76 results on '"Yuanyun Xie"'
Search Results
2. Reducing huntingtin by immunotherapy delays disease progression in a mouse model of Huntington disease
- Author
-
Stefan Bartl, Yuanyun Xie, Nalini Potluri, Ratnesh Kesineni, Katlin Hencak, Louisa Dal Cengio, Katja Balazs, Abid Oueslati, Michela Parth, Nina Salhat, Alberto Siddu, Oskar Smrzka, Francesca Cicchetti, Günther Straffler, Michael R. Hayden, and Amber L. Southwell
- Subjects
Huntington disease ,Immunotherapy ,Passive immunization ,Huntingtin lowering therapy ,Extracellular huntingtin ,Transgenic mice ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
In Huntington disease (HD), the mutant huntingtin (mtHTT) protein is the principal cause of pathological changes that initiate primarily along the cortico-striatal axis. mtHTT is ubiquitously expressed and there is, accordingly, growing recognition that HD is a systemic disorder with functional interplay between the brain and the periphery. We have developed a monoclonal antibody, C6–17, targeting an exposed region of HTT near the aa586 Caspase 6 cleavage site. As recently published, mAB C6–17 can block cell-to-cell propagation of mtHTT in vitro. In order to reduce the burden of the mutant protein in vivo, we queried whether extracellular mtHTT could be therapeutically targeted in YAC128 HD mice. In a series of proof of concept experiments, we found that systemic mAB C6–17 treatment resulted in the distribution of the mAB C6–17 to peripheral and CNS tissues and led to the reduction of HTT protein levels. Compared to CTRL mAB or vehicle treated mice, the mAB C6–17 treated YAC128 animals showed improved body weight and motor behaviors, a delayed progression in motor deficits and reduced striatal EM48 immunoreactivity. These results provide the first proof of concept for the feasibility and therapeutic efficacy of an antibody-based anti-HTT passive immunization approach and suggest this modality as a potential new HD treatment strategy.
- Published
- 2024
- Full Text
- View/download PDF
3. Characteristics and Influencing Factors of the Granite Weathering Profile: A Case Study of a High Latitude Area in Northeastern China
- Author
-
Ruonan Liu, Yunping Chi, Yuanyun Xie, Chunguo Kang, Lei Sun, Peng Wu, and Zhenyu Wei
- Subjects
granite weathering profile ,heavy minerals ,Sr-Nd isotope composition ,geochemical gene ,geochemistry ,kinetic-limited weathering ,Mineralogy ,QE351-399.2 - Abstract
Rock weathering, an important geological process on the earth’s surface, plays a key role in shaping surface morphology, providing nutrients needed by the ecosystem, and regulating the global climate. However, the regimes for controlling rock weathering in different regions are still controversial. In this respect, the heavy minerals, elements, Sr-Nd isotope, magnetic susceptibility, and chromaticity of the granite weathering profile in Harbin, a high latitude area of China, were analyzed for understanding the weathering characteristics and mechanisms of the granite weathering profile in the cold area. The results indicate that the profile underwent strengthened physical weathering (large volumes of cracks in the granite parent rock) and low–moderate chemical weathering (CIA = 56~68). However, the chemical weathering does not clearly affect the composition of the weathering products, making the weathering products a good inheritance from the parent rocks, as evidenced by the binary diagram (e.g., TiO2-Zr, and La/Sc-Co/Th) and geochemical genes (LG01 and LG03). The development process of the weathering profile has been affected by the input of external materials and biological activities, as evidenced by the Sr-Nd isotopic composition, Th/Zr values, chemical depletion fractions, ΔAl/Ti ratios, χfd%, and geochemical genes (LG03). Notably, a progressively decreasing weathering degree with a reduced depth is observed in the profile, which is likely to be related to an addition of external materials and/or effects of biological activities. In addition, the weathering regime of the profile does not vary in geology time, characterized by a kinetic-limited weathering regime with a limited supply.
- Published
- 2023
- Full Text
- View/download PDF
4. Cerebrospinal fluid mutant huntingtin is a biomarker for huntingtin lowering in the striatum of Huntington disease mice
- Author
-
Nicholas S. Caron, Raul Banos, Amirah E. Aly, Yuanyun Xie, Seunghyun Ko, Nalini Potluri, Christine Anderson, Hailey Findlay Black, Lisa M. Anderson, Benjamin Gordon, Amber L. Southwell, and Michael R. Hayden
- Subjects
Huntington disease ,biomarker ,neurodegeneration ,huntingtin ,cerebrospinal fluid ,antisense oligonucleotide ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Huntington disease (HD) is a neurodegenerative disease caused by a trinucleotide repeat expansion in the HTT gene encoding an elongated polyglutamine tract in the huntingtin (HTT) protein. Expanded mutant HTT (mHTT) is toxic and leads to regional atrophy and neuronal cell loss in the brain, which occurs earliest in the striatum. Therapeutic lowering of mHTT in the central nervous system (CNS) has shown promise in preclinical studies, with multiple approaches currently in clinical development for HD. Quantitation of mHTT in the cerebrospinal fluid (CSF) is being used as a clinical pharmacodynamic biomarker of target engagement in the CNS. We have previously shown that the CNS is a major source of mHTT in the CSF. However, little is known about the specific brain regions and cell types that contribute to CSF mHTT. Therefore, a better understanding of the origins of CSF mHTT and whether therapies targeting mHTT in the striatum would be expected to be associated with significant lowering of mHTT in the CSF is needed. Here, we use complementary pharmacological and genetic-based approaches to either restrict expression of mHTT to the striatum or selectively deplete mHTT in the striatum to evaluate the contribution of this brain region to mHTT in the CSF. We show that viral expression of a mHTT fragment restricted to the striatum leads to detectable mHTT in the CSF. We demonstrate that targeted lowering of mHTT selectively in the striatum using an antisense oligonucleotide leads to a significant reduction of mHTT in the CSF of HD mice. Furthermore, using a transgenic mouse model of HD that expresses full length human mHTT and wild type HTT, we show that genetic inactivation of mHTT selectively in the striatum results in a significant reduction of mHTT in the CSF. Taken together, our data supports the conclusion that the striatum contributes sufficiently to the pool of mHTT in the CSF that therapeutic levels of mHTT lowering in the striatum can be detected by this measure in HD mice. This suggests that CSF mHTT may represent a pharmacodynamic biomarker for therapies that lower mHTT in the striatum.
- Published
- 2022
- Full Text
- View/download PDF
5. Effects of Provenance, Transport Processes and Chemical Weathering on Heavy Mineral Composition: A Case Study From the Songhua River Drainage, NE China
- Author
-
Peng Wu, Yuanyun Xie, Chunguo Kang, Yunping Chi, Lei Sun, and Zhenyu Wei
- Subjects
heavy minerals ,Songhua River ,provenance ,fluvial processes ,chemical weathering ,TIMA analyses ,Science - Abstract
Understanding the heavy mineral composition of the Songhua River basin in NE China and the influencing factors (e.g., provenance, transport processes and chemical weathering) is crucial for the study of both the source-to-sink processes and the drainage evolution in the region. To this end, a total of 43 samples were collected from the river bars and terraces of the main and tributary streams of the Songhua River, and analyzed for heavy minerals in different grain-size fractions based on the novel automated TESCAN Integrated Mineral Analyzer (TIMA) combined with standard optical method. The results show that the tributaries originating from different mountains have significantly different heavy mineral composition. The locally occurring basic source signal in the tributaries of the Nenjiang River (the largest tributary of the Songhua River) are not well preserved in the Nenjiang River and the Songhua River trunk streams, indicating that the control of sources on heavy mineral composition is influenced by fluvial processes. Additionally, significant differences in the heavy mineral composition of different reaches of the same river also indicate that the heavy mineral composition is significantly influenced by fluvial processes. Influenced by hydraulic sorting during river processes, heavy minerals are enriched in different size fractions with the low-density minerals systematically overestimated in a wide window, suggesting an advantage of multi-window policy over wide window policy. In contrast to modern river sediments, the original heavy mineral composition of river terrace sediments has been severely damaged due to chemical weathering, so the degree of chemical weathering of terrace sediments needs to be evaluated first in provenance tracing and paleo-drainage evolution studies. TIMA has an irreplaceable role in identifying mineral species, additional images and elemental composition, and however, it performs poorly in identifying polycrystalline minerals, thus the combination with traditional methods can obtain more complete and accurate information.
- Published
- 2022
- Full Text
- View/download PDF
6. The composition of heavy minerals of the sandy lands, Northeast China and their implications for tracing detrital sources
- Author
-
Lei Sun, Yuanyun Xie, Chunguo Kang, Yunping Chi, Peng Wu, Zhenyu Wei, Siqi Li, Qian Zhao, and Shuo Liu
- Subjects
Medicine ,Science - Abstract
Comprehending heavy mineral composition of the sandy land in Northeast China (NESL) is of great significance for interpreting generation, pathways, source and geochemistry of sediments in this area. To this end, the fine-grained (
- Published
- 2022
7. The Interaction of Aging and Cellular Stress Contributes to Pathogenesis in Mouse and Human Huntington Disease Neurons
- Author
-
Emily Machiela, Ritika Jeloka, Nicholas S. Caron, Shagun Mehta, Mandi E. Schmidt, Helen J. E. Baddeley, Colton M. Tom, Nalini Polturi, Yuanyun Xie, Virginia B. Mattis, Michael R. Hayden, and Amber L. Southwell
- Subjects
Huntington (disease) ,iPSC (induced pluripotent stem cell) ,primary neuron culture ,mouse models of disease ,neurodegenaration ,DNA damage ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and the brains of HD mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in neurons and mouse brains that have undergone accelerated aging, including a selective increase in DNA damage. These findings suggest a role for aging in HD pathogenesis and an interaction between the biological age of HD neurons and sensitivity to exogenous stress.
