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Cre-dependent DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice

Hu Zhu, Dipendra K. Aryal, Reid H.J. Olsen, Daniel J. Urban, Amanda Swearingen, Stacy Forbes, Bryan L. Roth, Ute Hochgeschwender
2016 Genesis  
DREADDs, designer receptors exclusively activated by designer drugs, are engineered G proteincoupled receptors (GPCR) which can precisely control GPCR signaling pathways (for example, Gq, Gs and Gi). This chemogenetic technology for control of GPCR signaling has been successfully applied in a variety of in vivo studies, including in mice, to remotely control GPCR signaling, for example, in neurons, glia cells, pancreatic beta-cells, or cancer cells. In order to fully explore the in vivo
more » ... ions of the DREADD technology we generated hM3Dq and hM4Di strains of mice which allow for Cre recombinase-mediated restricted expression of these pathwayselective DREADDs. With the many Cre driver lines now available, these DREADD lines will be applicable to studying a wide array of research and preclinical questions. RESULTS AND DISCUSSION Using directed evolution in a yeast mutagenesis system mutant G protein coupled muscarinic receptors were isolated which lost the ability to respond to the natural ligand acetylcholine, but gained the ability to respond to an inert compound (clozapine-N-oxide; CNO) with nanomolar potencies (Armbruster et al. 2007). We also demonstrated that CNO is both pharmacologically inert and metabolically stable in C57Bl6 mice (Alexander et al. 2009). Importantly, mutant receptors were selected to have low basal activity thereby providing a maximal dynamic range in agonist-induced responses (Armbruster et al. 2007). Currently, the existing DREADDs include the Gq, Gi and Gs (e.g. hM3Dq, hM4Di, and GsD respectively) signaling pathways, allowing for remote and non-invasive activation, inhibition and modulation of GPCR signaling pathways and neurotransmission in a variety of cells in
doi:10.1002/dvg.22949 pmid:27194399 pmcid:PMC4990490 fatcat:k5tmvbqasjgdlialkvbo5nyhoi

Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine

Il Hwan Kim, Mark A Rossi, Dipendra K Aryal, Bence Racz, Namsoo Kim, Akiyoshi Uezu, Fan Wang, William C Wetsel, Richard J Weinberg, Henry Yin, Scott H Soderling
2015 Nature Neuroscience  
imaging verified that the axonal terminals of the GFP positive axons from the frontal cortex made Vglut1-positive excitatory synaptic contacts with TH-positive DA neurons within the VTA/SNc(Fig. 3j, k  ... 
doi:10.1038/nn.4015 pmid:25938885 pmcid:PMC4459733 fatcat:uoelqq3wxjhx5o55zh6t3zdiga

G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 inCaenorhabditis elegans

Jianjun Wang, Jiansong Luo, Dipendra K. Aryal, William C. Wetsel, Richard Nass, Jeffrey L. Benovic
2017 Journal of Biological Chemistry  
doi:10.1074/jbc.m116.760850 pmid:28213524 pmcid:PMC5392585 fatcat:ixkhelxaxvet5g2zkwuqfn4b3a

Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

Pavle Matak, Andrija Matak, Sarah Moustafa, Dipendra K. Aryal, Eric J. Benner, William Wetsel, Nancy C. Andrews
2016 Proceedings of the National Academy of Sciences of the United States of America  
Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset
more » ... dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice. iron | transferrin receptor | ferroportin | dopaminergic neuron | neurodegeneration
doi:10.1073/pnas.1519473113 pmid:26929359 pmcid:PMC4822577 fatcat:hdcugyyrrffeladqbovgcwvfym

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats

Xuhui Bao, Vidyalakshmi Chandramohan, Randall P. Reynolds, John N. Norton, William C. Wetsel, Ramona M. Rodriguiz, Dipendra K. Aryal, Roger E. McLendon, Edward D. Levin, Neil A. Petry, Michael R. Zalutsky, Bruce K. Burnett (+3 others)
2016 Investigational new drugs  
acute cohort) and 0, 0.05, 0.1, 0.35 µg (the chronic cohort) for approximately 72 hours by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 µg (5/10 rats) and 0.35 µg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No doserelated effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic
more » ... es from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 µg, and the no observed adverse effect level was 0.05 µg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.
doi:10.1007/s10637-015-0318-3 pmid:26728879 pmcid:PMC4788550 fatcat:fjihkpm4bjfshe5bwig563w2f4

