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Knock-in AND mice

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https://www.readbyqxmd.com/read/28819706/generation-of-a-functional-humanized-delta-like-ligand-4-transgenic-mouse-model
#1
John Wiseman, Pernilla Gregersson, Johan Johansson, Kerstin Magnell, Fernanda Pilataxi, Chris Morehouse, Philip Brohawn, Nicholas Holoweckyj, Patrick Strout, Song Cho
Humanized mouse models are important tools in many areas of biological drug development including, within oncology research, the development of antagonistic antibodies that have the potential to block tumor growth by controlling vascularization and are key to the generation of in vivo proof-of-concept efficacy data. However, due to cross reactivity between human antibodies and mouse target such studies regularly require mouse models expressing only the human version of the target molecule. Such humanized knock-in/knock-out, KIKO, models are dependent upon the generation of homozygous mice expressing only the human molecule, compensating for loss of the mouse form...
August 17, 2017: Transgenic Research
https://www.readbyqxmd.com/read/28819097/the-non-coding-rna-bc1-regulates-experience-dependent-structural-plasticity-and-learning
#2
Victor Briz, Leonardo Restivo, Emanuela Pasciuto, Konrad Juczewski, Valentina Mercaldo, Adrian C Lo, Pieter Baatsen, Natalia V Gounko, Antonella Borreca, Tiziana Girardi, Rossella Luca, Julie Nys, Rogier B Poorthuis, Huibert D Mansvelder, Gilberto Fisone, Martine Ammassari-Teule, Lutgarde Arckens, Patrik Krieger, Rhiannon Meredith, Claudia Bagni
The brain cytoplasmic (BC1) RNA is a non-coding RNA (ncRNA) involved in neuronal translational control. Absence of BC1 is associated with altered glutamatergic transmission and maladaptive behavior. Here, we show that pyramidal neurons in the barrel cortex of BC1 knock out (KO) mice display larger excitatory postsynaptic currents and increased spontaneous activity in vivo. Furthermore, BC1 KO mice have enlarged spine heads and postsynaptic densities and increased synaptic levels of glutamate receptors and PSD-95...
August 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28818867/exploring-potential-germline-associated-roles-of-the-trim-nhl-protein-nhl-2%C3%A2-through-rnai-screening
#3
Gregory M Davis, Wai Y Low, Joshua W T Anderson, Peter R Boag
TRIM-NHL proteins are highly conserved regulators of developmental pathways in vertebrates and invertebrates. The TRIM-NHL family member, NHL-2 in Caenorhabditis elegans functions as a miRNA cofactor to regulate developmental timing. Similar regulatory roles have been reported in other model systems, with the mammalian orthologue in mice, TRIM32, contributing to muscle and neuronal cell proliferation via miRNA activity. Given the interest associated with TRIM-NHL family proteins, we aimed to further investigate the role of NHL-2 in C...
August 17, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/28813526/mtor-has-a-developmental-stage-specific-role-in-mitochondrial-fitness-independent-of-conventional-mtorc1-and-mtorc2-and-the-kinase-activity
#4
Khalid W Kalim, Shuangmin Zhang, Xiaoyi Chen, Yuan Li, Jun-Qi Yang, Yi Zheng, Fukun Guo
The mammalian target of rapamycin (mTOR), present in mTOR complex 1 (mTORC1) and mTORC2, is a serine/threonine kinase that integrates nutrients, growth factors, and cellular energy status to control protein synthesis, cell growth, survival and metabolism. However, it remains elusive whether mTOR plays a developmental stage-specific role in tissue development and whether mTOR can function independent of its complexes and kinase activity. In this study, by inducible genetic manipulation approach, we investigated the role of mTOR and its dependence on mTOR complexes and kinase activity in mitochondrial fitness of early, progenitor stage (lineage-negative; Lin-) versus later, lineage-committed stage (lineage-positive; Lin+) of hematopoietic cells...
