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Meeting report: 2009 international conference on molecular neurodegeneration May 18-20, 2009, Xiamen, China
Yunwu Zhang, Lisa Owens, Guojun Bu
Molecular Neurodegeneration , 2009, DOI: 10.1186/1750-1326-4-43
Abstract: As life expectancy continues to increase and a growing number of people enter the aged population, neurodegenerative diseases have increasingly become a major problem for which treatments are critically needed. Although much progress has been made in the past 20 years on understanding the mechanisms of neurodegenerative diseases and on developing novel therapeutic strategies, most of these achievements are from the United Stated and European countries. Neurodegeneration research in Asian countries, most of which are very populated and also suffered severely with the spread of neurodegenerative diseases, is lagged far behind. The 2009 International Conference on Molecular Neurodegeneration is designed to bridge this gap. The major aim of this meeting is to provide a unique platform for Asian researchers and scientists from Western countries to exchange information and ideas, to share their most recent research advances, and to establish future collaborations in neurodegeneration studies.This conference is jointly sponsored by Molecular Neurodegeneration http://www.molecularneurodegeneration.com/ webcite, an open access, peer-reviewed online journal that publishes all aspects of neurodegeneration research, and Institute for Biomedical Research, Xiamen University http://biomed.xmu.edu.cn/ webcite, which is dedicated to revealing the fundamental molecular causes of diseases and devising the innovative therapies of tomorrow. Finacial supports of this meeting come from both foundations and pharmaceutical companies including Alzheimer's Association, Ellison Medical Foundation, National Natural Science Foundation of China, Science and Technology Bureau of Xiamen City, Raptor Pharmaceutical, GlaxoSmithKline, Beckman Coulter, Zeiss, Perkin Elmer, Millipore, Applied Biosystems, and Genetimes Techonolgoy, Inc. Drs. Guojun Bu from Washington University School of Medicine and Huaxi Xu from Burnham Institute for Medical Research, Editors-in-Chief of Molecular Neurodegeneration, ar
The cancer translational research informatics platform
Patrick McConnell, Rajesh C Dash, Ram Chilukuri, Ricardo Pietrobon, Kimberly Johnson, Robert Annechiarico, A Jamie Cuticchia
BMC Medical Informatics and Decision Making , 2008, DOI: 10.1186/1472-6947-8-60
Abstract: caTRIP has been developed as an N-tier architecture, with three primary tiers: domain services, the distributed query engine, and the graphical user interface, primarily making use of the caGrid infrastructure to ensure compatibility with other tools currently developed by caBIG. The application interface was designed so that users can construct queries using either the Simple Interface via drop-down menus or the Advanced Interface for more sophisticated searching strategies to using drag-and-drop. Furthermore, the application addresses the security concerns of authentication, authorization, and delegation, as well as an automated honest broker service for deidentifying data.Currently being deployed at Duke University and a few other centers, we expect that caTRIP will make a significant contribution to further the development of translational research through the facilitation of its data exchange and storage processes.In order to have an impact in society, discoveries in cancer research need to be translated into knowledge that can be directly applied to treatment and prevention. These discoveries usually start within the basic sciences, from experiments developed at the molecular level, slowly progressing to clinical research. Although this translational process is at the very basis of our ability to generate new biomedical knowledge, to date few tools have been developed to successfully link the basic and clinical science fields in a way that researchers from both arenas can easily make connections. More specifically, cancer research would benefit from the development of applications that can aggregate clinical and molecular data in a repository that is user-friendly, easily accessible, as well as compliant with regulatory requirements of privacy and security.In alignment with the requirements outlined above, the Duke Comprehensive Cancer Center (DCCC), in collaboration with SemanticBits LLC, has developed the Cancer Translational Research Informatics Platform (c
Bovine Brain: An in vitro Translational Model in Developmental Neuroscience and Neurodegenerative Research  [PDF]
Antonella Peruffo,Bruno Cozzi
Frontiers in Pediatrics , 2014, DOI: 10.3389/fped.2014.00074
Abstract: Animal models provide convenient and clinically relevant tools in the research on neurodegenerative diseases. Studies on developmental disorders extensively rely on the use of laboratory rodents. The present mini-review proposes an alternative translational model based on the use of fetal bovine brain tissue. The bovine (Bos taurus) possesses a large and highly gyrencephalic brain and the long gestation period (41 weeks) is comparable to human pregnancy (38–40 weeks). Primary cultures obtained from fetal bovine brain constitute a validated in vitro model that allows examinations of neurons and/or glial cells under controlled and reproducible conditions. Physiological processes can be also studied on cultured bovine neural cells incubated with specific substrates or by electrically coupled electrolyte-oxide-semiconductor capacitors that permit direct recording from neuronal cells. Bovine neural cells and specific in vitro cell culture could be an alternative in comparative neuroscience and in neurodegenerative research, useful for studying development of normal and altered circuitry in a long gestation mammalian species. Use of bovine tissues would promote a substantial reduction in the use of laboratory animals.