Elucidation of The Behavioral Program and Neuronal Network Encoded by Dorsal Raphe Serotonergic Neurons

Daniel J Urban, Hu Zhu, Catherine A Marcinkiewcz, Michael Michaelides, Hidehiro Oshibuchi, Darren Rhea, Dipendra K Aryal, Martilias S Farrell, Emily Lowery-Gionta, Reid H J Olsen, William C Wetsel, Thomas L Kash (+3 others)
2015 Neuropsychopharmacology  
Elucidating how the brain's serotonergic network mediates diverse behavioral actions over both relatively short (minutes-hours) and long period of time (days-weeks) remains a major challenge for neuroscience. Our relative ignorance is largely due to the lack of technologies with robustness, reversibility, and spatio-temporal control. Recently, we have demonstrated that our chemogenetic approach (eg, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)) provides a reliable and
more » ... ust tool for controlling genetically defined neural populations. Here we show how short-and long-term activation of dorsal raphe nucleus (DRN) serotonergic neurons induces robust behavioral responses. We found that both short-and long-term activation of DRN serotonergic neurons induce antidepressant-like behavioral responses. However, only short-term activation induces anxiogenic-like behaviors. In parallel, these behavioral phenotypes were associated with a metabolic map of whole brain network activity via a recently developed non-invasive imaging technology DREAMM (DREADD Associated Metabolic Mapping). Our findings reveal a previously unappreciated brain network elicited by selective activation of DRN serotonin neurons and illuminate potential therapeutic and adverse effects of drugs targeting DRN neurons.
doi:10.1038/npp.2015.293 pmid:26383016 pmcid:PMC4793125 fatcat:4fhcrsav5bhovlg7yztqfn5hpi

Deficiency of Asparagine Synthetase Causes Congenital Microcephaly and a Progressive Form of Encephalopathy

Elizabeth K. Ruzzo, José-Mario Capo-Chichi, Bruria Ben-Zeev, David Chitayat, Hanqian Mao, Andrea L. Pappas, Yuki Hitomi, Yi-Fan Lu, Xiaodi Yao, Fadi F. Hamdan, Kimberly Pelak, Haike Reznik-Wolf (+32 others)
2013 Neuron  
Axial T1W image (K) shows lack of myelin stripe in PLIC. Diffusion-weighted imaging (DWI) (L) is normal (as it was in all three siblings). See also Figure S1. ( Figure 1A ).  ... 
doi:10.1016/j.neuron.2013.08.013 pmid:24139043 pmcid:PMC3820368 fatcat:cxneuailxzeftc465qsjfla5sa

Page 129 of Current World Leaders Vol. 22, Issue 2 [page]

1979 Current World Leaders  
Rep. to UN: Sailendra K. Upadhyaya NETHERLANDS Head of State: Queen Juliana Louise Emma Marie Wilhelmina Cabinet Ministers: Prime Min., Min. of General Affairs: A. A. M. Van Agt Dep.  ...  Governments Health and Education: Joseph Detsimea Audoa Works and Community Services: Totouwa Orpaune NEPAL Head of State: His Majesty King Birendra Sir Bikram Shah Dev Crown Prince: His Royal Highness Prince Dipendra  ... 

Page 455 of Current World Leaders Vol. 22, Issue 6 [page]

1979 Current World Leaders  
National Governments NEPAL Head of State: His Majesty King Birendra Sir Bikram Shah Dev Crown Prince: His Royal Highness Prince Dipendra Bir Bikram Shah Dev Ministers: Prime Min.: Dr.  ...  Rep. to UN: Sailendra K. Upadhyaya NETHERLANDS Head of State: Juliana Louise Emma Marie Wilhelmina, Queen of the Netherlands Cabinet Ministers: Prime Min., Min. of General Affairs: A. A. M.  ... 

