Role of a Novel microRNA in Adult Neurogenesis.

Multipotent, self-renewing stem cells which are present throughout the developing nervous system remain in discrete regions of the adult brain. In the subventricular zone (SVZ) signaling molecules, including the bone morphogenetic proteins and their secreted inhibitor, Noggin appear to play a critical role in controlling neural stem cell (NSC) behavior. To examine the function of this signaling pathway in the intact nervous system, we have developed a transgenic mouse model in which Noggin expression can be induced specifically in NSC via a Nestin promoter-driven reverse tetracycline-controlled transactivator (rtTA). In adult animals, induction of Noggin expression promotes proliferation of NSC in the SVZ, and shifts the differentiation of NSC from mature astrocytes to transit amplifying cells and oligodendrocyte precursor cells without depleting the NSC population. Interestingly, over-expression of Noggin in the adult SVZ neural stem cells also inhibits the expression of a novel microRNA-410 (miR-410). miR-410 is expressed in the developing nervous system, remaining in the germinal zones of the adult brain. Over-expression of miR-410 in SVZ derived neurospheres consistently inhibited neuronal and oligodendrocyte differentiation while promoting the formation of astrocytes. Conversely, inhibition of miR-410 activity in NSC promoted neuronal and decreased astroglial differentiation. In addition, over-expression of miR-410 rescued the increase in neuronal differentiation and the decrease in astroglial differentiation caused by Noggin over-expression. Using computer prediction algorithms and luciferase reporter assays, we identified multiple neurogenic genes including Elavl4 as one of the downstream targets of miR-410 via the canonical miRNA-3’UTR interaction. Over-expression of Elavl4 transcripts without the endogenous 3’ UTR rescued the decrease in neuronal differentiation caused by miR-410 over-expression. Interestingly, we also observed that miR-410 affected neurite morphology. Over-expression of miR-410 resulted in the formation of short, unbranched neurites. These results demonstrate that miR-410 controls the crucial lineage choice of adult neural stem cells between neurons and glial cells by controlling the expression of neurogenic genes, and suggest a method to regulate NSC differentiation following disease, injury or aging.PhDCell and Developmental BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107309/1/yctsan_1.pd

Protective Effect of Caffeic Acid on Paclitaxel Induced Anti-Proliferation and Apoptosis of Lung Cancer Cells Involves NF-κB Pathway

Caffeic acid (CA), a natural phenolic compound, is abundant in medicinal plants. CA possesses multiple biological effects such as anti-bacterial and anti-cancer growth. CA was also reported to induce fore stomach and kidney tumors in a mouse model. Here we used two human lung cancer cell lines, A549 and H1299, to clarify the role of CA in cancer cell proliferation. The growth assay showed that CA moderately promoted the proliferation of the lung cancer cells. Furthermore, pre-treatment of CA rescues the proliferation inhibition induced by a sub-IC50 dose of paclitaxel (PTX), an anticancer drug. Western blot showed that CA up-regulated the pro-survival proteins survivin and Bcl-2, the down-stream targets of NF-κB. This is consistent with the observation that CA induced nuclear translocation of NF-κB p65. Our study suggested that the pro-survival effect of CA on PTX-treated lung cancer cells is mediated through a NF-κB signaling pathway. This may provide mechanistic insights into the chemoresistance of cancer calls

Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations

CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder

A Study on Peer Data Management Systems for P2P Networks

近年來，P2P技術已經漸漸地受到學術界與業界的重視，因此有越來越多的學者投入這方面的研究。目前已經有CAN、Pastry、Chord、Tapstry等許多P2P系統被提出來。然而，這類型的系統只能提供簡單的查詢。因此，有另一種類型的P2P系統被提出來，這類型的系統被稱之為PDMS (Peer Data Management System)。PDMS主要是利用metadata來對資源進行描述，不但使得對資源的描述變得更有彈性，也能支援複雜的查詢。不過大部分的PDMS依然是使用關鍵字進行查詢，只有少部分的PDMS是使用RDF進行查詢。因此，本論文提出了一個建構於ML-Chord架構下的分散式RDF儲存庫。主要作法是將節點依照本身所擁有的資源加入到適當的資源層中，查詢時只需要在適當的資源層當中進行搜尋，進一步提升了搜尋速度並降低了搜尋成本。In recent years, peer-to-peer (P2P) computing has attracted much attention in both research and industrial communities. Many P2P systems have been proposed such as CAN, Pastry, Chord, Tapstry, etc., but they can only support exact-match lookups. There is a new arena of P2P research, called peer data management system (PDMS), they use metadata which provide great flexibility for annotating resources to describe the shared resources and can support complex queries. However, most of them use the keywords to locate the corresponding resources, and only a few of them can support RDF queries to retrieve the RDF documents that describe the requested resources. In this thesis, we propose a distributed RDF repository called RDF-Chord. In RDF-Chord, nodes are assigned into the appropriate ring sets based on the shared resources and a query is forward only to a subset nodes that stores the indexes of the requested resources by using the appropriate ring sets. Via detailed simulations, we show that our approach is highly scalable and can resolve RDF queries efficiently.Acknowledgment i Abstract (in Chinese) ii Abstract (in English) iii Table of Contents iv List of Tables vi List of Figures vii Chapter 1 Introduction 1 1.1 Motivation 1 1.2 Organization 4 Chapter 2 Related PDMS Work 6 2.1 RDFStore 6 2.2 RDFPeers 6 2.3 Squid 8 2.4 Distributed Suffix Tree 9 2.5 Super-Peer 11 2.6 R-Chord 12 2.7 ML-Chord 13 Chapter 3 The Design of RDF-Chord 15 3.1 The Architecture of RDF-Chord 15 3.2 Successor and Predecessor 17 3.3 Finger Tables 18 3.4 Distributing Indexes 20 3.5 Query 23 3.6 Node Join 27 3.7 Maintenance 29 Chapter 4 Simulation Experiments and Analysis 32 4.1 Simulation Environment 32 4.2 Average Query Cost 33 4.3 Node Joining 36 4.4 Maintenance Costs 37 4.5 Total Costs 38 4.6 Node Leaving/Failures 39 Chapter 5 Conclusions and Future Works 41 References 4