Kinematic Design of a Translational Parallel Manipulator with Fine Adjustment of Platform Orientation  [PDF]
Masataka Tanabe,Yukio Takeda
Advances in Mechanical Engineering , 2010, DOI: 10.1155/2010/485358
Abstract: We present a kinematic design of a translational parallel manipulator with fine adjustment capability of platform orientation. In order to clarify possible kinematic structures for it, structural synthesis of fully decoupled mechanism and partially decoupled mechanism both with six degrees of freedom (dof) was carried out based on the synthesis results of translational and rotational parallel mechanisms with three dof. All possible kinematic structures were obtained. Of these, one partially decoupled mechanism was selected and a kinematic design of a prototype manipulator was done. Its characteristics in terms of workspace, singularity, orientation adjustment capability, and coupling characteristics between translational and rotational displacement were discussed with experimental results regarding fine adjustment capability of platform orientation. 1. Introduction A parallel manipulator that has three degrees of freedom (dof) and outputs translational motion without changing its orientation is called a “translational parallel manipulator.” A translational parallel manipulator has potential for use in assembly, machining, and coordinate measurements. The manipulator is composed of a base, platform, and multiple connecting chains arranged in parallel between the base and platform. Many researchers in recent years have shown interest in translational parallel manipulators and mechanisms. The kinematic conditions for the connecting chain to obtain translational motion of the platform have been investigated [1, 2]. Various kinematic structures for translational parallel manipulators have also been investigated [3, 4]. Further, optimization taking into consideration the manipulator’s workspace has been done [5–7]. Translational parallel mechanisms have been applied to medical robots [8] and micromanipulators [9]. The errors in the output pose of a manipulator caused by dimensional errors, such as these in links, can be classified into two groups. The first group contains errors that can be compensated for by calibration or full closed-loop control. Such errors are called “compensatable errors” [10, 11]. The tolerance requirements with respect to these compensatable errors depend on calibration or the performance of the controller, and these are not usually severe. The second group contains errors that cannot be compensated for by any means, either during or prior to manipulation. Such errors are called “uncompensatable errors” [10, 11]. They depend on kinematic structures and parameters and tolerances. In designing and controlling a lower-dof parallel
NeuroDNet - an open source platform for constructing and analyzing neurodegenerative disease networks  [cached]
Vasaikar Suhas V,Padhi Aditya K,Jayaram Bhyravabhotla,Gomes James
BMC Neuroscience , 2013, DOI: 10.1186/1471-2202-14-3
Abstract: Background Genetic networks control cellular functions. Aberrations in normal cellular function are caused by mutations in genes that disrupt the fine tuning of genetic networks and cause disease or disorder. However, the large number of signalling molecules, genes and proteins that constitute such networks, and the consequent complexity of interactions, has restrained progress in research elucidating disease mechanisms. Hence, carrying out a systematic analysis of how diseases alter the character of these networks is important. We illustrate this through our work on neurodegenerative disease networks. We created a database, NeuroDNet, which brings together relevant information about signalling molecules, genes and proteins, and their interactions, for constructing neurodegenerative disease networks. Description NeuroDNet is a database with interactive tools that enables the creation of interaction networks for twelve neurodegenerative diseases under one portal for interrogation and analyses. It is the first of its kind, which enables the construction and analysis of neurodegenerative diseases through protein interaction networks, regulatory networks and Boolean networks. The database has a three-tier architecture - foundation, function and interface. The foundation tier contains the human genome data with 23857 protein-coding genes linked to more than 300 genes reported in clinical studies of neurodegenerative diseases. The database architecture was designed to retrieve neurodegenerative disease information seamlessly through the interface tier using specific functional information. Features of this database enable users to extract, analyze and display information related to a disease in many different ways. Conclusions The application of NeuroDNet was illustrated using three case studies. Through these case studies, the construction and analyses of a PPI network for angiogenin protein in amyotrophic lateral sclerosis, a signal-gene-protein interaction network for presenilin protein in Alzheimer's disease and a Boolean network for a mammalian cell cycle was demonstrated. NeuroDNet is accessible at http://bioschool.iitd.ac.in/NeuroDNet/.