- Published
- 2020
- Full Text
- View/download PDF
8. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease
- Author
-
Amber L. Southwell, Sonia Franciosi, Erika B. Villanueva, Yuanyun Xie, Laurie A. Winter, Janaki Veeraraghavan, Alan Jonason, Boguslaw Felczak, Weining Zhang, Vlad Kovalik, Sabine Waltl, George Hall, Mahmoud A. Pouladi, Ernest S. Smith, William J. Bowers, Maurice Zauderer, and Michael R. Hayden
- Subjects
Semaphorin ,Immunotherapy ,Passive immunization ,Huntington disease ,Preclinical ,Transgenic mice ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Huntington disease (HD) is an inherited, fatal neurodegenerative disease with no disease-modifying therapy currently available. In addition to characteristic motor deficits and atrophy of the caudate nucleus, signature hallmarks of HD include behavioral abnormalities, immune activation, and cortical and white matter loss. The identification and validation of novel therapeutic targets that contribute to these degenerative cellular processes may lead to new interventions that slow or even halt the course of this insidious disease. Semaphorin 4D (SEMA4D) is a transmembrane signaling molecule that modulates a variety of processes central to neuroinflammation and neurodegeneration including glial cell activation, neuronal growth cone collapse and apoptosis of neural precursors, as well as inhibition of oligodendrocyte migration, differentiation and process formation. Therefore, inhibition of SEMA4D signaling could reduce CNS inflammation, increase neuronal outgrowth and enhance oligodendrocyte maturation, which may be of therapeutic benefit in the treatment of several neurodegenerative diseases, including HD. To that end, we evaluated the preclinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody, which prevents the interaction between SEMA4D and its receptors, in the YAC128 transgenic HD mouse model. Anti-SEMA4D treatment ameliorated neuropathological signatures, including striatal atrophy, cortical atrophy, and corpus callosum atrophy and prevented testicular degeneration in YAC128 mice. In parallel, a subset of behavioral symptoms was improved in anti-SEMA4D treated YAC128 mice, including reduced anxiety-like behavior and rescue of cognitive deficits. There was, however, no discernible effect on motor deficits. The preservation of brain gray and white matter and improvement in behavioral measures in YAC128 mice treated with anti-SEMA4D suggest that this approach could represent a viable therapeutic strategy for the treatment of HD. Importantly, this work provides in vivo demonstration that inhibition of pathways initiated by SEMA4D constitutes a novel approach to moderation of neurodegeneration.
- Published
- 2015
- Full Text
- View/download PDF
9. NP03, a novel low-dose lithium formulation, is neuroprotective in the YAC128 mouse model of Huntington disease
- Author
-
Mahmoud A. Pouladi, Elsa Brillaud, Yuanyun Xie, Paola Conforti, Rona K. Graham, Dagmar E. Ehrnhoefer, Sonia Franciosi, Weining Zhang, Patrick Poucheret, Elsa Compte, Jean-Claude Maurel, Chiara Zuccato, Elena Cattaneo, Christian Néri, and Michael R. Hayden
- Subjects
Huntington disease ,Transgenic mouse model ,Lithium ,Caspase-6 ,BDNF ,GSK-3 ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Huntington disease (HD), a neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene, remains without a treatment to modify the course of the illness. Lithium, a drug widely used for the treatment of bipolar disorder, has been shown to exert neuroprotective effects in a number of models of neurological disease but may have various toxic effects at conventional therapeutic doses. We examined whether NP03, a novel low-dose lithium microemulsion, would improve the disease phenotypes in the YAC128 mouse model of HD. We demonstrate that NP03 improves motor function, ameliorates the neuropathological deficits in striatal volume, neuronal counts, and DARPP-32 expression, and partially rescues testicular atrophy in YAC128 mice. These positive effects were accompanied by improvements in multiple biochemical endpoints associated with the pathogenesis of HD, including normalization of caspase-6 activation and amelioration of deficits in BDNF levels, and with no lithium-related toxicity. Our findings demonstrate that NP03 ameliorates the motor and neuropathological phenotypes in the YAC128 mouse model of HD, and represents a potential therapeutic approach for HD.
- Published
- 2012
- Full Text
- View/download PDF
10. Altered adult hippocampal neurogenesis in the YAC128 transgenic mouse model of Huntington disease
- Author
-
Jessica M. Simpson, Joana Gil-Mohapel, Mahmoud A. Pouladi, Mohamed Ghilan, Yuanyun Xie, Michael R. Hayden, and Brian R. Christie
- Subjects
Huntington disease ,Adult neurogenesis ,Cell proliferation ,Dentate gyrus ,Subventricular zone ,YAC128 transgenic mice ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Perturbations in neurogenesis in the adult brain have been implicated in impaired learning and memory. In the present study, we investigated which stages of the neurogenic process are affected in the transgenic YAC128 mouse model of Huntington disease (HD). Hippocampal neuronal proliferation was altered in the dentate gyrus (DG) of YAC128 mice as compared with wild-type (WT) littermate controls in early symptomatic to end-stage mice. In addition, we detected a significantly lower number of immature neurons in the DG of young, pre-symptomatic YAC128 mice. This decrease in neuronal differentiation persisted through the progression of the disease, and resulted in an overall reduction in the number of new mature neurons in the DG of YAC128 mice. There were no changes in cell proliferation and differentiation in the subventricular zone (SVZ). In this study, we demonstrate decreases in neurogenesis in the DG of YAC128 mice, and these deficits may contribute to the cognitive abnormalities observed in these animals.
- Published
- 2011
- Full Text
- View/download PDF
11. D04 Challenges and advances in cerebrospinal fluid HTT detection: in support of relative quantification
- Author
-
Rachel J Harding, Yuanyun Xie, Nalini Potluri, Cheryl H Arrowsmith, Blair R Leavitt, Douglas Langbehn, and Amber L Southwell
- Published
- 2022
12. Provenance evidence for the early-to-middle Pleistocene drainage reorganization of the Songhua River, NE China
- Author
-
Lei Sun, Yuanyun Xie, Chunguo Kang, Yunping Chi, Peng Wu, Zhenyu Wei, Siqi Li, Qian Zhao, and Shuo Liu
- Subjects
Earth-Surface Processes - Published
- 2023
13. Provenance variations of the loess deposits in the East Asian monsoon boundary zone, Northeast China: Response to the variations of climate and wind regimes
- Author
-
Peng Wu, Yuanyun Xie, Yue Li, Chunguo Kang, Yunping Chi, Lei Sun, and Zhenyu Wei
- Subjects
Earth-Surface Processes - Published
- 2023
14. Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease
- Author
-
Cynthia Brouwers, Pavlina Konstantinova, Amber L. Southwell, Hailey Findlay Black, Michael R. Hayden, Lisa M. Anderson, Nicholas S. Caron, Melvin M. Evers, Xiang Zhu, Seunghyun Ko, Louisa Dal Cengio, Yuanyun Xie, and Sander J. H. van Deventer
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,RNA Stability ,Genetic Vectors ,Gene Dosage ,Context (language use) ,Biology ,Pharmacology ,Animals, Genetically Modified ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Chemical Biology and Nucleic Acid Chemistry ,Trinucleotide Repeats ,Parvovirinae ,microRNA ,mental disorders ,Genetics ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,RNA, Messenger ,030304 developmental biology ,Neurons ,0303 health sciences ,Huntingtin Protein ,Base Sequence ,Wild type ,Dependovirus ,medicine.disease ,Corpus Striatum ,3. Good health ,Motor coordination ,Astrogliosis ,nervous system diseases ,Disease Models, Animal ,MicroRNAs ,Huntington Disease ,Tolerability ,nervous system ,Astrocytes ,Humanized mouse ,Neuroglia ,030217 neurology & neurosurgery ,Psychomotor Performance - Abstract
Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering.
- Published
- 2019
15. I09 In vivo mtHTT protein reduction in the CNS and periphery by passive immunization with the monoclonal antibody C6–17
- Author
-
Francesca Cicchetti, Günther Straffler, Abid Oueslati, Nalini Potluri, Stefan Bartl, Benjamin Gordon, Alberto Siddu, Nina Salhat, Michela Parth, Michael R. Hayden, Katja Balash, Oskar Smrzka, Amber L. Southwell, Yuanyun Xie, and Alicia Willenberg
- Subjects
Immunization ,medicine.drug_class ,In vivo ,Immunology ,medicine ,Biology ,Monoclonal antibody - Published
- 2021
16. Decoupling between circulation pattern and dust path since the last glacial in the Songnen Plain, NE China: Insights from quantitative provenance reconstruction of the Harbin dust sediments
- Author
-
Peng Wu, Yuanyun Xie, Yue Li, Chunguo Kang, Yunping Chi, Lei Sun, and Zhenyu Wei
- Subjects
Geology ,Earth-Surface Processes - Published
- 2022
17. Magnetostratigraphic dating of a drill core from the Northeast Plain of China: Implications for the evolution of Songnenpaleo-lake
- Author
-
Ye Yang, Yunping Chi, Xia Jiang, Yongfa Ma, Junyi Ge, Chunguo Kang, Zhongyuan Yu, Tao Zhan, Fangming Zeng, Xin Zhou, E Li, Jun Zhang, and Yuanyun Xie
- Subjects
Paleomagnetism ,Multidisciplinary ,Lithology ,Geochemistry ,010502 geochemistry & geophysics ,01 natural sciences ,Loess ,Geochronology ,East Asian Monsoon ,Sedimentary rock ,Quaternary ,Geology ,Magnetostratigraphy ,0105 earth and related environmental sciences - Abstract
Lacustrine sediments from the Northeast Plain of China are an ideal archive for recording the climatic history and variability of the East Asian monsoon during the Quaternary in mid-latitude East Asia. However, the lack of a high-resolution stratigraphy and high-precision geochronology of these sediments has limited our understanding of the mechanisms of Quaternary climatic and environmental changes in the region. In this study, we present a high-resolution magnetic susceptibility stratigraphy and precise paleomagnetic and optically stimulated luminescence (OSL) chronologies for core Qiananlingzi (QAL) from the Northeast Plain. Paleomagnetic data were obtained using alternating-field (AF) demagnetization with a peak AF of 80 mT and increments of 2.5−10 mT. In addition, OSL dating was conducted on coarse-grained quartz (90−150 µm) using the single aliquot regenerative dose (SAR) protocol. Correlation of the recognized polarity intervals of the QAL core to the geomagnetic polarity timescale was achieved by combining the magnetostratigraphic and OSL geochronologic data. The results indicate that the sedimentary sequence spans the interval from the Olduvai normal subchron to the end of the Brunhes normal chron. According to the lithology and the magnetic susceptibility record, the core can be divided into four intervals, from bottom to top: the Qian’an Formation (fluvial yellow-green, brown-red and grey-brown silty sand, interbedded with brown-black silty clay, with gravel layers in the lower part); the Lingzi Formation and Lindian Formation (lacustrine grey-green clay interbedded with grey-white silty sand, with fossil bivalves); and a loess-like soil (predominantly brown-yellow clayey silt, alternating with fluviolacustrine grey-white, brown and black clay). The magnetic susceptibilities (MS) of the sediments of the lower fluvial Qian’an Formation and upper loess-like soil strata are generally higher, indicating the neoformation of strongly magnetic minerals under predominantly oxidizing conditions. By contrast, lower MS values occur in the lacustrine sediments of the Lingzi Formation and Lindian Formation, which indicate a reducing environment. Overall, the MS record of the QAL core exhibits clear orbital-scale variations, with higher MS values in coarse-grained silt layers, and lower values in fine-grained clay layers. After the application of a 300 mT DC field, the isothermal remanence (IRM) is only 70%, and a hysteresis loop remained unclosed at 500 mT. These characteristics indicate the substantial presence of high-coercivity magnetic minerals in the intervals with low MS values. Thermomagnetic measurements ( χ - T ) curves show an abrupt decrease in the heating curve at 580°C, indicating that magnetite is the dominant magnetic mineral, and a further decrease above 580°C indicates the presence of hematite. After the application of an applied DC field of 300 mT, the IRM reached 90%, the hysteresis loop was closed, and the heating limb of the χ - T curve did not decrease significantly after 580°C, indicating that low-coercivity magnetic minerals contributed substantially to the magnetic properties within the intervals of higher MS. The lacustrine sediments of the core were dated to ~1180‒450 ka based on paleomagnetic and QSL dating, and interpolation of the age-depth relationship suggests that Songnen paleo-lake existed for ~730 ka. The grain-size record of the loess in the northeastern monsoon region shows no evidence of drought events at 450 ka, and records of MS and FeD/FeT from the deposits of the loess Plateau indicate a trend of increasing summer monsoon precipitation at this time. Therefore, the disappearance of the paleo-lake may be related to the multiple episodes of subsidence of the Yishu fault, which caused a diversion of the discharge of the Songhua River from the Songnen paleo-lake to the Sanjiang Plain. The high-resolution MS record and the precise chronology obtained in this study indicate that the lacustrine sedimentary sequence of QAL core can potentially resolve orbital-scale paleoclimate changes during the middle Pleistocene in mid-latitude East Asia. The Mid-Pleistocene Transition (MPT) is one of the most important climatic events in Quaternary paleoclimatology, and it is necessary to understand the response of different climatic systems to the MPT. Detailed environmental magnetic, sedimentological and geochemical studies of lacustrine sedimentary strata in the Northeast Plain in China should be carried out to explore the paleoclimatic record of the area, including the regional climatic response to the MPT.
