METTL3-mediated methylation of CYP2C19 mRNA may aggravate clopidogrel resistance in ischemic stroke patients.

Background: N6-methyladenosine (mA) is the most frequently occurring interior modification in eukaryotic messenger RNA (mRNA), and abnormal mRNA modifications can affect many biological processes. However, mA's effect on the metabolism of antiplatelet drugs for the prevention of ischemic stroke (IS) remains largely unclear.

Methods: We analyzed the mA enzymes and mA methylation in peripheral blood samples of IS patients with/without clopidogrel resistance (CR), and the peripheral blood and liver of rat models with/without CR.

MiR-184 Mediated the Expression of ZNF865 in Exosome to Promote Procession in the PD Model.

Exosomes are nanoscale small vesicles (EVs) secreted by cells that carry important bio information, including proteins, miRNAs, and more. Exosome contents are readily present in body fluids, including blood, and urine of humans and animals, and thereby act as markers of diseases. In patients with Parkinson's disease (PD), exosomes may spread alpha-synuclein and miR-184 between the cells contributing to dopaminergic neuronal loss.

The Mechanism and Role of -Methyladenosine (mA) Modification in Atherosclerosis and Atherosclerotic Diseases.

-methyladenosine (mA) modification is a newly discovered regulatory mechanism in eukaryotes. As one of the most common epigenetic mechanisms, mA's role in the development of atherosclerosis (AS) and atherosclerotic diseases (AD) has also received increasing attention. Herein, we elucidate the effect of mA on major risk factors for AS, including lipid metabolism disorders, hypertension, and hyperglycemia.

Mettl14-mediated m6A modification is essential for visual function and retinal photoreceptor survival.

Background: As the most abundant epigenetic modification of eukaryotic mRNA, N6-methyladenosine (m6A) modification has been shown to play a role in mammalian nervous system development and function by regulating mRNA synthesis and degeneration. However, the role of m6A modification in retinal photoreceptors remains unknown.

Results: We generated the first retina-specific Mettl14-knockout mouse models using the Rho-Cre and HRGP-Cre lines and investigated the functions of Mettl14 in retinal rod and cone photoreceptors.

Association Between Plasma Apolipoprotein M With Alzheimer's Disease: A Cross-Sectional Pilot Study From China.

Background: Recent evidence of genetics and metabonomics indicated a potential role of apolipoprotein M (ApoM) in the pathogenesis of Alzheimer's disease (AD). Here, we aimed to investigate the association between plasma ApoM with AD.

Methods: A multicenter, cross-sectional study recruited patients with AD ( = 67), age- and sex-matched cognitively normal (CN) controls ( = 73).

Low-density lipoprotein receptor and apolipoprotein A 5, myocardial infarction biomarkers in plasma-derived exosomes.

Objectives: Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. Previously, rare mutations in low-density lipoprotein receptor (LDLR) genes and apolipoprotein A V (APOA5) have been shown to contribute to MI risk in individual families. Exosomes provide a potential source of biomarkers for MI.

Platelet-derived growth factor (PDGF)-BB protects dopaminergic neurons via activation of Akt/ERK/CREB pathways to upregulate tyrosine hydroxylase.

Aims: The neurotropic growth factor PDGF-BB was shown to have vital neurorestorative functions in various animal models of Parkinson's disease (PD). Previous studies indicated that the regenerative property of PDGF-BB contributes to the increased intensity of tyrosine hydroxylase (TH) fibers in vivo. However, whether PDGF-BB directly modulates the expression of TH, and the underlying mechanism is still unknown.

PARIS farnesylation prevents neurodegeneration in models of Parkinson's disease.

Accumulation of the parkin-interacting substrate (PARIS; ), due to inactivation of parkin, contributes to Parkinson's disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; ) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the promoter.

Conditional deficiency of m6A methyltransferase Mettl14 in substantia nigra alters dopaminergic neuron function.

N6-Methyladenosine (m6A) is the most prevalent internal modification in messenger RNAs (mRNAs) of eukaryotes and plays a vital role in post-transcriptional regulation. Recent studies demonstrated that m6A is essential for the normal function of the central nervous system (CNS), and the deregulation of m6A leads to a series of CNS diseases. However, the functional consequences of m6A deficiency within the dopaminergic neurons of adult brain are elusive.

