Rare variants in MYH15 modify amyotrophic lateral sclerosis risk.

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by progressive muscular atrophy and respiratory failure. The G4C2 repeat expansion in the C9orf72 gene is the most prevalent genetic risk for ALS. Mutation carriers (C9ALS) display variability in phenotypes such as age-at-onset and duration, suggesting the existence of additional genetic factors. Here we introduce a three-step gene discovery strategy to identify genetic factors modifying the risk of both C9ALS and sporadic ALS (sALS) using limited samples. We first identified 135 candidate genetic modifiers of C9ALS using whole-genome sequencing (WGS) of extreme C9ALS cases diagnosed ~30 years apart. We then performed an unbiased genetic screen using a Drosophila model of the G4C2 repeat expansion with the genes identified from WGS analysis. This genetic screen identified the novel genetic interaction between G4C2 repeat-associated toxicity and 18 genetic factors, suggesting their potential association with C9ALS risk. We went on to test if 14 out of the 18 genes, those which were not known to be risk factors for ALS previously, are also associated with ALS risk in sALS cases. Gene-based-statistical analyses of targeted resequencing and WGS were performed. These analyses together reveal that rare variants in MYH15 represent a likely genetic risk factor for ALS. Furthermore, we show that MYH15 could modulate the toxicity of dipeptides produced from expanded G4C2 repeat. Our study presented here demonstrates the power of combining WGS with fly genetics to facilitate the discovery of fundamental genetic components of complex traits with a limited number of samples.

Highly Stretchable Superhydrophobic Composite Coating Based on Self-Adaptive Deformation of Hierarchical Structures.

With the rapid development of stretchable electronics, functional textiles, and flexible sensors, water-proof protection materials are required to be built on various highly flexible substrates. However, maintaining the antiwetting of superhydrophobic surface under stretching is still a big challenge since the hierarchical structures at hybridized micro-nanoscales are easily damaged following large deformation of the substrates. This study reports a highly stretchable and mechanically stable superhydrophobic surface prepared by a facile spray coating of carbon black/polybutadiene elastomeric composite on a rubber substrate followed by thermal curing. The resulting composite coating can maintain its superhydrophobic property (water contact angle ≈170° and sliding angle <4°) at an extremely large stretching strain of up to 1000% and can withstand 1000 stretching-releasing cycles without losing its superhydrophobic property. Furthermore, the experimental observation and modeling analysis reveal that the stable superhydrophobic properties of the composite coating are attributed to the unique self-adaptive deformation ability of 3D hierarchical roughness of the composite coating, which delays the Cassie-Wenzel transition of surface wetting. In addition, it is first observed that the damaged coating can automatically recover its superhydrophobicity via a simple stretching treatment without incorporating additional hydrophobic materials.

High correlations between plant clonality and ecosystem service functions after management in a chronosequence of evergreen conifer plantations.

Introduction: Climate change and mono-afforestation or mono-reforestation have continuously caused a decline in biodiversity and ecosystem services on forest plantations. Key plant functional traits in forests or plantations may affect ecosystem functions after forest management practices. Plant clonality, a key functional trait, frequently links to biodiversity and ecosystem functions and affects the biodiversity-ecosystem functioning relationship. However, little is known about how plant clonality affects ecosystem functions and services of plantations after forest management. Methods: We conducted a field experiment to discuss the diversity and proportion of clonal plants, plant diversity of the communities, and ecosystem service functions and their relationships under 10 years of close-to-nature (CTN) management, artificial gap management, and control (i.e., without management) in the three stages of C. Lanceolata plantations. Results: Our results showed that CTN and gap management modes significantly facilitated diversity of clonal plants, plant diversity of the communities, and parameters of ecosystem service functions in C. lanceolata plantations. Moreover, CTN management promoted plant community diversity, soil water conservation, and carbon storage the most in the earlier stand stages. Diversity of clonal plants was significantly positively correlated with ecosystem service functions after forest management. Structural equation modeling analysis indicated that forest gap or CTN management indirectly positively affected ecosystem service functions through increasing diversity of clonal woody plants and plant diversity of the communities. Conclusion: Our results indicate a highly positive effect of gap or CTN management on diversity and proportion of clonal plants and on plant diversity of the communities, which link to improvements in ecosystem service functions (i.e., water and soil conservation and carbon storage). The link between forest management, diversity, and ecosystem functions suggests that key functional traits or plant functional groups should be considered to underline the mechanism of traits-ecosystem functioning relationships and the restoration of degraded plantations.