- Published
- 2019
18. Author response for 'Transient sublethal hypoxia in neonatal rats causes reduced dendritic spines, aberrant synaptic plasticity, and impairments in memory'
- Author
-
Wenjie Tang, Nana Zhang, Yuanyun Xie, Bin Lai, Margaret O’Connor, Heng-Ye Man, Youzhen Wei, and Xiaoming Xin
- Subjects
Dendritic spine ,Synaptic plasticity ,medicine ,Transient (computer programming) ,Hypoxia (medical) ,medicine.symptom ,Biology ,Neuroscience - Published
- 2020
19. The Interaction of Aging and Cellular Stress Contributes to Pathogenesis in Mouse and Human Huntington Disease Neurons
- Author
-
Helen J E Baddeley, Nalini Polturi, Mandi E. Schmidt, Yuanyun Xie, Nicholas S. Caron, Colton M Tom, Ritika Jeloka, Emily Machiela, Shagun Mehta, Amber L. Southwell, Virginia B. Mattis, and Michael R. Hayden
- Subjects
0301 basic medicine ,Aging ,Huntingtin ,DNA damage ,Huntington (disease) ,Cognitive Neuroscience ,Mutant ,Biology ,medicine.disease_cause ,lcsh:RC321-571 ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,neurodegenaration ,medicine ,Aging brain ,primary neuron culture ,Induced pluripotent stem cell ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Original Research ,Mutation ,mouse models of disease ,Cell biology ,030104 developmental biology ,nervous system ,iPSC (induced pluripotent stem cell) ,030217 neurology & neurosurgery ,Oxidative stress ,Neuroscience - Abstract
Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and the brains of HD mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in neurons and mouse brains that have undergone accelerated aging, including a selective increase in DNA damage. These findings suggest a role for aging in HD pathogenesis and an interaction between the biological age of HD neurons and sensitivity to exogenous stress.
- Published
- 2020
20. Transient sublethal hypoxia in neonatal rats causes reduced dendritic spines, aberrant synaptic plasticity, and impairments in memory
- Author
-
Yuanyun Xie, Margaret O'Connor, Wenjie Tang, Xiaoming Xin, Nana Zhang, Bin Lai, Youzhen Wei, and Heng-Ye Man
- Subjects
0301 basic medicine ,Male ,endocrine system ,Dendritic spine ,Dendritic Spines ,Spatial Learning ,Biology ,Hippocampal formation ,Hippocampus ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Functional brain ,0302 clinical medicine ,Memory ,medicine ,Animals ,Effects of sleep deprivation on cognitive performance ,Hypoxia ,Maze Learning ,Cerebral Cortex ,Neuronal Plasticity ,Brain morphometry ,Hypoxia (medical) ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Animals, Newborn ,Synaptic plasticity ,Hypoxia-Ischemia, Brain ,Female ,Neuron ,medicine.symptom ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Hypoxic/ischemic insult, a leading cause of functional brain defects, has been extensively studied in both clinical and experimental animal research, including its etiology, neuropathogenesis, and pharmacological interventions. Transient sublethal hypoxia (TSH) is a common clinical occurrence in the perinatal period. However, its effect on early developing brains remains poorly understood. The present study was designed to investigate the effect of TSH on the dendrite and dendritic spine formation, neuronal and synaptic activity, and cognitive behavior of early postnatal Day 1 rat pups. While TSH showed no obvious effect on gross brain morphology, neuron cell density, or glial activation in the hippocampus, we found transient hypoxia did cause significant changes in neuronal structure and function. In brains exposed to TSH, hippocampal neurons developed shorter and thinner dendrites, with decreased dendritic spine density, and reduced strength in excitatory synaptic transmission. Moreover, TSH-treated rats showed impaired cognitive performance in spatial learning and memory. Our findings demonstrate that TSH in newborn rats can cause significant impairments in synaptic formation and function, and long-lasting brain functional deficits. Therefore, this study provides a useful animal model for the study of TSH on early developing brains and to explore potential pharmaceutical interventions for patients subjected to TSH insult.
- Published
- 2019
21. The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons
- Author
-
Mandi E. Schmidt, Nalini Potluri, Virginia B. Mattis, Colton M Tom, Shagun Mehta, Ritika Jeloka, Nicholas S. Caron, Emily Machiela, Michael R. Hayden, Yuanyun Xie, and Amber L. Southwell
- Subjects
Pathogenesis ,Mutation ,Huntingtin ,nervous system ,Mutant ,medicine ,Aging brain ,Biology ,medicine.disease_cause ,Induced pluripotent stem cell ,Phenotype ,Oxidative stress ,Cell biology - Abstract
Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in huntingtin (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in iPSC-derived neurons and mouse brains that have undergone accelerated aging. These findings suggest a role for aging in HD pathogenesis and interaction between biological age of HD neurons and sensitivity to exogenous stress.
- Published
- 2019
- Full Text
- View/download PDF
22. Geochemical and isotopic characteristics of sediments for the Hulun Buir Sandy Land, northeast China: implication for weathering, recycling and dust provenance
- Author
-
Chunguo Kang, Tao Zhan, Yunping Chi, Yuanyun Xie, and Fang Yuan
- Subjects
Provenance ,010504 meteorology & atmospheric sciences ,Geochemistry ,Fluvial ,Aeolian processes ,Weathering ,010502 geochemistry & geophysics ,China ,01 natural sciences ,Geomorphology ,Geology ,0105 earth and related environmental sciences ,Earth-Surface Processes - Abstract
Fluvial, lacustrine and aeolian sediments in the Hulun Buir Sandy Land (HBSL), northeast China are investigated for the first time to be a key supplementation of the Asian aeolian dust system. Fine-grained components (
- Published
- 2018
23. HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo
- Author
-
Sabine Waltl, Dagmar E. Ehrnhoefer, Boguslaw Felczak, Lorenzo Casal, Amber L. Southwell, Meenalochani Sivasubramanian, Lisa M. Anderson, Anita Fazeli, Xiaofan Qiu, Erika B. Villanueva, Yuanyun Xie, Michelle Tsang, and Michael R. Hayden
- Subjects
0301 basic medicine ,HECT domain ,Huntingtin ,NF-E2-Related Factor 2 ,Ubiquitin-Protein Ligases ,Nerve Tissue Proteins ,Context (language use) ,Biology ,Mitochondrion ,medicine.disease_cause ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Animals ,Molecular Biology ,Genetics (clinical) ,Tumor Suppressor Proteins ,Articles ,General Medicine ,medicine.disease ,Corpus Striatum ,Mitochondria ,3. Good health ,Astrogliosis ,Ubiquitin ligase ,Cell biology ,Neostriatum ,Disease Models, Animal ,Oxidative Stress ,Huntington Disease ,030104 developmental biology ,medicine.anatomical_structure ,Astrocytes ,biology.protein ,030217 neurology & neurosurgery ,Oxidative stress ,Astrocyte - Abstract
Oxidative stress is a prominent feature of Huntington disease (HD), and we have shown previously that reduced levels of hace1 (HECT domain and Ankyrin repeat containing E3 ubiquitin protein ligase 1) in patient striatum may contribute to the pathogenesis of HD. Hace1 promotes the stability of Nrf2 and thus plays an important role in antioxidant response mechanisms, which are dysfunctional in HD. Moreover, hace1 overexpression mitigates mutant huntingtin (mHTT)-induced oxidative stress in vitro through promotion of the Nrf2 antioxidant response. Here, we show that the genetic ablation of hace1 in the YAC128 mouse model of HD accelerates motor deficits and exacerbates cognitive and psychiatric phenotypes in vivo. We find that both the expression of mHTT and the ablation of hace1 alone are sufficient to cause deficits in astrocytic mitochondrial respiration. We confirm the crucial role of hace1 in astrocytes in vivo, since its ablation is sufficient to cause dramatic astrogliosis in wild-type FVB/N mice. Astrogliosis is not observed in the presence of mHTT but a strong dysregulation in the expression of astrocytic markers in HACE1-/- x YAC128 striatum suggests an additive effect of mHTT expression and hace1 loss on this cell type. HACE1-/- x YAC128 mice and primary cells derived from these animals therefore provide model systems that will allow for the further dissection of Nrf2 pathways and astrocyte dysfunction in the context of HD.