2017: PloS One
https://www.readbyqxmd.com/read/28812237/pharmacological-effects-on-ceroid-lipofuscin-and-neuronal-structure-in-cln3-%C3%A2-ex7-8-mouse-brain-cultures
#5
Douglas E Brenneman, David A Pearce, Attila Kovacs, Shawn DeFrees
Juvenile Batten disease (JBD) is an inherited disorder that is characterized by the development of blindness, seizures, and progressive motor, psychiatric, and cognitive impairment. A model of JBD expressing the predominant human mutation (Cln3 (∆ex7/8) ) has been explored. Dissociated brain cultures from Cln3 (∆ex7/8) knock-in mice were compared to wild type (WT) for effects on granules of ceroid lipofuscin (CL) and neuronal structure. Utilizing high content image analysis of CL granules identified with antibodies to mitochondrial ATP synthase subunit c or tripeptidyl peptidase-1, significant increases in the areas for both immunoreactive granules were observed in Cln3 (∆ex7/8) cultures in comparison to WT...
August 15, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28806762/a-becn1-mutation-mediates-hyperactive-autophagic-sequestration-of-amyloid-oligomers-and-improved-cognition-in-alzheimer-s-disease
#6
Altea Rocchi, Soh Yamamoto, Tabitha Ting, Yuying Fan, Katherine Sadleir, Yigang Wang, Weiran Zhang, Sui Huang, Beth Levine, Robert Vassar, Congcong He
Impairment of the autophagy pathway has been observed during the pathogenesis of Alzheimer's disease (AD), a neurodegenerative disorder characterized by abnormal deposition of extracellular and intracellular amyloid β (Aβ) peptides. Yet the role of autophagy in Aβ production and AD progression is complex. To study whether increased basal autophagy plays a beneficial role in Aβ clearance and cognitive improvement, we developed a novel genetic model to hyperactivate autophagy in vivo. We found that knock-in of a point mutation F121A in the essential autophagy gene Beclin 1/Becn1 in mice significantly reduces the interaction of BECN1 with its inhibitor BCL2, and thus leads to constitutively active autophagy even under non-autophagy-inducing conditions in multiple tissues, including brain...
August 14, 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28804446/induction-of-mir-155-after-brain-injury-promotes-type-1-interferon-and-has-a-neuroprotective-effect
#7
Emily B Harrison, Katy Emanuel, Benjamin G Lamberty, Brenda M Morsey, Min Li, Matthew L Kelso, Sowmya V Yelamanchili, Howard S Fox
Traumatic brain injury (TBI) produces profound and lasting neuroinflammation that has both beneficial and detrimental effects. Recent evidence has implicated microRNAs (miRNAs) in the regulation of inflammation both in the periphery and the CNS. We examined the expression of inflammation associated miRNAs in the context of TBI using a mouse controlled cortical impact (CCI) model and found increased levels of miR-21, miR-223 and miR-155 in the hippocampus after CCI. The expression of miR-155 was elevated 9-fold after CCI, an increase confirmed by in situ hybridization (ISH)...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28800037/primary-cilia-deficiency-induces-intracranial-aneurysm
#8
Min Liu, Jizong Zhao, Qian Zhou, Yong Peng, Yu Zhou, Yugang Jiang
BACKGROUND: Intracranial aneurysm (IA) rupture is life-threatening. However, the mechanisms underlying IA initiation, progression, and rupture remain poorly understood. In the present study, we examined the role of primary cilia in IA development. RESULTS: IA was experimentally induced in mice with elastase and angiotensin II treatment. The number of cells with primary cilia was determined in both IA and peri-IA regions. The role of primary cilia in IA development was assessed through knocking out or manipulating the expression of important components of primary cilia...
