Ataxia (FRDA) is a very common cause of hereditary autosomal recessive ataxia among western Europeans. We aim to define the frequency of FRDA in Chinese Han population due to the lack of reports of FRDA in China. The GAA trinucleotide repeats in the FXN gene were analyzed by triplet repeat-primed PCR (TP-PCR) in 122 unrelated hereditary ataxia (HA) and 114 unrelated hereditary spastic paraplegia (HSP) patients. The GAA copy numbers in the FXN gene of all the subjects ranged from 5 to 16. There were no FRDA patients that could be diagnosed base on the results of TP-PCR. It suggests that FRDA is a very rare cause of inheritance ataxia and FRDA genetic analysis should not be used as a routine genetic diagnosis test in China.

Chinese homozygous Machado-Joseph disease (MJD)/SCA3: a case report.

A young Chinese male patient was identified as homozygous for Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3. This patient had a 4-year medical history mainly presenting severe ataxia, abnormal eye movement and pyramidal signs. Magnetic resonance imaging of the brain and cervical spinal cord revealed no obvious abnormality despite the severe symptoms and the findings of an electromyogram. However, brainstem auditory evoked potential indicated peripheral impairment and visual evoked potential indicated central impairment of his visual pathways. Molecular diagnosis revealed the pattern of CAG repeat units of this patient was 71/71. This case demonstrates that homozygosity for MJD enhances the clinical severity of the disease, which suggests that genetic education is of great importance.