Expression of expanded GGC repeats within NOTCH2NLC causes behavioral deficits and neurodegeneration in a mouse model of neuronal intranuclear inclusion disease.

GGC repeat expansions within NOTCH2NLC have been identified as the genetic cause of neuronal intranuclear inclusion disease (NIID). To understand the molecular pathogenesis of NIID, here, we established both a transgenic mouse model and a human neural progenitor cells (hNPCs) model. Expression of the NOTCH2NLC with expanded GGC repeats produced widespread intranuclear and perinuclear polyglycine (polyG), polyalanine (polyA), and polyarginine (polyR) inclusions, leading to behavioral deficits and severe neurodegeneration, which faithfully mimicked the clinical and pathological features associated with NIID. Furthermore, conserved alternative splicing events were identified between the NIID mouse and hNPC models, among which was the enrichment of the binding motifs of hnRNPM, an RNA binding protein known as alternative splicing regulator. Expanded NOTCH2NLC-polyG and NOTCH2NLC-polyA could interact with and sequester hnRNPM, while overexpression of hnRNPM could ameliorate the cellular toxicity. These results together suggested that dysfunction of hnRNPM could play an important role in the molecular pathogenesis of NIID.

The Natural History of Spinocerebellar Ataxia Type 3 in Mainland China: A 2-Year Cohort Study.

Objective: The natural history of spinocerebellar ataxia type 3 (SCA3) has been reported in several populations and shows heterogeneity in progression rate and affecting factors. However, it remains unexplored in the population of Mainland China. This study aimed to identify the disease progression rate and its potential affecting factors in patients with SCA3 in Mainland China. Participants and Methods: We enrolled patients with genetically confirmed SCA3 in Mainland China. Patients were seen at three visits, i.e., baseline, 1 year, and 2 years. The primary outcome was the Scale for the Assessment and Rating of Ataxia (SARA), and the secondary outcomes were the Inventory of Non-Ataxia Signs (INAS) as well as the SCA Functional Index (SCAFI). Results: Between 1 October 2015, and 30 September 2016, we enrolled 263 patients with SCA3. We analyzed 247 patients with at least one follow-up visit. The annual progression rate of SARA was 1.49 points per year (SE 0.08, 95% confidence interval [CI] 1.33-1.65, p < 0.0001). The annual progression rates of INAS and SCAFI were 0.56 points per year (SE 0.05, 95% CI 0.47-0.66, p < 0.001) and -0.30 points per year (SE 0.01, 95% CI -0.33∼-0.28, p < 0.001), respectively. Faster progression in SARA was associated with longer length of the expanded allele of ATXN3 (p < 0.0001); faster progression in INAS was associated with lower INAS at baseline (p < 0.0001); faster decline in SCAFI was associated with shorter length of the normal allele of ATXN3 (p = 0.036) and higher SCAFI at baseline (p < 0.0001). Conclusion: Our results provide quantitative data on the disease progression of patients with SCA3 in Mainland China and its corresponding affecting factors, which could facilitate the sample size calculation and patient stratification in future clinical trials. Trial Registration: This study was registered with Chictr.org on 15 September 2015, number ChiCTR-OOC-15007124.

Therapeutic Development for CGG Repeat Expansion-Associated Neurodegeneration.

Non-coding repeat expansions, such as CGG, GGC, CUG, CCUG, and GGGGCC, have been shown to be involved in many human diseases, particularly neurological disorders. Of the diverse pathogenic mechanisms proposed in these neurodegenerative diseases, dysregulated RNA metabolism has emerged as an important contributor. Expanded repeat RNAs that form particular structures aggregate to form RNA foci, sequestering various RNA binding proteins and consequently altering RNA splicing, transport, and other downstream biological processes. One of these repeat expansion-associated diseases, fragile X-associated tremor/ataxia syndrome (FXTAS), is caused by a CGG repeat expansion in the 5'UTR region of the fragile X mental retardation 1 (FMR1) gene. Moreover, recent studies have revealed abnormal GGC repeat expansion within the 5'UTR region of the NOTCH2NLC gene in both essential tremor (ET) and neuronal intranuclear inclusion disease (NIID). These CGG repeat expansion-associated diseases share genetic, pathological, and clinical features. Identification of the similarities at the molecular level could lead to a better understanding of the disease mechanisms as well as developing novel therapeutic strategies. Here, we highlight our current understanding of the molecular pathogenesis of CGG repeat expansion-associated diseases and discuss potential therapeutic interventions for these neurological disorders.