Co-editing PINK1 and DJ-1 Genes Via Adeno-Associated Virus-Delivered CRISPR/Cas9 System in Adult Monkey Brain Elicits Classical Parkinsonian Phenotype.

Whether direct manipulation of Parkinson's disease (PD) risk genes in the adult monkey brain can elicit a Parkinsonian phenotype remains an unsolved issue. Here, we used an adeno-associated virus serotype 9 (AAV9)-delivered CRISPR/Cas9 system to directly co-edit PINK1 and DJ-1 genes in the substantia nigras (SNs) of two monkey groups: an old group and a middle-aged group. After the operation, the old group exhibited all the classic PD symptoms, including bradykinesia, tremor, and postural instability, accompanied by key pathological hallmarks of PD, such as severe nigral dopaminergic neuron loss (>64%) and evident α-synuclein pathology in the gene-edited SN.

Changes in the Morphology, Number, and Protein Levels of Plasma Exosomes in CADASIL Patients.

Background: Exosomes are nano-sized extracellular vesicles which are secreted by cells and usually found in body fluids. Previous research has shown that exosomal secretion and autophagy-lysosomal pathway synergistically participates in intracellular abnormal protein elimination. The main pathological manifestations of Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is abnormal accumulation of mutant NOTCH3, and CADASIL vascular smooth muscle cells have been found with autophagy-lysosomal dysfunction.

Vertical field enhancement of a spot-size converter using a nanopixel waveguide and window structure.

Spot-size converter (SSC) is an essential building block for integrated photonic circuits applied as a mode transformer between optical components. One typical issue for SSC is the difficulty of broadening the vertical field profile. Herein, we propose a nanopixel SSC (1 × 2 μm) with changing hole size and density.

Molecular Mechanism of Platelet-Derived Growth Factor (PDGF)-BB-Mediated Protection Against MPP Toxicity in SH-SY5Y Cells.

As an important endogenous growth factor, PDGF-BB can effectively promote neurogenesis, thus is considered as a potential agent for Parkinson's disease (PD) therapy. However, the protective function of PDGF-BB on neuronal cells, especially the molecular mechanism, remains less clear, which is needed to explore before its clinical practice. In this study, we investigated the function and mechanism of PDGF-BB against 1-methyl-4-phenylpyridinium (MPP) toxicity in SH-SY5Y cells, a widely used cellular tool for PD-related molecular study.

Fabrication and analysis of low-loss silicon high-mesa waveguides.

Breath sensing is an effective tool for health monitoring. Previously, high-mesa waveguide structures have been proposed by our group for realizing a compact breath-sensing photonic circuit. By using the doped as the waveguide core, 50% concentration has been detected.

A Pilot Study of Urinary Exosomes in Alzheimer's Disease.

Background: Exosomes are nano-sized extracellular vesicles secreted by most cell types and abundantly present in body fluids, including blood, saliva, urine, cerebrospinal fluid, and breast milk. Exosomes can spread toxic amyloid-beta (Aβ) and hyperphosphorylated tau between cells, contributing to neuronal loss in Alzheimer's disease (AD).

Objective: To explore changes in the morphology, number, and pathological protein levels of urinary exosomes in AD patients compared with age-matched healthy subjects.

Changes in the Morphology, Number, and Pathological Protein Levels of Plasma Exosomes May Help Diagnose Alzheimer's Disease.

Exosomes are nano-sized extracellular vesicles that are secreted by cells and usually found in body fluids. Since they freely cross the blood-brain barrier, neuronal exosomes respond directly to changes in the brain's environment. Recent studies have shown that exosomes contain both amyloid-β (Aβ) and tau proteins and have a controversial role in the Alzheimer's disease (AD) process.

Parkin interacting substrate zinc finger protein 746 is a pathological mediator in Parkinson's disease.

α-Synuclein misfolding and aggregation plays a major role in the pathogenesis of Parkinson's disease. Although loss of function mutations in the ubiquitin ligase, parkin, cause autosomal recessive Parkinson's disease, there is evidence that parkin is inactivated in sporadic Parkinson's disease. Whether parkin inactivation is a driver of neurodegeneration in sporadic Parkinson's disease or a mere spectator is unknown.

Requirement of the Mowat-Wilson Syndrome Gene Zeb2 in the Differentiation and Maintenance of Non-photoreceptor Cell Types During Retinal Development.