- Published
- 2017
24. Loess accumulation in Harbin with implications for late Quaternary aridification in the Songnen Plain, Northeast China
- Author
-
Yunping Chi, Yuexin Zhang, Peng Wu, Zhenyu Wei, Lei Sun, Yuanyun Xie, Chunguo Kang, and Man Zhang
- Subjects
Total organic carbon ,010506 paleontology ,δ13C ,media_common.quotation_subject ,Paleontology ,010502 geochemistry & geophysics ,Oceanography ,01 natural sciences ,Arid ,Tectonics ,Desertification ,Aridification ,Loess ,Physical geography ,Quaternary ,Ecology, Evolution, Behavior and Systematics ,Geology ,0105 earth and related environmental sciences ,Earth-Surface Processes ,media_common - Abstract
The Harbin loess in Northeast China, located in the easternmost part of the Eurasian loess belt, has great potential to reconstruct the aridity history of the Songnen Plain and to reveal its dynamic process. However, the relationship between coupled tectonic-climate-drainage evolution and the aridification in the Songnen Plain is currently poorly understood. In this study, we present a high-resolution magnetic susceptibility, grain-size, trace element, Sr Nd isotope, total organic carbon (TOC), and organic carbon isotope composition (δ13C) record retrieved from the Harbin loess-paleosol sequences to reveal the aridification history in the Songnen Plain. These results reveal a long-term drying trend in the Songnen Plain since 0.46 Ma, indicating the birth of the Songnen Sandy Land at that time. Superimposed on the major aridification trend, two significant abrupt drying events were found at ~300 ka and ~ 380 ka. However, the climate in the Songnen Plain became wetter and warmer under the background of the long-term drought since 180 ka. The global ice/temperature changes, regional tectonics (i.e., uplift of the Songliao divide) and drainage change (i.e., river pattern shift in the Songnen Plain from endorheic to exorheic drainage, and termination of the Songnen paleolake) were collectively responsible for the aridification in the Songnen Plain. This study has further improved knowledge of the process of the aridification in Northeast China, which is of great significance to control land desertification and ecological imbalance.
- Published
- 2021
25. Geochemistry of loess deposits in northeastern China: constraint on provenance and implication for disappearance of the large Songliao palaeolake
- Author
-
Tao Zhan, Yuanyun Xie, Yunping Chi, Yongfa Ma, Fang Yuan, and Chunguo Kang
- Subjects
Provenance ,010504 meteorology & atmospheric sciences ,Rare earth ,Geochemistry ,Geology ,Weathering ,010502 geochemistry & geophysics ,01 natural sciences ,Paleosol ,Loess ,Aeolian processes ,China ,0105 earth and related environmental sciences - Abstract
The Harbin loess, typical of the loess in NE China, is located in the easternmost margin of the Eurasian loess belt, and was recently investigated from the perspective of an Asian aeolian dust system. Before this study, the geochemical composition and provenance of the Harbin loess remained poorly understood. More importantly, the study of the Harbin loess also provides a unique opportunity to understand the geomorphological evolution process of the large Songliao palaeolake in the Northeast Plain. This study presents the results on the geochemical characteristics (major elements, trace elements, rare earth elements and Sr–Nd isotope) of the Harbin loess. There are markedly consistent geochemical compositions in and between the loess and palaeosol sediments, revealing stable dust sources and identical sources for the loess and palaeosol. Various indicators illustrating weathering and recycling indicate that the Harbin loess–palaeosol sediments were derived from sources with a low degree of weathering and from material with first-cycle alluvial–lacustrine deposits. Combinations of various provenance tracing indicators indicate that the Harbin loess has a strong geochemical affinity with the Songnen Sandy Land and to a certain extent the Horqin Sandy Land but not with the Hulun Buir Sandy Land, which indicates that these loess deposits are derived from a mixed provenance, with the dominant source being the neighbouring Songnen Sandy Land and a second, distal source being the Horqin Sandy Land. Finally, we advocate that the Harbin loess accumulation could serve as the direct record of the Songliao palaeolake disappearance. Supplementary material: Data for the NE Sandy Lands of China, and full provenance discrimination diagrams are available at https://doi.org/10.6084/m9.figshare.c.3835009.
- Published
- 2017
26. Huntingtin suppression restores cognitive function in a mouse model of Huntington’s disease
- Author
-
Amber L. Southwell, Hailey Findlay-Black, Yuanyun Xie, Bethany Fitsimmons, Michael E. Østergaard, C. Frank Bennett, Niels H. Skotte, Louisa Dal Cengio, Punit P. Seth, Crystal N. Doty, Michael R. Hayden, Erika B. Villanueva, Douglas R. Langbehn, Lynn A. Raymond, Lisa M. Anderson, Holly B. Kordasiewicz, Eric E. Swayze, Matthew P. Parsons, and Nicholas S. Caron
- Subjects
Male ,Primates ,0301 basic medicine ,Dopamine and cAMP-Regulated Phosphoprotein 32 ,congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,Mutant ,Single-nucleotide polymorphism ,Disease ,Anxiety ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Cognition ,0302 clinical medicine ,Limbic system ,Huntington's disease ,mental disorders ,Limbic System ,medicine ,Animals ,Humans ,Huntingtin Protein ,Mutation ,Behavior, Animal ,Brain ,General Medicine ,Oligonucleotides, Antisense ,medicine.disease ,nervous system diseases ,3. Good health ,Cortex (botany) ,Disease Models, Animal ,Huntington Disease ,030104 developmental biology ,medicine.anatomical_structure ,nervous system ,Female ,Mutant Proteins ,Atrophy ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a mutation in the huntingtin (HTT) protein, resulting in acquisition of toxic functions. Previous studies have shown that lowering mutant HTT has the potential to be broadly beneficial. We previously identified HTT single-nucleotide polymorphisms (SNPs) tightly linked to the HD mutation and developed antisense oligonucleotides (ASOs) targeting HD-SNPs that selectively suppress mutant HTT. We tested allele-specific ASOs in a mouse model of HD. Both early and late treatment reduced cognitive and behavioral impairments in mice. To determine the translational potential of the treatment, we examined the effect of ASO administration on HTT brain expression in nonhuman primates. The treatment induced robust HTT suppression throughout the cortex and limbic system, areas implicated in cognition and psychiatric function. The results suggest that ASOs specifically targeting mutated HTT might have therapeutic effects on HD-mediated cognitive impairments.
- Published
- 2018
27. Reversal of the middle-upper Songhua River in the late Early Pleistocene, Northeast China
- Author
-
Chunguo Kang, Peng Wu, Lei Sun, Yunping Chi, Zhenyu Wei, Jiaxin Wang, and Yuanyun Xie
- Subjects
Provenance ,Early Pleistocene ,010504 meteorology & atmospheric sciences ,Heavy mineral ,Climate change ,010502 geochemistry & geophysics ,01 natural sciences ,Headward erosion ,Tectonics ,Physical geography ,Drainage ,China ,Geology ,0105 earth and related environmental sciences ,Earth-Surface Processes - Abstract
The study of drainage evolution in the Songnen Plain, Northeast China, is essential for understanding the interactions between tectonics-topography-climate-drainage evolution in the region. Despite this, it remains unclear whether the paleo-Songhua River (upper-middle reaches of the Songhua River) once flowed westward into the Songnen Plain and what forcings influenced the drainage development of the Songnen Plain. In this contribution, we provide insight into drainage development on the Songnen Plain using an integrated approach of magnetic susceptibility, geochemical (elemental and Sr Nd isotopic) and heavy mineral composition recovered from a 102-m sediment core sediments extracted from the eastern edge of the Songnen Plain with sedimentological and topographic archives. Our results show that a dramatic provenance shift occurred at the depth of 62.2 m (~0.94 Ma) in the core sediments. It is proposed that the Songhua River was separated by the Jia-Yi (Jiamushi-Yilan) divide into two segments before ~0.94 Ma, the west-flowing proto-Songhua River and the east-flowing proto-Sanjiang River (lower reach of the Songhua River). However, the proto-Songhua River reversed direction at ~0.94 Ma when the Jia-Yi divide was cut through by headward erosion of the proto-Sanjiang River, marking the birth of the Songhua River as a single, eastward-flowing river system. Tectonics is suggested as the first-order control on the evolution of the Songhua River before 1.20 Ma, whereas climate changes may be responsible after 1.20 Ma.
- Published
- 2020
28. Structural and molecular myelination deficits occur prior to neuronal loss in the YAC128 and BACHD models of Huntington disease
- Author
-
Roy Tang Yi Teo, Reshmi Rajendran, Carsten Calaminus, Liang Juin Tan, Michael R. Hayden, Libo Yu-Taeger, Yuanyun Xie, Xuan Vinh To, Kai-Hsiang Chuang, Xin Hong, Arianna Novati, Mahmoud A. Pouladi, Olaf Riess, Ling Guo, Huu P. Nguyen, and Yihui Huang
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Huntingtin ,Gene Expression ,Mice, Transgenic ,Nerve Tissue Proteins ,Biology ,Corpus callosum ,Corpus Callosum ,White matter ,Pathogenesis ,03 medical and health sciences ,Myelin ,Mice ,0302 clinical medicine ,Atrophy ,Huntington's disease ,Genetics ,medicine ,Animals ,Humans ,Molecular Biology ,Genetics (clinical) ,Myelin Sheath ,Neurons ,Brain ,General Medicine ,Articles ,medicine.disease ,Phenotype ,White Matter ,Corpus Striatum ,Rats ,Neostriatum ,Disease Models, Animal ,Oligodendroglia ,030104 developmental biology ,medicine.anatomical_structure ,Diffusion Tensor Imaging ,Huntington Disease ,030217 neurology & neurosurgery - Abstract
White matter (WM) atrophy is a significant feature of Huntington disease (HD), although its aetiology and early pathological manifestations remain poorly defined. In this study, we aimed to characterize WM-related features in the transgenic YAC128 and BACHD models of HD. Using diffusion tensor magnetic resonance imaging (DT-MRI), we demonstrate that microstructural WM abnormalities occur from an early age in YAC128 mice. Similarly, electron microscopy analysis of myelinated fibres of the corpus callosum indicated that myelin sheaths are thinner in YAC128 mice as early as 1.5 months of age, well before any neuronal loss can be detected. Transcript levels of myelin-related genes in striatal and cortical tissues were significantly lower in YAC128 mice from 2 weeks of age, and these findings were replicated in differentiated primary oligodendrocytes from YAC128 mice, suggesting a possible mechanistic explanation for the observed structural deficits. Concordant with these observations, we demonstrate reduced expression of myelin-related genes at 3 months of age and WM microstructural abnormalities using DT-MRI at 12 months of age in the BACHD rats. These findings indicate that WM deficits in HD are an early phenotype associated with cell-intrinsic effects of mutant huntingtin on myelin-related transcripts in oligodendrocytes, and raise the possibility that WM abnormalities may be an early contributing factor to the pathogenesis of HD.