No genetic evidence for the involvement of GGC repeat expansions of the NOTCH2NLC gene in Chinese patients with multiple system atrophy.

Recent studies have identified an expanded GGC repeat in the 5' untranslated region of the NOTCH2NLC gene as a possible pathogenic genetic cause of neuronal intranuclear inclusion disease. Converging evidence verifying the presence of the same GGC repeat expansion in patients with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases has also received increased attention. Inspired by some of the clinical similarities between neuronal intranuclear inclusion disease and multiple system atrophy (MSA), we used repeat-primed PCR to explore the occurrence of GGC repeats in 328 patients with MSA in mainland China. Our result failed to detect any GGC repeat expansion in these patients with MSA, indicating that the NOTCH2NLC gene may not be involved in the pathogenesis of MSA.

Corrigendum: Alterations of the Gut Microbiota in Multiple System Atrophy Patients.

[This corrects the article DOI: 10.3389/fnins.2019.01102.].

Alterations of the Gut Microbiota in Multiple System Atrophy Patients.

Multiple system atrophy (MSA) is a fatal neurodegenerative disease, and the pathogenesis is still quite challenging. Emerging evidence has shown that the brain-gut-microbiota axis served a pivotal role in neurological diseases; however, researches utilizing metagenomic sequencing to analyze the alteration in gut microbiota of MSA patients were quite rare. Here, we carried out metagenomic sequencing in feces of 15 MSA patients and 15 healthy controls, to characterize the alterations in gut microbial composition and function of MSA patients in mainland China. The results showed that gut microbial community of MSA patients was significantly different from healthy controls, characterized by increased genus Akkermansia and species Roseburia hominis, Akkermansia muciniphila, Alistipes onderdonkii, Streptococcus parasanguinis, and Staphylococcus xylosus, while decreased genera Megamonas, Bifidobacterium, Blautia, and Aggregatibacter and species Bacteroides coprocola, Megamonas funiformis, Bifidobacterium pseudocatenulatum, Clostridium nexile, Bacteroides plebeius, and Granulicatella adiacens. Further, functional analysis based on the KEGG database revealed aberrant functional pathways in fecal microbiome of MSA patients. In conclusion, our findings provided evidence for dysbiosis in gut microbiota of Chinese MSA cohorts and helped develop new testable hypotheses on pathophysiology of MSA.

Effects of exogenous 6-BA and NAA on growth and contents of medicinal ingredient of Phellodendron chinense seedlings.

Using Phellodendron chinense seedlings as material, and treated with different concentrations of exogenous 6-Benzylaminopurine (6-BA) and α-naphthyacetic acid (NAA), then observed the growth status. Furthermore, we detected the contents of chlorophyll and soluble sugar, the activities of antioxidases by spectrophotometry, and determined the contents of secondary metabolite by high performance liquid chromatograph. The results showed that different concentrations of exogenous 6-BA increases the fresh weights and plant heights of Phellodendron chinense seedlings, and enhances the contents of chlorophyll and soluble sugar. NAA promoted growth, but deduced the contents of soluble sugar. Compared with control, culturing for 40 d, proper concentrations 6-BA enhanced the activity levels of superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT), proper concentrations NAA increased the activity levels of SOD and CAT, but decreased the levels of POD compared with CK. Suitable concentrations 6-BA enhanced contents of berberine, phellodendrine and palmatine in stems, proper concentrations NAA increased contents of berberine and phellodendrine, but deduced contents of palmatine compared with CK. Based on these results, we concluded that the exogenous 6-BA and NAA had key regulation on the growth and contents of medicinal ingredient of Phellodendron chinense seedlings.

Roles of Post-translational Modifications in Spinocerebellar Ataxias.