Mutations in the human transcription factor gene ZEB2 cause Mowat-Wilson syndrome, a congenital disorder characterized by multiple and variable anomalies including microcephaly, Hirschsprung disease, intellectual disability, epilepsy, microphthalmia, retinal coloboma, and/or optic nerve hypoplasia. Zeb2 in mice is involved in patterning neural and lens epithelia, neural tube closure, as well as in the specification, differentiation and migration of neural crest cells and cortical neurons. At present, it is still unclear how Zeb2 mutations cause retinal coloboma, whether Zeb2 inactivation results in retinal degeneration, and whether Zeb2 is sufficient to promote the differentiation of different retinal cell types.

Parkin mediates the ubiquitination of VPS35 and modulates retromer-dependent endosomal sorting.

Mutations in a number of genes cause familial forms of Parkinson's disease (PD), including mutations in the vacuolar protein sorting 35 ortholog (VPS35) and parkin genes. In this study, we identify a novel functional interaction between parkin and VPS35. We demonstrate that parkin interacts with and robustly ubiquitinates VPS35 in human neural cells.

Robust kinase- and age-dependent dopaminergic and norepinephrine neurodegeneration in LRRK2 G2019S transgenic mice.

Mutations in LRRK2 are known to be the most common genetic cause of sporadic and familial Parkinson's disease (PD). Multiple lines of LRRK2 transgenic or knockin mice have been developed, yet none exhibit substantial dopamine (DA)-neuron degeneration. Here we develop human tyrosine hydroxylase (TH) promoter-controlled tetracycline-sensitive LRRK2 G2019S (GS) and LRRK2 G2019S kinase-dead (GS/DA) transgenic mice and show that LRRK2 GS expression leads to an age- and kinase-dependent cell-autonomous neurodegeneration of DA and norepinephrine (NE) neurons.

Automatic seed picking for brachytherapy postimplant validation with 3D CT images.

Purpose: Postimplant validation is an indispensable part in the brachytherapy technique. It provides the necessary feedback to ensure the quality of operation. The ability to pick implanted seed relates directly to the accuracy of validation.

PINK1 Primes Parkin-Mediated Ubiquitination of PARIS in Dopaminergic Neuronal Survival.

Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin cause autosomal-recessive Parkinson's disease through a common pathway involving mitochondrial quality control. Parkin inactivation leads to accumulation of the parkin interacting substrate (PARIS, ZNF746) that plays an important role in dopamine cell loss through repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α) promoter activity. Here, we show that PARIS links PINK1 and parkin in a common pathway that regulates dopaminergic neuron survival.

High-Content Genome-Wide RNAi Screen Reveals as a Key Mediator of Neuronal Cell Death.

Neuronal loss caused by ischemic injury, trauma, or disease can lead to devastating consequences for the individual. With the goal of limiting neuronal loss, a number of cell death pathways have been studied, but there may be additional contributors to neuronal death that are yet unknown. To identify previously unknown cell death mediators, we performed a high-content genome-wide screening of short, interfering RNA (siRNA) with an siRNA library in murine neural stem cells after exposure to -methyl--nitroso-'-nitroguanidine (MNNG), which leads to DNA damage and cell death.

Adult Conditional Knockout of PGC-1α Leads to Loss of Dopamine Neurons.

Parkinson's disease (PD) is a chronic progressive neurodegenerative disorder. Recent studies have implicated a role for peroxisome proliferator-activated receptor γ coactivator protein-1α (PGC-1α) in PD and in animal or cellular models of PD. The role of PGC-1α in the function and survival of substantia nigra pars compacta (SNpc) dopamine neurons is not clear.

Cultured networks of excitatory projection neurons and inhibitory interneurons for studying human cortical neurotoxicity.

Translating neuroprotective treatments from discovery in cell and animal models to the clinic has proven challenging. To reduce the gap between basic studies of neurotoxicity and neuroprotection and clinically relevant therapies, we developed a human cortical neuron culture system from human embryonic stem cells or human inducible pluripotent stem cells that generated both excitatory and inhibitory neuronal networks resembling the composition of the human cortex. This methodology used timed administration of retinoic acid to FOXG1(+) neural precursor cells leading to differentiation of neuronal populations representative of the six cortical layers with both excitatory and inhibitory neuronal networks that were functional and homeostatically stable.