Assessment of Soil Nutrient Status under Different Cropping Systems in Khotang, Nepal

Pawan Devkota, Dipendra Aryal, Baburam Khanal
2019 International Journal of Applied Sciences and Biotechnology  
The highest K content (306.50 mg/kg) was recorded from Maize – Vegetable cropping system and lowest K content (34.80 mg/kg) was observed in Cardamom based system which is statistically similar to Rice  ...  Soil samples from 0-15 cm depth were collected from each site and evaluated for soil pH, soil organic carbon (SOC), total nitrogen (N), available phosphorus (P), and available potassium (K).  ...  Pawan Devkota, Dipendra Aryal & Baburam Khanal analysed the data; Pawan Devkota & Dipendra Aryal prepared the manuscript, critical revised and all authors finalized the manuscript.  ... 
doi:10.3126/ijasbt.v7i3.25697 fatcat:2qncdwr7abc3lnvagmofqhe6ci

List of Completed Dissertations

The Editor
2007 Journal of Nepalese Business Studies  
of NITT Pokhara Center Deepak Gautam cfO{ =Pg=Pkm= kfn' ' jf k/fdz{ ;] jf s] Gb| sf] Pr=cfO{ =eL= tyf P8\ ; :j} lR5s k/fdz{ tyf /Qm kl/If0f Ps cWooog Dipendra Dhakal kf] v/f /f] on ;xsf/L ;+  ...  For In ternet Digendra Paudel A Case Study of BhimpokharaYouth club Baglung Dil Maya Pun cGgk" 0f{ ;' k/ dfs] { 6 k| f=ln= Ps cWoog Dipendra Poudel A Case Study of Shree Jana Chetan Secondary  ... 
doi:10.3126/jnbs.v2i1.64 fatcat:7g2ie7pdjzgkngxaeox5mmyck4

List of Completed Dissertations

The Editor
2006 Journal of Nepalese Business Studies  
of NITT Pokhara Center Deepak Gautam cfO{ =Pg=Pkm= kfn' ' jf k/fdz{ ;] jf s] Gb| sf] Pr=cfO{ =eL= tyf P8\ ; :j} lR5s k/fdz{ tyf /Qm kl/If0f Ps cWooog Dipendra Dhakal kf] v/f /f] on ;xsf/L ;+  ...  For In ternet Digendra Paudel A Case Study of BhimpokharaYouth club Baglung Dil Maya Pun cGgk" 0f{ ;' k/ dfs] { 6 k| f=ln= Ps cWoog Dipendra Poudel A Case Study of Shree Jana Chetan Secondary  ... 
doi:10.3126/jnbs.v1i1.48 fatcat:bbwhg5ponraq7ptkym3sckdzfm

Things that Should not Be Said: Censorship and Self-Censorship in the Nepali Press Media, 2001–02

Michael Hutt
2006 Journal of Asian Studies  
It was Dipendra, Dipendra and only Dipendra!"  ...  The lone character who destroyed his lineage is Dipendra. Only Dipendra, solely Dipendra, none other than Dipendra."  ... 
doi:10.1017/s0021911806000696 fatcat:litsrb3q5nek3eiwsyd3jmfnui

List of Fieldwork Reports Submitted in 2060 (2004)

The Editor
2006 Journal of Nepalese Business Studies  
Lamichhane >L hgr] tg dfWolds ljBfno M Ps cWoog Dipendra Shrestha Gf] kfn g] qlxg ;+ # sf:sL zfvf M Ps cWoog Dipendra Subedi Kff] v/f /f] on ;xsf/L ;+ :yf ln= kf] v/fsf] shf{ k| jfx M Ps cWoog Durga  ...  ljsf; cleofg ;DjlGw M Ps cWoog Jyoti Gurung Impact of Tourism on Social Structure, Livelihood and Natural Resources ( a Case Study at Ghandruk Village of Kaski) Jynanhari Acharya A Khumkanta Aryal  ... 
doi:10.3126/jnbs.v1i1.49 fatcat:5bky34ffqjg6zpz7tqpobyp6mu

Assessment of urban heat island in Kathmandu valley (1999-2017)

Chhabi Lal Chidi, Ramesh Kumar Salami Magar, Dipendra Salami Magar
2021 Geographical Journal of Nepal  
Mountainous country like Nepal is highly affected by global warming especially in highland areas (Chaudhary and Aryal, 2009 ).  ...  radiance (watts/m² *sr*µm) K 1 = Thermal conversion constant for the band K 2 = Thermal conversion constant for the band Here, the output is in Kelvin unit of top of atmospheric brightness temperature  ... 
doi:10.3126/gjn.v14i0.35544 fatcat:yl5ccboranhrzdcc467ds2ej4u
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