Inducible expression of noggin selectively expands neural progenitors in the adult SVZ

Multipotent, self-renewing stem cells are present throughout the developing nervous system remaining in discrete regions of the adult brain. In the subventricular zone (SVZ) signaling molecules, including the bone morphogenetic proteins and their secreted inhibitor, noggin appear to play a critical role in controlling neural stem cell (NSC) behavior. To examine the function of this signaling pathway in the intact nervous system, we developed a transgenic mouse model in which noggin expression can be induced specifically in NSC via a nestin-driven reverse tetracycline-controlled transactivator (rtTA). In adult animals, the induction of noggin expression promotes the proliferation of neural progenitors in the SVZ, and shifts the differentiation of B cells (NSC) from mature astrocytes to transit amplifying C cells and oligodendrocyte precursor cells without depleting the NSC population. Noggin expression significantly increases neuronal and oligodendrocyte differentiation both in vivo and in vitro when NSCs are grown as neurospheres. These results demonstrate that noggin/BMP interactions tightly control cell fate in the SVZ

miR-410 controls adult SVZ neurogenesis by targeting neurogenic genes

Over-expression of the early neural inducer, Noggin, in nestin positive subventricular zone (SVZ), neural stem cells (NSC) promotes proliferation and neuronal differentiation of neural progenitors and inhibits the expression of a CNS-enriched microRNA-410 (miR-410) (Morell et al., 2015). When expressed in neurospheres derived from the adult SVZ, miR-410 inhibits neuronal and oligodendrocyte differentiation, and promotes astrocyte differentiation. miR-410 also reverses the increase in neuronal differentiation and decreased astroglial differentiation caused by Noggin over-expression. Conversely, inhibition of miR-410 activity promotes neuronal and decreases astroglial differentiation of NSC. Using computer prediction algorithms and luciferase reporter assays we identified multiple neurogenic genes including Elavl4 as downstream targets of miR-410 via the canonical miRNA-3′UTR interaction. Over-expression of Elavl4 transcripts without the endogenous 3′UTR rescued the decrease in neuronal differentiation caused by miR-410 overexpression. Interestingly, we also observed that miR-410 affected neurite morphology; over-expression of miR-410 resulted in the formation of short, unbranched neurites. We conclude that miR-410 expression provides a new link between BMP signaling and the crucial lineage choice of adult neural stem cells via its ability to bind and control the expression of neurogenic gene transcripts

INTERFACIAL-TENSION-DIRECTED SELF-ASSEMBLY OF NANOWIRES ON SUPERHYDROPHOBIC SURFACES

ABSTRACT This paper describes a novel method of nanowire assembly using a superhydrophobic surface as a template. Welldefined superhydrophobic structures on a template surface direct the site-specific self-assembly of nanowires due to interfacial tension in evaporation, enabling simple but highlyefficient and ordered assembly of nanowires. High-aspect-ratio (HAR) microstructures with tapered tips are fabricated by deep reactive ion etch (DRIE) and are coated with a self-assembled monolayer (SAM) of octadecyltrichlorosilane (OTS) for hydrophobicity. Nickel nanowires are fabricated in a porous alumina membrane by electrodeposition. A uniformly-dispersed nanowire suspension is dispensed and evaporated on the superhydrophobic template surface. Due to surface superhydrophobicity, a three-phase (i.e., liquid-solid-gas) interface is created on the surface structures, enabling the nanowires to reside only over the interface. After complete evaporation, the nanowires are mostly left on the structural tips, driven by the interfacial forces constituted at the three-phase boundary. Although the alignment yield rate of the nanowires to the surface pattern has not reached 100%, current experimental results demonstrate that the idea of using interfacial tension on superhydrophobic surfaces can serve as a novel nano-assembly technique with high throughput and high rate. The key parameters affecting the yield of self-assembly and alignment will continue to be studied for further improvement