- Published
- 2016
29. Sr-Nd isotopic characteristics of the Northeast Sandy Land, China and their implications for tracing sources of regional dust
- Author
-
Yunping Chi, Chunguo Kang, Lu Liu, and Yuanyun Xie
- Subjects
010504 meteorology & atmospheric sciences ,Earth science ,04 agricultural and veterinary sciences ,Tracing ,01 natural sciences ,NESL ,040103 agronomy & agriculture ,0401 agriculture, forestry, and fisheries ,China ,computer ,Geology ,0105 earth and related environmental sciences ,Earth-Surface Processes ,computer.programming_language - Abstract
The Sr-Nd isotopic study of the Northeast Sandy Land (NESL), China is of great significance for a thorough understanding of the dust system in this area. The 162 bulk (
- Published
- 2020
30. I09 Antibodies inhibit cell to cell transmission of mutant HTT
- Author
-
Alberto Siddu, Abid Oueslati, Halyna Pankevych, Yuanyun Xie, Oskar W. Smrzka, Francesca Cicchetti, Amber L. Southwell, Louisa Dal Cengio, Michael R. Hayden, Michela Parth, Markus Burkert, Seungyun Ko, Nina Salhat, Linda Suzanne David, Erika B. Villanueva, and Stefan Bartl
- Subjects
medicine.anatomical_structure ,biology ,Mutant protein ,Mutant ,Cell ,biology.protein ,medicine ,Huntingtin Protein ,Extracellular ,Antibody ,Mode of action ,Intracellular ,Cell biology - Abstract
The toxic functions of the mutant Huntingtin protein (mutHTT) were studied extensively and in addition to neuronal based symptoms, also peripheral changes upon mutHTT expression were described. An important finding in Huntington’s disease (HD) research from the last years is the discovery of extracellular mutHTT and evidence of cell to cell spreading of the mutant protein. This offers new opportunities for targeting mutHTT by antibodies or target-specific vaccines. Recent publications revealed that mutHTT protein was largely present in a free, non-encapsulated form in the extracellular compartment thereby making it accessible by antibodies. We previously demonstrated peripheral target engagement in actively and passively vaccinated YAC128 mice. In these experiments, mutHTT lowering was accompanied by motor improvement in rotarod assays. We sought to generate an in vitro model for testing the molecular mode of action of newly developed mutHTT targeting antibodies and vaccines. Lead antibody C6–17 was capable of depleting mutHTT and blocking intercellular mutHTT transmission, thereby interfering with a potentially disease amplifying mechanism. Our work sets the ground for the development of new antibody-based therapeutics targeting extracellular HD. It is expected that, besides mutHTT depletion, systemic antibody-based targeting will provide inhibition of mutHTT spreading and intercellular transmission. We understand our systemic approach as an addition to forthcoming tissue-specific mutHTT lowering approaches.
- Published
- 2018
31. Grain-size and Sr–Nd isotopic compositions of dry- and wet-deposited dusts during the same dust-storm event in Harbin, China: implications for source, transport–deposition modes, dynamic mechanism and formation of eolian loess
- Author
-
Yanru Wang, Linfeng Guo, Yuanyun Xie, Jie Meng, and Yunping Chi
- Subjects
Global and Planetary Change ,geography ,geography.geographical_feature_category ,Atmospheric circulation ,Soil Science ,Mineralogy ,Geology ,Storm ,Pollution ,Grain size ,Sink (geography) ,Dust storm ,Loess ,Environmental Chemistry ,Environmental science ,Aeolian processes ,Deposition (law) ,Earth-Surface Processes ,Water Science and Technology - Abstract
A strong dust-storm event occurred in Harbin, China on May 11, 2011. The dry and wet dust deposits from this dust-storm event were examined in terms of grain-size and Sr–Nd isotopic compositions, along with scanning electron microscope. The dry-deposited dusts are characterized by bimodal grain-size distributions with fine mode of 3.6 μm and coarse mode of 28 μm, while the wet-deposited dusts are indicative of unimodal grain-size modes with a fine mode of 6 μm. These dust-storm depositions are derived from distal sources, for instance >1000 km away from dust sink spot, regardless of the occurrence of relatively coarse component with coarse mode at 28 μm for dry-deposited dusts. The Sr–Nd isotopic compositions of the dust-storm depositions are suggestive of the derivation from Horqin Sandy Land and, to a certain extent, Hunsandake Sandy Land, for both dry-deposited dust and wet-deposited dust. The fine mode (
- Published
- 2015
32. Anti-semaphorin 4D immunotherapy ameliorates neuropathology and some cognitive impairment in the YAC128 mouse model of Huntington disease
- Author
-
Boguslaw Felczak, Sabine Waltl, George Hall, Erika B. Villanueva, Yuanyun Xie, Michael R. Hayden, Weining Zhang, Ernest S. Smith, Amber L. Southwell, Maurice Zauderer, Vlad Kovalik, Laurie A. Winter, Alan S. Jonason, Sonia Franciosi, William J. Bowers, Mahmoud A. Pouladi, and Janaki Veeraraghavan
- Subjects
SEMA4D ,Mice, Transgenic ,Semaphorins ,Neuropathology ,Motor Activity ,Mouse behavior ,lcsh:RC321-571 ,Mice ,Atrophy ,Semaphorin ,Antigens, CD ,medicine ,Animals ,Transgenic mice ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Neuroinflammation ,Passive immunization ,Neurodegeneration ,Antibodies, Monoclonal ,Brain ,Huntington disease ,medicine.disease ,Preclinical ,Oligodendrocyte ,Disease Models, Animal ,medicine.anatomical_structure ,Neurology ,Immunotherapy ,Cognition Disorders ,Psychology ,Cell activation ,Neuroscience ,Signal Transduction - Abstract
Huntington disease (HD) is an inherited, fatal neurodegenerative disease with no disease-modifying therapy currently available. In addition to characteristic motor deficits and atrophy of the caudate nucleus, signature hallmarks of HD include behavioral abnormalities, immune activation, and cortical and white matter loss. The identification and validation of novel therapeutic targets that contribute to these degenerative cellular processes may lead to new interventions that slow or even halt the course of this insidious disease. Semaphorin 4D (SEMA4D) is a transmembrane signaling molecule that modulates a variety of processes central to neuroinflammation and neurodegeneration including glial cell activation, neuronal growth cone collapse and apoptosis of neural precursors, as well as inhibition of oligodendrocyte migration, differentiation and process formation. Therefore, inhibition of SEMA4D signaling could reduce CNS inflammation, increase neuronal outgrowth and enhance oligodendrocyte maturation, which may be of therapeutic benefit in the treatment of several neurodegenerative diseases, including HD. To that end, we evaluated the preclinical therapeutic efficacy of an anti-SEMA4D monoclonal antibody, which prevents the interaction between SEMA4D and its receptors, in the YAC128 transgenic HD mouse model. Anti-SEMA4D treatment ameliorated neuropathological signatures, including striatal atrophy, cortical atrophy, and corpus callosum atrophy and prevented testicular degeneration in YAC128 mice. In parallel, a subset of behavioral symptoms was improved in anti-SEMA4D treated YAC128 mice, including reduced anxiety-like behavior and rescue of cognitive deficits. There was, however, no discernible effect on motor deficits. The preservation of brain gray and white matter and improvement in behavioral measures in YAC128 mice treated with anti-SEMA4D suggest that this approach could represent a viable therapeutic strategy for the treatment of HD. Importantly, this work provides in vivo demonstration that inhibition of pathways initiated by SEMA4D constitutes a novel approach to moderation of neurodegeneration.
- Published
- 2015
33. Mutant Huntingtin Is Cleared from the Brain via Active Mechanisms in Huntington Disease.
- Author
-
Caron, Nicholas S., Banos, Raul, Yanick, Christopher, Aly, Amirah E., Byrne, Lauren M., Smith, Ethan D., Yuanyun Xie, Smith, Stephen E. P., Potluri, Nalini, Black, Hailey Findlay, Casal, Lorenzo, Seunghyun Ko, Daphne Cheung, Hyeongju Kim, Ihn Sik Seong, Wild, Edward J., Ji-Joon Song, Hayden, Michael R., and Southwell, Amber L.