August 9, 2017: Shock
https://www.readbyqxmd.com/read/28798321/crispr-cas9-mediated-deletion-of-foxn1-in-nod-scid-il2rg-mice-results-in-severe-immunodeficiency
#9
Xinru Wei, Yunxin Lai, Baiheng Li, Le Qin, Youdi Xu, Simiao Lin, Suna Wang, Qiting Wu, Qiubin Liang, Guohua Huang, Qiuhua Deng, Pentao Liu, Donghai Wu, Liangxue Lai, Yao Yao, Peng Li
Immunodeficient mice engrafted with either normal or cancerous human cells are widely used in basic and translational research. In particular, NOD/SCID/IL2rg(-/-) mice can support the growth of various types of human cancer cells. However, the hairs of these mice interfere with the observation and imaging of engrafted tissues. Therefore, novel hairless strains exhibiting comparable immunodeficiency would be beneficial. Recently, the CRISPR/Cas9 system has been used for efficient multiplexed genome editing. In the present study, we generated a novel strain of nude NOD/SCID/IL2rg(-/-) (NSIN) mice by knocking out Foxn1 from NOD/SCID/IL2rg(-/-) (NSI) mice using the CRISPR/Cas9 system...
August 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28794483/impaired-lymphocyte-trafficking-in-mice-deficient-in-the-kinase-activity-of-pkn1
#10
Rana Mashud, Akira Nomachi, Akihide Hayakawa, Koji Kubouchi, Sally Danno, Takako Hirata, Kazuhiko Matsuo, Takashi Nakayama, Ryosuke Satoh, Reiko Sugiura, Manabu Abe, Kenji Sakimura, Shigeharu Wakana, Hiroyuki Ohsaki, Shingo Kamoshida, Hideyuki Mukai
Knock-in mice lacking PKN1 kinase activity were generated by introducing a T778A point mutation in the catalytic domain. PKN1[T778A] mutant mice developed to adulthood without apparent external abnormalities, but exhibited lower T and B lymphocyte counts in the peripheral blood than those of wild-type (WT) mice. T and B cell development proceeded in an apparently normal fashion in bone marrow and thymus of PKN1[T778A] mice, however, the number of T and B cell counts were significantly higher in the lymph nodes and spleen of mutant mice in those of WT mice...
August 9, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28793320/microsomal-triglyceride-transfer-protein-contributes-to-lipid-droplet-maturation-in-adipocytes
#11
Larry L Swift, Joseph D Love, Carla M Harris, Benny H Chang, W Gray Jerome
Previous studies in our laboratory have established the presence of MTP in both white and brown adipose tissue in mice as well as in 3T3-L1 cells. Additional studies demonstrated an increase in MTP levels as 3T3-L1 cells differentiate into adipocytes concurrent with the movement of MTP from the juxtanuclear region of the cell to the surface of lipid droplets. This suggested a role for MTP in lipid droplet biogenesis and/or maturation. To probe the role of MTP in adipocytes, we used a Cre-Lox approach with aP2-Cre and Adipoq-Cre recombinase transgenic mice to knock down MTP expression in brown and white fat of mice...
2017: PloS One
https://www.readbyqxmd.com/read/28792272/trigeminovascular-calcitonin-gene-related-peptide-function-in-cacna1a-r192q-mutated-knock-in-mice
#12
Kayi Y Chan, Alejandro Labastida-Ramírez, Martha B Ramírez-Rosas, Sieneke Labruijere, Ingrid M Garrelds, Alexander Hj Danser, Arn Mjm van den Maagdenberg, Antoinette MaassenVanDenBrink
Familial hemiplegic migraine type 1 (FHM1) is a rare migraine subtype. Whereas transgenic knock-in mice with the human pathogenic FHM1 R192Q missense mutation in the Cacna1a gene reveal overall neuronal hyperexcitability, the effects on the trigeminovascular system and calcitonin gene-related peptide (CGRP) receptor are largely unknown. This gains relevance as blockade of CGRP and its receptor are therapeutic targets under development. Hence, we set out to test these effects in FHM1 mice. We characterized the trigeminovascular system of wild-type and FHM1 mice through: (i) in vivo capsaicin- and CGRP-induced dural vasodilation in a closed-cranial window; (ii) ex vivo KCl-induced CGRP release from isolated dura mater, trigeminal ganglion and trigeminal nucleus caudalis; and (iii) peripheral vascular function in vitro ...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28783585/downregulated-nlrp3-and-nlrp1-inflammasomes-signaling-pathways-in-the-development-and-progression-of-type-1-diabetes-mellitus
#13
Huawei Liu, Ruiying Xu, Qingyu Kong, Jiling Liu, Zhen Yu, Cuifen Zhao
BACKGROUND: NLRP3 and NLRP1 inflammasomes signaling pathways may play an important role in the development and progression of type 1 diabetes mellitus (T1DM). However, relative research is rare. METHODS: The blood mononuclear cells (PBMCs) and granulocytes (GCs) were collected from T1DM patients. The mRNA and protein expression levels were detected by qRT-PCR and Western blotting, respectively. The NLRP3/NLRP1was knocked down by transfected with siRNA, or ovexpressed by infected with lentiviral vectors in PBMCs and GCs from non obese diabetic (NOD) mice, respectively...