Leucine-Rich α2-Glycoprotein Is a Novel Biomarker of Neurodegenerative Disease in Human Cerebrospinal Fluid and Causes Neurodegeneration in Mouse Cerebral Cortex  [PDF]
Masakazu Miyajima, Madoka Nakajima, Yumiko Motoi, Masao Moriya, Hidenori Sugano, Ikuko Ogino, Eri Nakamura, Norihiro Tada, Miyuki Kunichika, Hajime Arai
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074453
Abstract: Leucine-rich α2-glycoprotein (LRG) is a protein induced by inflammation. It contains a leucine-rich repeat (LRR) structure and easily binds with other molecules. However, the function of LRG in the brain during aging and neurodegenerative diseases has not been investigated. Here, we measured human LRG (hLRG) concentration in the cerebrospinal fluid (CSF) and observed hLRG expression in post-mortem human cerebral cortex. We then generated transgenic (Tg) mice that over-expressed mouse LRG (mLRG) in the brain to examine the effects of mLRG accumulation. Finally, we examined protein-protein interactions using a protein microarray method to screen proteins with a high affinity for hLRG. The CSF concentration of hLRG increases with age and is significantly higher in patients with Parkinson’s disease with dementia (PDD) and progressive supranuclear palsy (PSP) than in healthy elderly people, idiopathic normal pressure hydrocephalus (iNPH) patients, and individuals with Alzheimer’s disease (AD). Tg mice exhibited neuronal degeneration and neuronal decline. Accumulation of LRG in the brains of PDD and PSP patients is not a primary etiological factor, but it is thought to be one of the causes of neurodegeneration. It is anticipated that hLRG CSF levels will be a useful biomarker for the early diagnosis of PDD and PSP.
Non-coding RNA and pseudogenes in neurodegenerative diseases: “The (un)Usual Suspects”  [PDF]
Valerio Costa,Roberta Esposito,Marianna Aprile,Alfredo Ciccodicola
Frontiers in Genetics , 2012, DOI: 10.3389/fgene.2012.00231
Abstract: Neurodegenerative disorders and cancer are severe diseases threatening human health. The glaring differences between neurons and cancer cells mask the processes involved in their pathogenesis. Defects in cell cycle, DNA repair, and cell differentiation can determine unlimited proliferation in cancer, or conversely, compromise neuronal plasticity, leading to cell death and neurodegeneration. Alteration in regulatory networks affecting gene expression contribute to human diseases onset, including neurodegenerative disorders, and deregulation of non-coding RNAs – particularly microRNAs (miRNAs) – is supposed to have a significant impact. Recently, competitive endogenous RNAs (ceRNAs) – acting as sponges – have been identified in cancer, indicating a new and intricate regulatory network. Given that neurodegenerative disorders and cancer share altered genes and pathways, and considering the emerging role of miRNAs in neurogenesis, we hypothesize ceRNAs may be implicated in neurodegenerative diseases. Here we propose, and computationally predict, such regulatory mechanism may be shared between the diseases. It is predictable that similar regulation occurs in other complex diseases, and further investigation is needed.