- Subjects
HUNTINGTON disease ,SPINOCEREBELLAR ataxia ,TRINUCLEOTIDE repeats ,BRAIN ,EXTRACELLULAR space ,NEURODEGENERATION - Abstract
Huntington disease (HD) is a neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene. Therapeutics that lower HTT have shown preclinical promise and are being evaluated in clinical trials. However, clinical assessment of brain HTT lowering presents challenges. We have reported that mutant HTT (mHTT) in the CSF of HD patients correlates with clinical measures, including disease burden as well as motor and cognitive performance. We have also shown that lowering HTT in the brains of HD mice results in correlative reduction of mHTT in the CSF, prompting the use of this measure as an exploratory marker of target engagement in clinical trials. In this study, we investigate the mechanisms of mHTT clearance from the brain in adult mice of both sexes to elucidate the significance of therapy-induced CSF mHTT changes. We demonstrate that, although neurodegeneration increases CSF mHTT concentrations, mHTT is also present in the CSF of mice in the absence of neurodegeneration. Importantly, we show that secretion of mHTT from cells in the CNS followed by glymphatic clearance from the extracellular space contributes to mHTT in the CSF. Furthermore, we observe secretion of wild type HTT from healthy control neurons, suggesting that HTT secretion is a normal process occurring in the absence of pathogenesis. Overall, our data support both passive release and active clearance of mHTT into CSF, suggesting that its treatment-induced changes may represent a combination of target engagement and preservation of neurons. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
34. In Vivo Evaluation of Candidate Allele-specific Mutant Huntingtin Gene Silencing Antisense Oligonucleotides
- Author
-
Holly Kordasiewicz, Michael R. Hayden, Clarence Frank Bennett, Crystal N. Doty, Erika B. Villanueva, Punit P. Seth, Kuljeet Vaid, Susan M. Freier, Niels H. Skotte, Eugenia Petoukhov, Amber L. Southwell, Jeffrey B. Carroll, Michael E. Østergaard, Eric E. Swayze, Andrew T. Watt, and Yuanyun Xie
- Subjects
Huntingtin ,Mutant ,Nerve Tissue Proteins ,Single-nucleotide polymorphism ,Biology ,Polymorphism, Single Nucleotide ,Injections ,Rats, Sprague-Dawley ,Mice ,Drug Discovery ,Genetics ,Huntingtin Protein ,Animals ,Humans ,Gene silencing ,Gene Silencing ,Molecular Targeted Therapy ,Cognitive decline ,Molecular Biology ,Pharmacology ,Oligonucleotide ,Brain ,Oligonucleotides, Antisense ,Thionucleotides ,Molecular biology ,Rats ,3. Good health ,Mice, Inbred C57BL ,Disease Models, Animal ,Huntington Disease ,Humanized mouse ,Cancer research ,Molecular Medicine ,Mutant Proteins ,Original Article - Abstract
Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than nonselective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering. Here we evaluate ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs. We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 16 weeks or more after a single intracerebroventricular (ICV) injection. With further validation, these ASOs could provide a therapeutic option for individuals afflicted with HD.
- Published
- 2014
35. REE geochemistry of modern eolian dust deposits in Harbin city, Heilongjiang province, China: Implications for provenance
- Author
-
Linfeng Guo, Yuanyun Xie, and Jie Meng
- Subjects
Provenance ,Geochemistry ,Aeolian processes ,China ,Geology ,Earth-Surface Processes - Abstract
There has long been disagreement about the provenance of sandy dust deposits in Harbin city, Heilongjiang province, China. The present paper contributes to a better understanding of the source of sandy dust deposits in Harbin by the application of REE geochemistry. The REE composition of samples from sand–dust deposit events in Harbin was compared with that of three different grain size fractions (
- Published
- 2014
36. A fully humanized transgenic mouse model of Huntington disease
- Author
-
Michael R. Hayden, X. William Yang, Erika B. Villanueva, Niels H. Skotte, Crystal N. Doty, Amber L. Southwell, Jeffrey B. Carroll, Vlad Kovalik, Sonia Franciosi, Weining Zhang, Mahmoud A. Pouladi, Jennifer A. Collins, Simon C. Warby, and Yuanyun Xie
- Subjects
Genetically modified mouse ,congenital, hereditary, and neonatal diseases and abnormalities ,Transgene ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Polymorphism, Single Nucleotide ,Loss of heterozygosity ,Mice ,Huntington's disease ,mental disorders ,Genetics ,medicine ,Animals ,Humans ,Gene silencing ,Gene Silencing ,Allele ,Promoter Regions, Genetic ,Molecular Biology ,Genetics (clinical) ,Mutation ,Articles ,General Medicine ,medicine.disease ,nervous system diseases ,Disease Models, Animal ,Huntington Disease ,Rotarod Performance Test ,Humanized mouse - Abstract
Silencing the mutant huntingtin gene (muHTT) is a direct and simple therapeutic strategy for the treatment of Huntington disease (HD) in principle. However, targeting the HD mutation presents challenges because it is an expansion of a common genetic element (a CAG tract) that is found throughout the genome. Moreover, the HTT protein is important for neuronal health throughout life, and silencing strategies that also reduce the wild-type HTT allele may not be well tolerated during the long-term treatment of HD. Several HTT silencing strategies are in development that target genetic sites in HTT that are outside of the CAG expansion, including HD mutation-linked single-nucleotide polymorphisms and the HTT promoter. Preclinical testing of these genetic therapies has required the development of a new mouse model of HD that carries these human-specific genetic targets. To generate a fully humanized mouse model of HD, we have cross-bred BACHD and YAC18 on the Hdh(-/-) background. The resulting line, Hu97/18, is the first murine model of HD that fully genetically recapitulates human HD having two human HTT genes, no mouse Hdh genes and heterozygosity of the HD mutation. We find that Hu97/18 mice display many of the behavioral changes associated with HD including motor, psychiatric and cognitive deficits, as well as canonical neuropathological abnormalities. This mouse line will be useful for gaining additional insights into the disease mechanisms of HD as well as for testing genetic therapies targeting human HTT.
- Published
- 2012
37. Altered adult hippocampal neurogenesis in the YAC128 transgenic mouse model of Huntington disease
- Author
-
Mohamed Ghilan, Jessica M. Simpson, Brian R. Christie, Mahmoud A. Pouladi, Yuanyun Xie, Joana Gil-Mohapel, and Michael R. Hayden
- Subjects
Genetically modified mouse ,medicine.medical_specialty ,Subventricular zone ,Neurogenesis ,Transgene ,Hippocampus ,Mice, Transgenic ,Nerve Tissue Proteins ,Hippocampal formation ,Biology ,Adult neurogenesis ,lcsh:RC321-571 ,Mice ,Internal medicine ,Neuroplasticity ,medicine ,Animals ,Humans ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Cell proliferation ,Huntingtin Protein ,Neuronal Plasticity ,Dentate gyrus ,Nuclear Proteins ,YAC128 transgenic mice ,Disease Models, Animal ,Huntington Disease ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Neurology ,Dentate Gyrus ,Cognition Disorders ,Neuroscience - Abstract
Perturbations in neurogenesis in the adult brain have been implicated in impaired learning and memory. In the present study, we investigated which stages of the neurogenic process are affected in the transgenic YAC128 mouse model of Huntington disease (HD). Hippocampal neuronal proliferation was altered in the dentate gyrus (DG) of YAC128 mice as compared with wild-type (WT) littermate controls in early symptomatic to end-stage mice. In addition, we detected a significantly lower number of immature neurons in the DG of young, pre-symptomatic YAC128 mice. This decrease in neuronal differentiation persisted through the progression of the disease, and resulted in an overall reduction in the number of new mature neurons in the DG of YAC128 mice. There were no changes in cell proliferation and differentiation in the subventricular zone (SVZ). In this study, we demonstrate decreases in neurogenesis in the DG of YAC128 mice, and these deficits may contribute to the cognitive abnormalities observed in these animals.
- Published
- 2011
38. Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression
- Author
-
Yuanyun Xie, Paolo Paganetti, Nagat Bissada, Dagmar E. Ehrnhoefer, Michael R. Hayden, Mahmoud A. Pouladi, Robert M. Friedlander, Rona K. Graham, X. William Yang, Niels H. Skotte, Jeong Eun Kim, and Blair R. Leavitt
- Subjects
Male ,Genetically modified mouse ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Huntingtin ,animal diseases ,medicine.medical_treatment ,Transgene ,Central nervous system ,Gene Expression ,Mice, Transgenic ,Nerve Tissue Proteins ,Biology ,Mice ,Insulin-like growth factor ,Internal medicine ,mental disorders ,Gene expression ,Genetics ,medicine ,Huntingtin Protein ,Animals ,Humans ,Insulin-Like Growth Factor I ,Molecular Biology ,Genetics (clinical) ,Body Weight ,Brain ,Nuclear Proteins ,Articles ,General Medicine ,nervous system diseases ,Disease Models, Animal ,Huntington Disease ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Signal transduction ,Signal Transduction - Abstract
Levels of full-length huntingtin (FL htt) influence organ and body weight, independent of polyglutamine length. The growth hormone-insulin like growth factor-1 (GH-IGF-1) axis is well established as a regulator of organ growth and body weight. In this study, we investigate the involvement of the IGF-1 pathway in mediating the effect of htt on body weight. IGF-1 expression was examined in transgenic mouse lines expressing different levels of FL wild-type (WT) htt (YAC18 mice), FL mutant htt (YAC128 and BACHD mice) and truncated mutant htt (shortstop mice). We demonstrate that htt influences body weight by modulating the IGF-1 pathway. Plasma IGF-1 levels correlate with body weight and htt levels in the transgenic YAC mice expressing human htt. The effect of htt on IGF-1 expression is independent of CAG size. No effect on body weight is observed in transgenic YAC mice expressing a truncated N-terminal htt fragment (shortstop), indicating that FL htt is required for the modulation of IGF-1 expression. Treatment with 17beta-estradiol (17beta-ED) lowers the levels of circulating IGF-1 in mammals. Treatment of YAC128 with 17beta-ED, but not placebo, reduces plasma IGF-1 levels and decreases the body weight of YAC128 animals to WT levels. Furthermore, given the ubiquitous expression of IGF-1 within the central nervous system, we also examined the impact of FL htt levels on IGF-1 expression in different regions of the brain, including the striatum, cerebellum of YAC18, YAC128 and littermate WT mice. We demonstrate that the levels of FL htt influence IGF-1 expression in striatal tissues. Our data identify a novel function for FL htt in influencing IGF-1 expression.
- Published
- 2010
39. Differences in c-jun and nNOS expression levels in motoneurons following different kinds of axonal injury in adult rats
- Author
-
Lin-Lin Wang, Zhi-Bin Yao, Li-Hua Zhou, Shu Han, and Yuanyun Xie
- Subjects
medicine.medical_specialty ,Time Factors ,Proto-Oncogene Proteins c-jun ,medicine.medical_treatment ,Fluorescent Antibody Technique ,Cell Count ,Nitric Oxide Synthase Type I ,Biology ,Rats, Sprague-Dawley ,Avulsion ,Cellular and Molecular Neuroscience ,Downregulation and upregulation ,Internal medicine ,medicine ,Animals ,Radiculopathy ,Motor Neurons ,Analysis of Variance ,fungi ,c-jun ,Axotomy ,Cell Biology ,musculoskeletal system ,Immunohistochemistry ,Axons ,Nerve Regeneration ,Rats ,Up-Regulation ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Peripheral nervous system ,Nerve Degeneration ,Female ,tissues ,Neuronal Nitric Oxide Synthase ,Neuroscience ,Developmental biology - Abstract
In the peripheral nervous system (PNS), root avulsion causes motoneuron degeneration, but the majority of motoneurons can survive axotomy. In order to study the mechanism of motoneuron degeneration, we compared the expression patterns of c-jun and neuronal nitric oxide synthase (nNOS), the well-known molecular players in PNS regeneration and degeneration, among adult rats having undergone axotomy (Ax), avulsion (Av), or pre-axotomy plus secondary avulsion (Ax + Av) of the brachial plexus. Our results showed that the highest and longest-lasting c-jun activation occurred in Ax, which was much stronger than those in Av and Ax + Av. The time course and intensity of c-jun expression in Ax + Av were similar to those in Av except on day 1, while the pre-axotomy condition resulted in a transient up-regulation of c-jun to a level comparable to that in Ax. Axotomy alone did not induce nNOS expression in motoneurons. Pre-axotomy left-shifted the time course of nNOS induction in Ax + Av compared to that in Av. Motoneuron loss was not evident in Ax, while it was 70% in Av and more than 85% in Ax + Av at 8 weeks postinjury. The survival of motoneurons was positively correlated with c-jun induction, but not with nNOS expression in motoneurons. Moreover, c-jun induction was negatively correlated with nNOS induction in injured motoneurons. Our results indicate that functional crosstalk between c-jun and nNOS might play an important role in avulsion-induced motoneuron degeneration, while c-jun might act as a prerequisite survival factor and nNOS might act as a predictor for the onset of motoneuron degeneration.
