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Parkinson's disease (PD) is among the most common neurodegenerative disorders, and its etiology involves both genetic and environmental factors. The leucine-rich repeat kinase (LRRK2) G2019S mutation is the most common genetic cause of familial and sporadic PD. Current treatment is limited to dopaminergic supplementation, as no disease-modifying therapy is available yet. Recent evidence reveals that HMG-CoA reductase (HMGR) inhibitors (statins) exert neuroprotection through anti-neuroinflammatory effects, and histone deacetylase (HDAC) inhibitors mitigate neurodegeneration by promoting the transcription of neuronal survival factors. We designed and synthesized a dual inhibitor, statin hydroxamate JMF3086, that simultaneously inhibits HMGR and HDAC, and examined its neuroprotective effects on LRRK2-G2019S parkinsonism. JMF3086 restored dopaminergic neuron loss in aged LRRK2-G2019S flies and rescued neurite degeneration in primary hippocampal and dopaminergic neurons isolated from transgenic LRRK2-G2019S mice. The molecular mechanisms included downregulation of ERK1/2 phosphorylation, increased anti-apoptotic Akt phosphorylation, and inhibition of GSK3β activity to maintain cytoskeletal stability in stably transfected LRRK2-G2019S SH-SY5Y human dopaminergic cells. JMF3086 also promoted a-tubulin acetylation and kinesin-1 expression, facilitating antegrade mitochondrial transport in axons. Our findings demonstrate that JMF3086 exerted beneficial effects on restoring LRRK2-G2019S neurite degeneration by maintaining microtubule stability. This dual-target compound may be a promising mechanism-based therapy for PD.

Adipic acid is an important petrochemical product, and its production process emits a high concentration of greenhouse gas N2O. This paper aims to provide quantitative references for relevant authorities to formulate greenhouse gas control roadmaps. The forecasting method of this paper is consistent with the published national inventory in terms of caliber. Based on the N2O abatement technical parameters of adipic acid and the production trend, this paper combines the scenario analysis and provides a measurement of comprehensive N2O abatement effect of the entire industry in China. Four future scenarios are assumed. The baseline scenario (BAUS) is a frozen scenario. Three emission abatement scenarios (ANAS, SNAS, and ENAS) are assumed under different strength of abatement driving parameters. The results show that China’s adipic acid production process can achieve increasingly significant N2O emission abatement effects. Compared to the baseline scenario, by 2030, the N2O emission abatements of the three emission abatement scenarios can reach 207–399 kt and the emission abatement ratios can reach 32.5%–62.6%. By 2050, the N2O emission abatements for the three emission abatement scenarios can reach 387–540 kt and the emission abatement ratios can reach 71.4%–99.6%.

Summary: Human ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) is an evolutionarily conserved core subunit of mitochondrial respiratory chain complex III. We recently identified the disease-associated variants of UQCRC1 from patients with familial parkinsonism, but its function remains unclear. Here we investigate the endogenous function of UQCRC1 in the human neuronal cell line and the Drosophila nervous system. Flies with neuronal knockdown of uqcrc1 exhibit age-dependent parkinsonism-resembling defects, including dopaminergic neuron reduction and locomotor decline, and are ameliorated by UQCRC1 expression. Lethality of uqcrc1-KO is also rescued by neuronally expressing UQCRC1, but not the disease-causing variant, providing a platform to discern the pathogenicity of this mutation. Furthermore, UQCRC1 associates with the apoptosis trigger cytochrome c (cyt-c), and uqcrc1 deficiency increases cyt-c in the cytoplasmic fraction and activates the caspase cascade. Depleting cyt-c or expression of the anti-apoptotic p35 ameliorates uqcrc1-mediated neurodegeneration. Our findings identify a role for UQCRC1 in regulating cyt-c-induced apoptosis.

In recent years, flash memory has been widely used in embedded systems, portable devices, and high-performance storage products due to its nonvolatility, shock resistance, low power consumption, and high performance natures. To reduce the product cost, multi-level-cell (MLC) flash memory has been proposed; compared with the traditional single-level-cell (SLC) flash memory that only stores one bit of data per cell, each MLC cell can store two or more bits of data. Thus MLC can achieve a larger capacity and reduce the cost per unit. However, MLC also suffers from the degradation in both performance and reliability. In this paper, we try to enhance the reliability and reduce the product cost of flash-memory-based solid-state drive (SSD) from a totally different perspective. We propose the half-level-cell (HLC) scheme to manage and reuse the worn-out space in SSD; through our management scheme, the system can treat two bad pages as a normal page without sacrificing performance and reliability. The proposed scheme is purely on software/firmware-level, thus there is no need to change the hardware. The experiment results show that the lifetime of SSD with our proposed HLC scheme can be extended to 50.56% under the Windows workload and up to 65.45% under the multimedia workload. When we apply the HLC scheme to flash-memory cache of hybrid storage systems, the response time can be improved up to 20.57%.

