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Knock-in AND mice

Amber Kempton, Matt Cefalu, Cody Justice, Tesla Baich, Mohamed Derbala, Benjamin Canan, Paul M L Janssen, Peter J Mohler, Sakima A Smith
Background: Left ventricular assist devices (LVADs) have revolutionized and improved the care of the sickest heart failure (HF) patients, and it is imperative that they receive appropriate ventricular unloading. Assessing this critical parameter with current methodologies (labs, imaging) is usually suboptimal in this patient population. Hence it is imperative to elucidate the molecular underpinnings involved in ventricular unloading. We have previously identified the cytoskeletal protein βII spectrin as an essential nodal protein involved in post-translational targeting and βII spectrin protein levels are significantly altered in multiple forms of human and animal HF...
January 2018: Heliyon
Elise Sofie Hovingh, Rob Mariman, Luis Solans, Daniëlle Hijdra, Hendrik-Jan Hamstra, Ilse Jongerius, Marjolein van Gent, Frits Mooi, Camille Locht, Elena Pinelli
Whooping cough, caused by Bordetella pertussis, has resurged and presents a global health burden worldwide. B. pertussis strains unable to produce the acellular pertussis vaccine component pertactin (Prn), have been emerging and in some countries represent up to 95% of recent clinical isolates. Knowledge on the effect that Prn deficiency has on infection and immunity to B. pertussis is crucial for the development of new strategies to control this disease. Here, we characterized the effect of Prn production by B...
March 21, 2018: Emerging Microbes & Infections
Yuhan Zhao, Lihua Wu, Xuetian Yue, Cen Zhang, Jianming Wang, Jun Li, Xiaohui Sun, Yiming Zhu, Zhaohui Feng, Wenwei Hu
Tumor suppressor p53 prevents early death due to cancer development. However, the role of p53 in aging process and longevity has not been well-established. In humans, single nucleotide polymorphism (SNP) with either arginine (R72) or proline (P72) at codon 72 influences p53 activity; the P72 allele has a weaker p53 activity and function in tumor suppression. Here, employing a mouse model with knock-in of human TP53 gene carrying codon 72 SNP, we found that despite increased cancer risk, P72 mice that escape tumor development display a longer lifespan than R72 mice...
March 20, 2018: ELife
Karen Müller Smith
GABAergic interneuron loss, maturational delay or imbalance of glutamatergic to GABAergic signaling has been implicated in several neuropsychiatric disorders including Tourette syndrome and attention-deficit/hyperactivity disorder (ADHD). In schizophrenia, decreases in parvalbumin (PV), somatostatin (Sst) and glutamic acid decarboxylase (GAD) RNA have been observed and seem to indicate a failure in maturation in PV and Sst neurons. In Tourette syndrome, which has a high level of comorbid ADHD, reduced numbers of parvalbumin expressing neurons have been observed in the basal ganglia of affected patients...
March 19, 2018: Attention Deficit and Hyperactivity Disorders
Hyun Jik Kim, Young Hun Seo, Sujin An, Ara Jo, Ick Chan Kwon, Sehoon Kim
Rationale: Hydrogen peroxide (H2 O2 ) provides an important mechanism for resisting infectious pathogens within the respiratory tract, and accordingly, the in situ analysis of H2 O2 generation in real time provides a valuable tool for assessing immune response. Methods: In this study, we applied a chemiluminescent nanoparticle-based real-time imaging approach to noninvasive evaluation of the Duox2-mediated H2 O2 generation after viral infection, and assessed its usefulness for analytical purposes in mouse nasal mucosa...
2018: Theranostics
Ping Li, Sungyong You, Christopher Nguyen, Yanping Wang, Jayoung Kim, Deepika Sirohi, Asha Ziembiec, Daniel Luthringer, Shih-Chieh Lin, Timothy Daskivich, Jonathan Wu, Michael R Freeman, Rola Saouaf, Debiao Li, Hyung L Kim
MRI is used to image prostate cancer and target tumors for biopsy or therapeutic ablation. The objective was to understand the biology of tumors not visible on MRI that may go undiagnosed and untreated. Methods: Prostate cancers visible or invisible on multiparametric MRI were macrodissected and examined by RNAseq. Differentially expressed genes (DEGs) based on MRI visibility status were cross-referenced with publicly available gene expression databases to identify genes associated with disease progression...
2018: Theranostics
Matthew A White, Eosu Kim, Amanda Duffy, Robert Adalbert, Benjamin U Phillips, Owen M Peters, Jodie Stephenson, Sujeong Yang, Francesca Massenzio, Ziqiang Lin, Simon Andrews, Anne Segonds-Pichon, Jake Metterville, Lisa M Saksida, Richard Mead, Richard R Ribchester, Youssef Barhomi, Thomas Serre, Michael P Coleman, Justin Fallon, Timothy J Bussey, Robert H Brown, Jemeen Sreedharan
Amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) constitutes a devastating disease spectrum characterized by 43-kDa TAR DNA-binding protein (TDP-43) pathology. Understanding how TDP-43 contributes to neurodegeneration will help direct therapeutic efforts. Here we have created a TDP-43 knock-in mouse with a human-equivalent mutation in the endogenous mouse Tardbp gene. TDP-43Q331K mice demonstrate cognitive dysfunction and a paucity of parvalbumin interneurons. Critically, TDP-43 autoregulation is perturbed, leading to a gain of TDP-43 function and altered splicing of Mapt, another pivotal dementia-associated gene...