- Published
- 2008
40. Skin-Derived Precursors Generate Myelinating Schwann Cells That Promote Remyelination and Functional Recovery after Contusion Spinal Cord Injury
- Author
-
Wolfram Tetzlaff, Jie Liu, Freda D. Miller, Joseph S. Sparling, Jason R. Plemel, Yuanyun Xie, Casey P. Shannon, and Jeff Biernaskie
- Subjects
Male ,Cord ,Cell Survival ,Subventricular zone ,Mice, Transgenic ,Motor Activity ,Biology ,Wounds, Nonpenetrating ,Rats, Sprague-Dawley ,Mice ,Neurosphere ,medicine ,Animals ,Remyelination ,Spinal cord injury ,Cells, Cultured ,Myelin Sheath ,Spinal Cord Injuries ,Pain Measurement ,Skin ,integumentary system ,Stem Cells ,General Neuroscience ,Graft Survival ,Cell Differentiation ,Recovery of Function ,Articles ,medicine.disease ,Spinal cord ,Axons ,Neural stem cell ,Rats ,Transplantation ,Disease Models, Animal ,Treatment Outcome ,medicine.anatomical_structure ,nervous system ,Schwann Cells ,Neuroscience ,Stem Cell Transplantation - Abstract
Transplantation of exogenous cells is one approach to spinal cord repair that could potentially enhance the growth and myelination of endogenous axons. Here, we asked whether skin-derived precursors (SKPs), a neural crest-like precursor that can be isolated and expanded from mammalian skin, could be used to repair the injured rat spinal cord. To ask this question, we isolated and expanded genetically tagged murine SKPs and either transplanted them directly into the contused rat spinal cord or differentiated them into Schwann cells (SCs), and performed similar transplantations with the isolated, expanded SKP-derived SCs. Neuroanatomical analysis of these transplants 12 weeks after transplantation revealed that both cell types survived well within the injured spinal cord, reduced the size of the contusion cavity, myelinated endogenous host axons, and recruited endogenous SCs into the injured cord. However, SKP-derived SCs also provided a bridge across the lesion site, increased the size of the spared tissue rim, myelinated spared axons within the tissue rim, reduced reactive gliosis, and provided an environment that was highly conducive to axonal growth. Importantly, SKP-derived SCs provided enhanced locomotor recovery relative to both SKPs and forebrain subventricular zone neurospheres, and had no impact on mechanical or heat sensitivity thresholds. Thus, SKP-derived SCs provide an accessible, potentially autologous source of cells for transplantation into and treatment of the injured spinal cord.
- Published
- 2007
41. Visualization of corticofugal projections during early cortical development in a τ-GFP-transgenic mouse
- Author
-
Anthony T. Campagnoni, Vilma Spreur, Celia W. Campagnoni, Robin S. Fisher, Yuanyun Xie, Samuel D. Reyes, Vikram Kalra, Erin C. Jacobs, Yan Hong-Hu, Vance Handley, and Kathy Kampf
- Subjects
Neocortex ,medicine.anatomical_structure ,General Neuroscience ,Cortex (anatomy) ,Subplate ,Superior colliculus ,Geniculate ,Thalamus ,medicine ,Biology ,Commissure ,Neuroscience ,Green fluorescent protein - Abstract
The first postmitotic neurons in the developing neocortex establish the preplate layer. These early-born neurons have a significant influence on the circuitry of the developing cortex. However, the exact timing and trajectory of their projections, between cortical hemispheres and intra- and extra-cortical regions, remain unresolved. Here, we describe the creation of a transgenic mouse using a 1.3 kb golli promoter element of the myelin basic protein gene to target expression of a tau-green fluorescent protein (GFP) fusion protein in the cell bodies and processes of pioneer cortical neurons. During embryonic and early neonatal development, the timing and patterning of process extension from these neurons was examined. Analysis of tau-GFP fluorescent fibers revealed that progression of early labeled projections was interrupted unexpectedly by transient pauses at the corticostriatal and telencephalic-diencephalic boundaries before invading the thalamus just prior to birth. After birth the pioneering projections differentially invaded the thalamus, excluding some nuclei, e.g. medial and lateral geniculate, until postnatal days 10-14. Early labeled projections were also found to cross to the contralateral hemisphere as well as to the superior colliculus. These results indicate that early corticothalamic projections appear to pause before invading specific subcortical regions during development, that there is developmental regulation of innervation of individual thalamic nuclei, and that these early-generated neurons also establish early projections to commissural and subcortical targets.
- Published
- 2007
42. Combined serial analysis of gene expression and transcription factor binding site prediction identifies novel-candidate-target genes of Nr2e1 in neocortex development
- Author
-
Slavita Bohacec, Russell J. Bonaguro, David J. Arenillas, Steven J.M. Jones, Siaw H. Wong, Jean-François Schmouth, Elizabeth M. Simpson, Kathleen G. Banks, Marco A. Marra, Wyeth W. Wasserman, Yuanyun Xie, and Ximena Corso-Díaz
- Subjects
Neurogenesis ,Receptors, Cytoplasmic and Nuclear ,Subventricular zone ,Neocortex ,Laser Capture Microdissection ,Computational biology ,Biology ,SAGE ,Mice ,Genetics ,medicine ,Animals ,Serial analysis of gene expression ,Transcription factor ,Binding Sites ,Gene Expression Regulation, Developmental ,DNA binding site ,medicine.anatomical_structure ,Nuclear receptor ,DNA microarray ,Nr2e1 ,Transcriptome ,Transcription Factors ,Research Article ,Biotechnology - Abstract
Background Nr2e1 (nuclear receptor subfamily 2, group e, member 1) encodes a transcription factor important in neocortex development. Previous work has shown that nuclear receptors can have hundreds of target genes, and bind more than 300 co-interacting proteins. However, recognition of the critical role of Nr2e1 in neural stem cells and neocortex development is relatively recent, thus the molecular mechanisms involved for this nuclear receptor are only beginning to be understood. Serial analysis of gene expression (SAGE), has given researchers both qualitative and quantitative information pertaining to biological processes. Thus, in this work, six LongSAGE mouse libraries were generated from laser microdissected tissue samples of dorsal VZ/SVZ (ventricular zone and subventricular zone) from the telencephalon of wild-type (Wt) and Nr2e1-null embryos at the critical development ages E13.5, E15.5, and E17.5. We then used a novel approach, implementing multiple computational methods followed by biological validation to further our understanding of Nr2e1 in neocortex development. Results In this work, we have generated a list of 1279 genes that are differentially expressed in response to altered Nr2e1 expression during in vivo neocortex development. We have refined this list to 64 candidate direct-targets of NR2E1. Our data suggested distinct roles for Nr2e1 during different neocortex developmental stages. Most importantly, our results suggest a possible novel pathway by which Nr2e1 regulates neurogenesis, which includes Lhx2 as one of the candidate direct-target genes, and SOX9 as a co-interactor. Conclusions In conclusion, we have provided new candidate interacting partners and numerous well-developed testable hypotheses for understanding the pathways by which Nr2e1 functions to regulate neocortex development. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-1770-3) contains supplementary material, which is available to authorized users.
- Published
- 2015
43. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression
- Author
-
A Sturrock, Yuanyun Xie, Tessa R. Davis, Adam G. Schrum, Blair R. Leavitt, Min Li Ye, Jennifer A. Collins, Michael R. Hayden, Amber L. Southwell, Erika B. Villanueva, Nicholas S. Caron, and Stephen E. P. Smith
- Subjects
Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,Immunoprecipitation ,Recombinant Fusion Proteins ,Immunoblotting ,Mutant ,Nerve Tissue Proteins ,Biology ,Severity of Illness Index ,Article ,Flow cytometry ,Mice ,Cerebrospinal fluid ,mental disorders ,medicine ,Huntingtin Protein ,Animals ,Humans ,Gene silencing ,Aged ,Multidisciplinary ,medicine.diagnostic_test ,Brain ,Middle Aged ,Flow Cytometry ,Molecular biology ,nervous system diseases ,3. Good health ,Cell biology ,Disease Models, Animal ,Huntington Disease ,nervous system ,Mutation ,Biomarker (medicine) ,Female - Abstract
Quantitation of huntingtin protein in the brain is needed, both as a marker of Huntington disease (HD) progression and for use in clinical gene silencing trials. Measurement of huntingtin in cerebrospinal fluid could be a biomarker of brain huntingtin, but traditional protein quantitation methods have failed to detect huntingtin in cerebrospinal fluid. Using micro-bead based immunoprecipitation and flow cytometry (IP-FCM), we have developed a highly sensitive mutant huntingtin detection assay. The sensitivity of huntingtin IP-FCM enables accurate detection of mutant huntingtin protein in the cerebrospinal fluid of HD patients and model mice, demonstrating that mutant huntingtin levels in cerebrospinal fluid reflect brain levels, increasing with disease stage and decreasing following brain huntingtin suppression. This technique has potential applications as a research tool and as a clinical biomarker.