Background Heterozygous pathogenic variants in STUB1 are implicated in autosomal dominant spinocerebellar ataxia type 48 (SCA48), which is a rare familial ataxia disorder. We investigated the clinical, genetic and functional characteristics of STUB1 mutations identified from a Taiwanese ataxia cohort. Methods We performed whole genome sequencing in a genetically undiagnosed family with an autosomal dominant ataxia syndrome. Further Sanger sequencing of all exons and intron–exon boundary junctions of STUB1 in 249 unrelated patients with cerebellar ataxia was performed. The pathogenicity of the identified novel STUB1 variant was investigated. Results We identified a novel heterozygous frameshift variant, c.832del (p.Glu278fs), in STUB1 in two patients from the same family. This rare mutation is located in the U-box of the carboxyl terminus of the Hsc70-interacting protein (CHIP) protein, which is encoded by STUB1. Further in vitro experiments demonstrated that this novel heterozygous STUB1 frameshift variant impairs the CHIP protein’s activity and its interaction with the E2 ubiquitin ligase, UbE2D1, leading to neuronal accumulation of tau and α-synuclein, caspase-3 activation, and promoting cellular apoptosis through a dominant-negative pathogenic effect. The in vivo study revealed the influence of the CHIP expression level on the differentiation and migration of cerebellar granule neuron progenitors during cerebellar development. Conclusions Our findings provide clinical, genetic, and a mechanistic insight linking the novel heterozygous STUB1 frameshift mutation at the highly conserved U-box domain of CHIP as the cause of autosomal dominant SCA48. Our results further stress the importance of CHIP activity in neuronal protein homeostasis and cerebellar functions.

Neurodegeneration with brain iron accumulation (NBIA) is a genetically and phenotypically heterogeneous group of inherited neurodegenerative disorder characterized by basal ganglia iron deposition. Mutations in Pantothenate Kinase 2 (PANK2) are major genetic causes for patients with NBIA. The location of PANK2 in the mitochondria suggests mutant PANK2 causing mitochondrial dysfunction in the pathogenesis of NBIA. Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a female patient having compound heterozygous mutations in PANK2. This cellular model could provide a platform for pathophysiological studies of NBIA in the future.

Parkinson’s disease (PD) is among the most common neurodegenerative disorders, and its etiology involves both genetic and environmental factors. The leucine-rich repeat kinase (LRRK2) G2019S mutation is the most common genetic cause of familial and sporadic PD. Current treatment is limited to dopaminergic supplementation, as no disease-modifying therapy is available yet. Recent evidence reveals that HMG-CoA reductase (HMGR) inhibitors (statins) exert neuroprotection through anti-neuroinflammatory effects, and histone deacetylase (HDAC) inhibitors mitigate neurodegeneration by promoting the transcription of neuronal survival factors. We designed and synthesized a dual inhibitor, statin hydroxamate JMF3086, that simultaneously inhibits HMGR and HDAC, and examined its neuroprotective effects on LRRK2-G2019S parkinsonism. JMF3086 restored dopaminergic neuron loss in aged LRRK2-G2019S flies and rescued neurite degeneration in primary hippocampal and dopaminergic neurons isolated from transgenic LRRK2-G2019S mice. The molecular mechanisms included downregulation of ERK1/2 phosphorylation, increased anti-apoptotic Akt phosphorylation, and inhibition of GSK3β activity to maintain cytoskeletal stability in stably transfected LRRK2-G2019S SH-SY5Y human dopaminergic cells. JMF3086 also promoted a-tubulin acetylation and kinesin-1 expression, facilitating antegrade mitochondrial transport in axons. Our findings demonstrate that JMF3086 exerted beneficial effects on restoring LRRK2-G2019S neurite degeneration by maintaining microtubule stability. This dual-target compound may be a promising mechanism-based therapy for PD.

Parkinson’s disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson’s disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A>C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson’s disease probands with autosomal-dominant Parkinson’s disease and 1934 patients with sporadic Parkinson’s disease revealed another two variants in UQCRC1 in the probands with familial Parkinson’s disease, c.931A>C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G>A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson’s disease.