August 4, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28782641/nitric-oxide-cgmp-signaling-via-guanylyl-cyclase-isoform-1-modulates-glutamate-and-gaba-release-in-somatosensory-cortex-of-mice
#14
Qi Wang, Evanthia Mergia, Doris Koesling, Thomas Mittmann
In hippocampus, two guanylyl cyclases (NO-GC1 and NO-GC2) are involved in the transduction of the effects of nitric oxide (NO) on synaptic transmission. However, the respective roles of the NO-GC isoforms on synaptic transmission are less clear in other regions of the brain. In the present study, we used knock-out mice deficient for the NO-GC1 isoform (NO-GC1 KO) to analyze its role in the glutamatergic and GABAergic neurotransmission at pyramidal neurons in layers II/III of somatosensory cortex. NO-GC1 KO slices revealed reduced frequencies of miniature excitatory- and inhibitory-postsynaptic currents, increased paired-pulse ratios and decreased input-output curves of evoked signals, which indicated the reduction of glutamate and GABA release in NO-GC1 KO mice...
August 4, 2017: Neuroscience
https://www.readbyqxmd.com/read/28782255/pou3f2-participates-in-cognitive-function-and-adult-hippocampal-neurogenesis-via-mammalian-characteristic-amino-acid-repeats
#15
Koichi Hashizume, Masashi Yamanaka, Shintaroh Ueda
POU3F2/BRN-2 is a transcription factor that is mainly expressed in the central nervous system and plays an important role in brain development. The transactivation domain of POU3F2 includes multiple mammalian-characteristic tandem amino acid repeats (homopolymeric amino acid repeats). We previously generated knock-in mice (Pou3f2(Δ)(/Δ) mice) in which all three homopolymeric amino acid repeats were deleted from the Pou3f2 transactivation domain and identified phenotypic impairments in maternal behavior and pup recognition...
August 7, 2017: Genes, Brain, and Behavior
https://www.readbyqxmd.com/read/28780615/a-knock-in-knock-out-mouse-model-of-hspb8-associated-distal-hereditary-motor-neuropathy-and-myopathy-reveals-toxic-gain-of-function-of-mutant-hspb8
#16
Delphine Bouhy, Manisha Juneja, Istvan Katona, Anne Holmgren, Bob Asselbergh, Vicky De Winter, Tino Hochepied, Steven Goossens, Jody J Haigh, Claude Libert, Chantal Ceuterick-de Groote, Joy Irobi, Joachim Weis, Vincent Timmerman
Mutations in the small heat shock protein B8 gene (HSPB8/HSP22) have been associated with distal hereditary motor neuropathy, Charcot-Marie-Tooth disease, and recently distal myopathy. It is so far not clear how mutant HSPB8 induces the neuronal and muscular phenotypes and if a common pathogenesis lies behind these diseases. Growing evidence points towards a role of HSPB8 in chaperone-associated autophagy, which has been shown to be a determinant for the clearance of poly-glutamine aggregates in neurodegenerative diseases but also for the maintenance of skeletal muscle myofibrils...