Post-translational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, SUMOylation, etc., of proteins can modulate protein properties such as intracellular distribution, activity, stability, aggregation, and interactions. Therefore, PTMs are vital regulatory mechanisms for multiple cellular processes. Spinocerebellar ataxias (SCAs) are hereditary, heterogeneous, neurodegenerative diseases for which the primary manifestation involves ataxia. Because the pathogenesis of most SCAs is correlated with mutant proteins directly or indirectly, the PTMs of disease-related proteins might functionally affect SCA development and represent potential therapeutic interventions. Here, we review multiple PTMs related to disease-causing proteins in SCAs pathogenesis and their effects. Furthermore, we discuss these PTMs as potential targets for treating SCAs and describe translational therapies targeting PTMs that have been published.

High-efficient extraction of principal medicinal components from fresh Phellodendron bark (cortex phellodendri).

There are three key medicinal components (phellodendrine, berberine and palmatine) in the extracts of Phellodendron bark, as one of the fundamental herbs of traditional Chinese medicine. Different extraction methods and solvent combinations were investigated to obtain the optimal technologies for high-efficient extraction of these medicinal components. RESULTS: The results showed that combined solvents have higher extracting effect of phellodendrine, berberine and palmatine than single solvent, and the effect of ultrasonic extraction is distinctly better than those of distillation and soxhlet extraction. CONCLUSION: The hydrochloric acid/methanol-ultrasonic extraction has the best effect for three medicinal components of fresh Phellodendron bark, providing an extraction yield of 103.12 mg/g berberine, 24.41 mg/g phellodendrine, 1.25 mg/g palmatine.

Cross-Linking the Surface of Cured Polydimethylsiloxane via Hyperthemal Hydrogen Projectile Bombardment.

Cross-linking of polydimethylsiloxane (PDMS) is increasingly important with recent focus on its top surface stiffness. In this paper, we demonstrate that hyperthermal hydrogen projectile bombardment, a surface sensitive cross-linking technology, is superior in enhancing the mechanical properties of a cured PDMS surface without significantly degrading its hydrophobicity. Both water contact angle measurements and time-of-flight secondary ion mass spectrometry are used to investigate the variations in surface chemistry and structure upon cross-linking. Using nanoindentation and atomic force microscopy, we confirm that the thickness of the cross-linked PDMS is controllable by the bombardment time, which opens opportunities for tuning cross-linking degree in compliance with arising requirements from the practice.

[Intestinal obstruction caused by gallstone: report of 5 cases and review of the literature].

OBJECTIVE: To explore clinical features, diagnostic methods and treatment of gallstone ileus. METHODS: Clinical data of 5 patients with gallstone ileus were analyzed retrospectively. Pertinent literature from China between 2000 and 2009 were reviewed. The disease onset, clinical manifestations, imaging characteristics, diagnosis and treatment of gallstone ileus were studied. RESULTS: Four out of 5 patients were female aged over 60, of whom 3 had a previous history of cholelithiasis, 2 had a history of cholangiojejunostomy internal drainage procedure. Four patients underwent enterotomy and gallstone extraction combined with hepatobiliary operation, while one underwent enterotomy alone. There was no postoperative recurrence. A review of the literature from China revealed 441 cases with intestinal obstruction caused by gallstone, consisting 1.15% of all the cases with bowel obstruction. 67.12% were female. 73.56% were elderly. 87.92% were from cystoenteral fistula. Site of bowel obstruction in ileum was 64.17% of the cases. 71.89% were misdiagnosed with other types of obstruction. Two hundred twenty-five patients underwent enterotomy and gallstone extraction combined with hepatobiliary operation, which carried a lower rate of postoperative recurrence and malignancy (P<0.05) than enterotomy alone. There were no statistical significant differences in the occurrence of postoperative cystoenteral fistula, wound infection, pulmonary infection, cure rate, and mortality(P>0.05). CONCLUSIONS: The incidence of gallstone ileus is low and more common in female elderly. The gallstones often drain through cystoenteral fistula and lodge in the ileum. Enterotomy without hepatobiliary operation is associated with potential risk of recurrence and development of gallbladder malignancy. Combined hepatobiliary operation is recommended in patients without significant comorbidities.