- Published
- 2015
44. 696. Pre-Clinical Evaluation of Allele-Specific Mutant Huntingtin Gene Silencing Antisense Oligonucleotides
- Author
-
Crystal N. Doty, Eric E. Swayze, Michael R. Hayden, Nicholas S. Caron, Holly Kordasiewicz, Susan M. Freier, C. Frank Bennet, Yuanyun Xie, Amber L. Southwell, Niels H. Skotte, Boguslaw Felczak, Punit P. Seth, Erika B. Villanueva, and Michael Oestergaard
- Subjects
Pharmacology ,Huntingtin ,Mutant ,Single-nucleotide polymorphism ,Neuropathology ,Biology ,Humanized mouse ,Drug Discovery ,Genetics ,Gene silencing ,Molecular Medicine ,Cognitive decline ,Gene ,Molecular Biology - Abstract
Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than non-selective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering. We have evaluated ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs. We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 36 weeks or more after a single intracerebroventricular injection.We next conducted a pre-clinical therapeutic efficacy trial of lead ASOs and evaluated them for effect on the HD-like phenotypes of Hu97/18 mice. Treated mice underwent longitudinal behavioral and biochemical assessment followed by terminal neuropathology. Thus far we have determined that pre-symptomatic allele-specific muHTT silencing prevents onset of behavioral HD-like phenotypes. Evaluation of neuropathology and post-symptomatic intervention is ongoing. Contingent on findings from these studies and using delivery and dosing information gained from ongoing CNS ASO clinical trials, a primary SNP-targeted ASO drug could be fairly rapidly translated for human applications.
- Published
- 2015
- Full Text
- View/download PDF
45. Features of sand-dust deposits in Harbin city, China
- Author
-
Jia Zhou, Yuanyun Xie, Chunguo Kang, Kui He, and Yan Zhang
- Subjects
Pollution ,Lithosphere ,Loess ,media_common.quotation_subject ,Geography, Planning and Development ,General Earth and Planetary Sciences ,Mineralogy ,Composition (visual arts) ,Silt ,Enrichment factor ,Chemical composition ,Grain size ,media_common - Abstract
From the sedimentologic view, this paper analyses the grain-size distribution and the chemical composition of the deposits from sand-dust storm, occurring in Harbin on March 20, 2002. The result indicates that there exist plentiful coarse matters in the sand-dust deposits in Harbin, and the sand-dust composition presents obvious three peak distribution characteristics, indicating that the sand-dust in Harbin is composed of multi-origin components. The grain-size composition consists of silt (4–8Φ), accounting for 71.18% of the total, sand (>4Φ), 21.70%, and clay (
- Published
- 2006
46. Delayed Implantation of a Peripheral Nerve Graft Reduces Motoneuron Survival but Does Not Affect Regeneration following Spinal Root Avulsion in Adult Rats
- Author
-
Yuanyun Xie, Li-Hua Zhou, Hong Chai, Wutian Wu, Huai-Yu Gu, and Jian-Yi Zhang
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Cell Survival ,medicine.medical_treatment ,Growth Cones ,Nitric Oxide Synthase Type I ,Receptors, Nerve Growth Factor ,Receptor, Nerve Growth Factor ,Neurosurgical Procedures ,Rhizotomy ,Rats, Sprague-Dawley ,Avulsion ,Lesion ,medicine ,Animals ,Peripheral Nerves ,RNA, Messenger ,Radiculopathy ,Motor Neurons ,biology ,business.industry ,Regeneration (biology) ,fungi ,Motor neuron ,musculoskeletal system ,medicine.disease ,Nerve Regeneration ,Rats ,Surgery ,Nitric oxide synthase ,Nerve growth factor ,medicine.anatomical_structure ,Gene Expression Regulation ,nervous system ,Tissue Transplantation ,biology.protein ,Neurology (clinical) ,Nitric Oxide Synthase ,Avulsion injury ,medicine.symptom ,Spinal Nerve Roots ,business ,tissues - Abstract
Adult spinal motoneurons can regenerate their axons into a peripheral nerve (PN) graft following root avulsion injury if the graft is implanted immediately after the lesion is induced. The present study was designed to determine how avulsed motoneurons respond to a PN graft if implantation takes place a few days to a few weeks later. Survival, regeneration, and gene expression changes of injured motoneurons after delayed PN graft implantation were studied. The survival rates of spinal motoneurons were 78%, 65%, 57%, or 53% if a PN graft was implanted immediately, 1, 2, or 3 weeks after root avulsion, respectively. Interestingly, most of the surviving motoneurons were able to regenerate their axons into the graft regardless of the delay. All regenerating motoneurons expressed p75, but not nNOS, while all motoneurons that failed to regenerate expressed nNOS, but not p75. p75 and nNOS may, therefore, be used as markers for success or failure to regenerate axons. In the group with immediate graft implantation, 85% of the surviving motoneurons extended axons into the PN graft, while in the groups in which implantation was delayed 1, 2, or 3 weeks, 84%, 82%, and 83% of the surviving motoneurons, respectively, were found to have regenerated into the grafts. These findings indicate that avulsed spinal motoneurons retain the ability to regenerate for at least 3 weeks, and perhaps for as long as they survive. Therefore, the delayed implantation of a PN graft after root avulsion may provide a continued conducive environment to support regeneration.
- Published
- 2004
47. GDNF and BDNF Alter the Expression of Neuronal NOS, c-Jun, and p75 and Prevent Motoneuron Death following Spinal Root Avulsion in Adult Rats
- Author
-
Ronald W. Oppenheim, Leung-Wah Yick, Yi Yang, Hong Chai, Wutian Wu, Linxi Li, Yuanyun Xie, and David Prevette
- Subjects
Male ,medicine.medical_specialty ,Proto-Oncogene Proteins c-jun ,medicine.medical_treatment ,Nitric Oxide Synthase Type I ,Receptors, Nerve Growth Factor ,Ciliary neurotrophic factor ,Receptor, Nerve Growth Factor ,Rats, Sprague-Dawley ,Lesion ,Neurotrophic factors ,Internal medicine ,Glial cell line-derived neurotrophic factor ,medicine ,Animals ,Glial Cell Line-Derived Neurotrophic Factor ,Nerve Growth Factors ,Radiculopathy ,Motor Neurons ,Cell Death ,biology ,business.industry ,Brain-Derived Neurotrophic Factor ,c-jun ,musculoskeletal system ,Rats ,Nitric oxide synthase ,Endocrinology ,Gene Expression Regulation ,nervous system ,biology.protein ,Neurology (clinical) ,Nitric Oxide Synthase ,medicine.symptom ,Axotomy ,business ,tissues ,Neuroscience ,Neurotrophin - Abstract
In the present study, we examined the effects of glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and insulin growth factor (IGF-1) on adult motoneuron survival following spinal root avulsion. The expression of neuronal nitric oxide synthase (nNOS), c-Jun, and the low-affinity neurotrophin receptor (P75) following treatment with these neurotrophic factors was also examined. In control animals, approximately 80% of spinal motoneurons were nNOS positive at 3 weeks following the lesion, whereas in GDNF or BDNF treated animals no nNOS positive motoneurons were found at the same time point. Following injury and treatment with GDNF and BDNF increased numbers of motoneurons were c-Jun and P75 positive. By 6 weeks following the lesion, only approximately 28% of motoneurons persisted in control animals whereas about 90% of motoneurons survived injury following treatment with either GDNF or BDNF. In contrast, CNTF and IGF-1 were ineffective in either inhibiting nNOS expression or preventing motoneuron death. Our results provide in vivo evidence that the survival of injured adult mammalian motoneurons can be promoted by specific neurotrophic factors, and that this effect is associated with inhibition of nNOS expression and up-regulation of c-Jun and P75 expression.
- Published
- 2003
48. A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles
- Author
-
Crystal N. Doty, Diepiriye G. Iworima, Niels H. Skotte, Daphne Cheung, Mahmoud A. Pouladi, Ramy A. Slama, Xiaofeng Gu, X. William Yang, Jolene Ooi, Hailey Findlay-Black, Louisa Dal Cengio, Erika B. Villanueva, Michael E. Østergaard, Michael R. Hayden, Holly Kordasiewicz, Eric E. Swayze, Sabine Waltl, Chris Kay, Amber L. Southwell, Eugenia Petoukhov, Yuanyun Xie, and Punit P. Seth
- Subjects
0301 basic medicine ,Heterozygote ,congenital, hereditary, and neonatal diseases and abnormalities ,Huntingtin ,Transgene ,Mutant ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Mice ,03 medical and health sciences ,Exon ,0302 clinical medicine ,mental disorders ,Genetics ,medicine ,Animals ,Humans ,Allele ,Molecular Biology ,Alleles ,Genetics (clinical) ,Huntingtin Protein ,Mutation ,Exons ,General Medicine ,Molecular biology ,Phenotype ,Disease Models, Animal ,Huntington Disease ,030104 developmental biology ,Humanized mouse ,030217 neurology & neurosurgery - Abstract
Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent.
- Published
- 2017
49. Survival of motor neurons and expression of β-amyloid protein in the aged rat spinal cord
- Author
-
Yuanyun Xie, Wutian Wu, and Yao Zb
- Subjects
Male ,Aging ,medicine.medical_specialty ,Cell Survival ,Immunocytochemistry ,Cell Count ,Rats, Sprague-Dawley ,Amyloid beta-Protein Precursor ,Internal medicine ,mental disorders ,medicine ,Amyloid precursor protein ,Animals ,Young adult ,Muridae ,Motor Neurons ,Amyloid beta-Peptides ,Cell Death ,biology ,General Neuroscience ,Age Factors ,Anatomy ,Motor neuron ,Spinal cord ,biology.organism_classification ,Immunohistochemistry ,Rats ,medicine.anatomical_structure ,Endocrinology ,Spinal Cord ,nervous system ,Ageing ,Peripheral nervous system ,biology.protein - Abstract
The present study investigated expression of beta-amyloid protein (AP) and Amyloid precursor protein (APP) in spinal motor neurons of young adult (3 month old) and aged (26-30 month old) rats. The total number of spinal motor neurons in the seventh cervical (C7) spinal segment was also examined in both young adult and aged rats. There was an approximately 21% (p
- Published
- 2000
50. HACE1 is essential for astrocyte mitochondrial function and influences Huntington disease phenotypes in vivo.
- Author
-
Ehrnhoefer, Dagmar E., Southwell, Amber L., Sivasubramanian, Meenalochani, Xiaofan Qiu, Villanueva, Erika B., Yuanyun Xie, Waltl, Sabine, Anderson, Lisa, Fazeli, Anita, Casal, Lorenzo, Felczak, Boguslaw, Tsang, Michelle, and Hayden, Michael R.
- Published
- 2018
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.