August 5, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28780075/brca1-associated-protein-increases-invasiveness-of-esophageal-squamous-cell-carcinoma
#17
Yanjie Zhao, Lixuan Wei, Mingming Shao, Xudong Huang, Jiang Chang, Jian Zheng, Jiahui Chu, Qionghua Cui, Linna Peng, Yingying Luo, Wenle Tan, Wen Tan, Dongxin Lin, Chen Wu
BACKGROUND & AIMS: We performed a screen for genes whose expression correlates with invasiveness of esophageal squamous-cell carcinoma (ESCC) cells. We studied the effects of overexpression and knockdown of these genes in cell lines and expression levels in patient samples. METHODS: We selected genes for analysis from 11 loci associated with risk of ESCC. We analyzed the effects of knocking down expression of 47 of these genes using RNA interference on-chip analysis in ESCC cells and HeLa cells...
August 2, 2017: Gastroenterology
https://www.readbyqxmd.com/read/28774822/browning-deficiency-and-low-mobilization-of-fatty-acids-in-gonadal-white-adipose-tissue-leads-to-decreased-cold-tolerance-of-transglutaminase-2-knock-out-mice
#18
András Mádi, Ixchelt Cuaranta-Monroy, Kinga Lénárt, Attila Pap, Zoltán András Mezei, Endre Kristóf, Anna Oláh, György Vámosi, Zsolt Bacsó, Péter Bai, László Fésüs
During cold-exposure 'beige' adipocytes with increased mitochondrial content are activated in white adipose tissue (WAT). These cells, similarly to brown adipocytes (BAT), dissipate stored chemical energy in the form of heat with the help of uncoupling protein 1 (UCP1). We investigated the effect of TG2 ablation on the function of ATs in mice. Although TG2(+/+) and TG2(-/-) mice had the same amount of WAT and BAT, we found that TG2(+/+) animals could tolerate acute cold exposure for 4h, whereas TG2(-/-) mice only for 3h...
July 31, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28774593/inhibiton-of-fkbp10-attenuates-hypertrophic-scarring-through-suppressing-fibroblast-activity-and-extracellualr-matrix-deposition
#19
Xiao Liang, Bangda Chai, Ran Duan, Yiwen Zhou, Xiaolu Huang, Qingfeng Li
Hypertrophic scar (HS) is a pathogenic form of scar formation with no recognized treatment to date. Its molecular mechanism is related to the abnormal proliferation and transition of fibroblasts and overproduction of extracellular matrix (ECM). FK506-binding protein 10 (FKBP10) is a molecular chaperone able of regulating α-SMA expression and pro-collagen maturation in fibroblasts. However, no research has investigated the biological function of FKBP10 in scar formation to date. In this study, we aim to assess the expression and function of FKBP10 in hypertrophic scarring...
July 31, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28771630/absence-of-microrna-21-does-not-reduce-muscular-dystrophy-in-mouse-models-of-lama2-cmd
#20
Bernardo Moreira Soares Oliveira, Madeleine Durbeej, Johan Holmberg
MicroRNAs (miRNAs) are short non-coding RNAs that modulate gene expression post-transcriptionally. Current evidence suggests that miR-21 plays a significant role in the progression of fibrosis in muscle diseases. Laminin-deficient congenital muscular dystrophy (LAMA2-CMD) is a severe form of congenital muscular dystrophy caused by mutations in the gene encoding laminin α2 chain. Mouse models dy3K/dy3K and dy2J/dy2J, respectively, adequately mirror severe and milder forms of LAMA2-CMD. Both human and mouse LAMA2-CMD muscles are characterized by extensive fibrosis and considering that fibrosis is the final step that destroys muscle during the disease course, anti-fibrotic therapies may be effective strategies for prevention of LAMA2-CMD...
2017: PloS One
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