Human Ubiquinol-Cytochrome C Reductase Core Protein 1 (UQCRC1) is an evolutionarily conserved core subunit of mitochondrial respiratory chain complex III. We recently identified the disease-associated variants of UQCRC1 from patients with familial Parkinsonism, while its function remains unclear. Here we investigate the endogenous function of UQCRC1 in human neuronal cell line and Drosophila nervous system. Flies with neuronal knockdown of uqcrc1 exhibited age-dependent parkinsonism-resembling defects, including dopaminergic neuron reduction and locomotor decline, were ameliorated by UQCRC1 expression. Lethality of uqcrc1-KO was also rescued by neuron-expression of UQCRC1 but not the disease-causing variant, providing a platform to discern the pathogenicity of this mutation. Furthermore, UQCRC1 associated with the apoptosis trigger cytochrome c (cyt-c), and uqcrc1 deficiency increased cytoplasmic fraction of cyt-c and activated the caspase cascade. RNAi of cyt-c or expression of the anti-apoptotic P35 ameliorated uqcrc1-mediated neurodegeneration. Our findings thus identify a novel role of UQCRC1 in regulating cyt-c-induced apoptosis.

Additional file 1 Supplementary Table 1. The 40 candidate genes involved in PD and related neurodegenerative disorders that were used for targeted NGS in the study.

A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) gene causes a heterogeneous neurodegenerative disorder that includes amyotrophic lateral sclerosis (ALS), frontotemporal degeneration (FTD), and parkinsonism. Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a male patient with an increased hexanucleotide repeat expansion in C9orf72. The resulting iPSCs exhibited pluripotency, confirmed by immunofluorescent staining for pluripotency markers, and differentiated into three germ layers in vivo. This cellular model will provide a useful platform for further pathophysiological studies of C9orf72-related neurodegeneration.

Objective Emerging evidence suggests that gut microbiome composition alterations affect neurodegeneration through neuroinflammation in the pathogenesis of Parkinson’s disease (PD). Here, we evaluate gut microbiota alterations and host cytokine responses in a population of Taiwanese patients with PD. Methods Fecal microbiota communities from 80 patients with PD and 77 age and gender-matched controls were assessed by sequencing the V3–V4 region of the 16S ribosomal RNA gene. Diet and comorbidities were controlled in the analyses. Plasma concentrations of IL-1β, IL-2, IL-4, IL-6, IL-13, IL-18, GM-CSF, IFNγ, and TNFα were measured by a multiplex immunoassay and relationships between microbiota, clinical characteristics, and cytokine levels were analyzed in the PD group. We further examined the cytokine changes associated with the altered gut microbiota seen in patients with PD in another independent cohort of 120 PD patients and 120 controls. Results Microbiota from patients with PD was altered relative to controls and dominated by Verrucomicrobia, Mucispirillum, Porphyromonas, Lactobacillus, and Parabacteroides. In contrast, Prevotella was more abundant in controls. The abundances of Bacteroides were more increased in patients with non-tremor PD subtype than patients with tremor subtype. Bacteroides abundance was correlated with motor symptom severity defined by UPDRS part III motor scores (rho = 0.637 [95% confidence interval 0.474 to 0.758], P

Supplementary methods. (DOCX 21Â kb)

Table S1 Clinical characteristics of the study participants. Table S2 General linear models for fecal genera based on differences between patients with PD and healthy controls. (DOCX 19Â kb)

Mutations in the podocalyxin-like gene (PODXL) have been recently identified in a consanguineous Indian family with juvenile-onset Parkinson's disease (PD) and 3 unrelated patients with PD. However, the pathogenicity of PODXL mutations in the disease and their role in other PD populations remain unclear. The aim of this study was to investigate the PODXL mutations in a Taiwanese cohort with familial and young-onset PD. Among 531 participants, including 161 probands from PD pedigrees without known PD-causative gene mutations and 370 patients with early-onset PD (age of onset50 years), all exons and exon-intron boundary junctions of PODXL were analyzed by Sanger sequencing. We did not find any pathogenic coding variants or previously reported mutations, indicating that PODXL mutations may not play a role in familial or early-onset PD in this Taiwanese population.

We establish a computerized diabetes educational system which may provide a personal educational advice come after a prior questionnaire. The questionnaire and educational advice were formed by a team of a physician, a dietitian, 3 nurses, and 3 information technology (IT) personnel. The questionnaire comprises the basic data of age, weight, height, and the level of blood pressure, lipid profile, and also the status of retinaopthy, nephropathy, and neuropathy. Our IT personnel design the programmatic link bewteen the result of questionnaire and educational advice on website, which using open source software, including Apache software, with Hypertext Preprocesssor (PHP) and MySQL database server. The precision and fluency of the advice was modified after repeated discussion on multiple clinical conditions. The final version was first applied on 14 patients (10 men, 4 women), the mean age is 51.6± 11.0 years (from 30 to 71 years). Furthermore, a satisfaction survey was performed and showed this system is helpful, feasible, and satisfied to them, also learning motivation was raised. Conclusion: We developed a web-base computerized diabetic educational system which may provide individualized education, and the system is helpful and feasible to people with diabetes. Disclosure K. Chen: None. Y. Chuang: None. C. Liu: None. Y. Chiu: None. H. Lin: None.