Zoom in on neurodegeneration
Guojun Bu, Huaxi Xu, Todd E Golde
Molecular Neurodegeneration , 2006, DOI: 10.1186/1750-1326-1-1
Abstract: We are proud to introduce you to a new home for neurodegeneration research, Molecular Neurodegeneration. Through the open-access format we plan to bring you the most timely and exciting research focusing on the molecular and cellular mechanisms underlying neurodegenerative disease processes and on potential therapeutic interventions for these devastating diseases. Molecular Neurodegeneration will also provide a forum to discuss and review the current research and foster creative thinking in this exciting field.The increased prevalence of certain age-associated neurodegenerative diseases is largely attributable to the increase in average lifespan among individuals who live in industrialized nations. From a patient perspective, diseases such as Alzheimer's, Parkinson's or amyotrophic lateral sclerosis are feared because of their slow and progressive nature and because there are no effective treatments or cures for these diseases. The economic and social burden of neurodegenerative diseases is huge and growing all too rapidly. We have made significant progress with respect to understanding certain aspects of neurodegenerative diseases. However, compared to our understanding of other human diseases such as cancer and cardiovascular disorders, our knowledge on the mechanisms of neurodegeneration is still in its infancy. Indeed, for most neurodegenerative diseases, we can only guess as to why neurons ultimately die.Most existing scientific journals that publish research papers related to neurodegenerative diseases focus on the genetic epidemiology and pathological aspects of these diseases. Molecular Neurodegeneration will uniquely focus on the molecular and cellular aspects of the disease mechanisms, identification of potential therapeutic targets, and preclinical studies evaluating potential therapeutic interventions in model systems. Studies of the physiological and pathophysiological functions of cellular proteins contributing to neurodegeneration are strongly encoura
Disruption of SUMO-Specific Protease 2 Induces Mitochondria Mediated Neurodegeneration  [PDF]
Jiang Fu,H.-M. Ivy Yu,Shang-Yi Chiu,Anthony J. Mirando,Eri O. Maruyama,Jr-Gang Cheng,Wei Hsu
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004579
Abstract: Post-translational modification of proteins by small ubiquitin-related modifier (SUMO) is reversible and highly evolutionarily conserved from yeasts to humans. Unlike ubiquitination with a well-established role in protein degradation, sumoylation may alter protein function, activity, stability and subcellular localization. Members of SUMO-specific protease (SENP) family, capable of SUMO removal, are involved in the reversed conjugation process. Although SUMO-specific proteases are known to reverse sumoylation in many well-defined systems, their importance in mammalian development and pathogenesis remains largely elusive. In patients with neurodegenerative diseases, aberrant accumulation of SUMO-conjugated proteins has been widely described. Several aggregation-prone proteins modulated by SUMO have been implicated in neurodegeneration, but there is no evidence supporting a direct involvement of SUMO modification enzymes in human diseases. Here we show that mice with neural-specific disruption of SENP2 develop movement difficulties which ultimately results in paralysis. The disruption induces neurodegeneration where mitochondrial dynamics is dysregulated. SENP2 regulates Drp1 sumoylation and stability critical for mitochondrial morphogenesis in an isoform-specific manner. Although dispensable for development of neural cell types, this regulatory mechanism is necessary for their survival. Our findings provide a causal link of SUMO modification enzymes to apoptosis of neural cells, suggesting a new pathogenic mechanism for neurodegeneration. Exploring the protective effect of SENP2 on neuronal cell death may uncover important preventive and therapeutic strategies for neurodegenerative diseases.
A translational platform for prototyping closed-loop neuromodulation systems  [PDF]
Pedram Afshar,Ankit Khambhati,David Carlson,Siddharth Dani,Maciej Lazarewicz,Peng Cong,Tim Denison
Frontiers in Neural Circuits , 2013, DOI: 10.3389/fncir.2012.00117
Abstract: While modulating neural activity through stimulation is an effective treatment for neurological diseases such as Parkinson's disease and essential tremor, an opportunity for improving neuromodulation therapy remains in automatically adjusting therapy to continuously optimize patient outcomes. Practical issues associated with achieving this include the paucity of human data related to disease states, poorly validated estimators of patient state, and unknown dynamic mappings of optimal stimulation parameters based on estimated states. To overcome these challenges, we present an investigational platform including: an implanted sensing and stimulation device to collect data and run automated closed-loop algorithms; an external tool to prototype classifier and control-policy algorithms; and real-time telemetry to update the implanted device firmware and monitor its state. The prototyping system was demonstrated in a chronic large animal model studying hippocampal dynamics. We used the platform to find biomarkers of the observed states and transfer functions of different stimulation amplitudes. Data showed that moderate levels of stimulation suppress hippocampal beta activity, while high levels of stimulation produce seizure-like after-discharge activity. The biomarker and transfer function observations were mapped into classifier and control-policy algorithms, which were downloaded to the implanted device to continuously titrate stimulation amplitude for the desired network effect. The platform is designed to be a flexible prototyping tool and could be used to develop improved mechanistic models and automated closed-loop systems for a variety of neurological disorders.
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