Several excellent researches have been proposed to improve the performance of solid-state drives (SSDs) by exploiting I/O parallelism of multi-channel architecture. However, these researches do not fully explore the internal parallelism and do not take wear leveling into consideration. In this paper, I/O performance is further improved by interleaving requests in channel level and striping sub-requests in plane level. A wear-leveling-aware distributed garbage collector is proposed to improve SSD lifetime and reclamation efficiency. To balance the utilization of user space among all channels, data migration is performed implicitly during channel selection and explicitly during garbage collection. To the best of our knowledge, this is the first paper on the design of distributed garbage collector for multi-channel flash-memory storage system. The experimental results showed that the proposed scheme can achieve good wear leveling and improve the overall performance by 34% for the Windows workload, 56.5% for the Linux workload, 88.4% for the multimedia workload, and 9.3% for the on-line transaction processing (OLTP) workload under the two-die-two-plane architecture, compared with the related work.

There are two theories, SN1 and SN2, for the mechanism of the deaquation of aquopentaamincobalt (III) bromide (AAC-B). Both of the theories are supported by some experimental and calculated data. But there are not any experiments to determine directly the structure of the intermediates at different reaction tune. In this paper the structures of the intermediates at different reaction time in deaquation-anation of AACB were determined by extended X-ray absorption fine structure (EXAFS) and the reaction process was studied by the combination of X-ray powder diffraction and EXAFS. It was demonstrated that the deaquation-anation of AACB obeys the SN2 theory.

Evidence exists that protein kinase C and the mammalian target of rapamycin are important regulators of cardiac hypertrophy. We examined the contribution of these signaling kinases to cardiac growth in spontaneously hypertensive rats (SHRs). Systolic blood pressure was increased ( P P P P P P P

for presentation at ALAA2016 conference.

Previous studies reported that diets high in simple carbohydrates could increase blood pressure in rodents. We hypothesized that the converse, a low-carbohydrate/high-fat diet, might reduce blood pressure. Six-week-old spontaneously hypertensive rats (SHR; n = 54) and Wistar-Kyoto rats (WKY; n = 53, normotensive control) were fed either a control diet (C; 10% fat, 70% carbohydrate, 20% protein) or a low-carbohydrate/high-fat diet (HF; 20% carbohydrate, 60% fat, 20% protein). After 10 wk, SHR-HF had lower ( P < 0.05) mean arterial pressure than SHR-C (148 ± 3 vs. 159 ± 3 mmHg) but a similar degree of cardiac hypertrophy (33.4 ± 0.4 vs. 33.1 ± 0.4 heart weight/tibia length, mg/mm). Mesenteric arteries and the entire aorta were used to assess vascular function and endothelial nitric oxide synthase (eNOS) signaling, respectively. Endothelium-dependent (acetylcholine) relaxation of mesenteric arteries was improved ( P < 0.05) in SHR-HF vs. SHR-C, whereas contraction (potassium chloride, phenylephrine) was reduced ( P < 0.05). Phosphorylation of eNOSSer1177 increased ( P < 0.05) in arteries from SHR-HF vs. SHR-C. Plasma glucose, insulin, and homoeostatic model of insulin assessment were lower ( P < 0.05) in SHR-HF vs. SHR-C, whereas peripheral insulin sensitivity (insulin tolerance test) was similar. After a 10-h fast, insulin stimulation (2 U/kg ip) increased ( P < 0.05) phosphorylation of AktSer473 and S6 in heart and gastrocnemius similarly in SHR-C vs. SHR-HF. In conclusion, a low-carbohydrate/high-fat diet reduced blood pressure and improved arterial function in SHR without producing signs of insulin resistance or altering insulin-mediated signaling in the heart, skeletal muscle, or vasculature.

The pervasive popularity of the Internet in the past decade has changed the way many students live and learn, in part, because modern technology has made it possible for learners to access Real-Time Multimedia information on the Internet, or research any topic of interest to them from virtually any computer anywhere in the world. Students can also receive immediate feedback from their peers and/or their teachers when involved in collaborative projects. As a result, teachers of all disciplines need to incorporate the Internet and the concept of mobile learning into today’s classrooms to take advantage of this technology. This research investigated the response of English majors to a mobile learning platform (NCCU-MLP) developed at National Chengchi University (NCCU) in which they were involved as participants. The goal of the NCCU-MLP is to improve the students’ English ability as well as to update the teachers’ understanding of how to use the technology. The purpose of this research was to investigate the responses of students to a mobile learning environment. The research involved 18 participants in a pilot study and 37 participants in a follow-up study who participated in a group activity involving mobile learning activities. The students were asked to complete the activity following which they completed a brief survey of their response to the mobile learning activity. The findings indicate a positive response from the participants regarding the content and procedures involved in the activity. Technical support for the project was found to need enhancement for future projects of this nature.