March 19, 2018: Nature Neuroscience
Sreeharsha Gurrapu, Emanuela Pupo, Giulia Franzolin, Letizia Lanzetti, Luca Tamagnone
Semaphorin 4C (Sema4C) expression in human breast cancers correlates with poor disease outcome. Surprisingly, upon knock-down of Sema4C or its receptor PlexinB2 in diverse mammary carcinoma cells (but not their normal counterparts), we observed dramatic growth inhibition associated with impairment of G2/M phase transition, cytokinesis defects and the onset of cell senescence. Mechanistically, we demonstrated a Sema4C/PlexinB2/LARG-dependent signaling cascade that is required to maintain critical RhoA-GTP levels in cancer cells...
March 19, 2018: Cell Death and Differentiation
Dong Liu, Adam Stowie, Nuria de Zavalia, Tanya Leise, Salil Saurav Pathak, Lester R Drewes, Alec J Davidson, Shimon Amir, Nahum Sonenberg, Ruifeng Cao
Mammalian/mechanistic target of rapamycin (mTOR) signaling controls cell growth, proliferation, and metabolism in dividing cells. Less is known regarding its function in postmitotic neurons in the adult brain. Here we created a conditional mTOR knockout mouse model to address this question. Using the Cre-LoxP system, the mTOR gene was specifically knocked out in cells expressing Vip (vasoactive intestinal peptide), which represent a major population of interneurons widely distributed in the neocortex, suprachiasmatic nucleus (SCN), olfactory bulb (OB), and other brain regions...
March 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
Frank Zach, Franziska Polzer, Alexandra Mueller, André Gessner
The sequestosome 1 gene encodes the p62 protein and is the major genetic risk factor associated with Paget's disease of bone. In 2004, p62 was reported to up-regulate osteoclast differentiation by activating the transcription factors Nfatc1 and NF-κB. Here, we characterized the osteoclastogenic potential of murine p62-/- -derived cells compared with WT cells. Our data confirmed previous findings indicating that that p62 is induced during murine osteoclast differentiation. Surprisingly, an indispensable role for p62 in i n vitro osteoclast differentiation was not reproducible, since p62-deficient osteoclasts exhibited robust activation of Nfatc1, NF-κB, and osteoclast marker enzymes...
March 19, 2018: Journal of Biological Chemistry
Matthew A Mitsche, Helen H Hobbs, Jonathan C Cohen
Fatty liver disease (FLD) is a burgeoning health problem. A missense variant (I148M) in patatin-like phospholipase domain containing protein 3 (PNPLA3) confers susceptibility to FLD, although the mechanism is not known. To glean first insights into the physiological function of PNPLA3, we performed detailed lipidomic profiling of liver lysates and lipid droplets (LDs) from wildtype (WT), Pnpla3-/- (KO), and knock-in (ki) mice expressing either the 148M variant (IM-ki mice) or a variant (S47A) that renders the protein catalytically inactive (SA-ki mice)...
March 19, 2018: Journal of Biological Chemistry
Maria José Costa, Jyothirmayee Kudaravalli, Wen-Hui Liu, Jeffrey Stock, Sophanna Kong, Shu-Hui Liu
The development of therapeutic monoclonal antibodies through mouse immunization often originates drug candidates that are not cross-reactive to the mouse ortholog. In such cases, and particularly in oncology, drug efficacy studies are performed on human tumor xenografts or with "surrogate" anti-mouse ortholog antibodies if targeting tumor host cells. Safety assessment of drug candidate(s) is performed at a later development stage in healthy non-human primates. While the latter remains necessary before a drug advances into human subjects, it precludes evaluation of safety in disease conditions and drug de-risking during early development...
2018: PloS One
Julie Kovářová, Andrew W Pountain, David Wildridge, Stefan Weidt, Frédéric Bringaud, Richard J S Burchmore, Fiona Achcar, Michael P Barrett
Transketolase (TKT) is part of the non-oxidative branch of the pentose phosphate pathway (PPP). Here we describe the impact of removing this enzyme from the pathogenic protozoan Leishmania mexicana. Whereas the deletion had no obvious effect on cultured promastigote forms of the parasite, the Δtkt cells were not infective to mice. Δtkt promastigotes were more susceptible to oxidative stress and various leishmanicidal drugs than wild-type, and metabolomics analysis revealed profound changes to metabolism in these cells...
March 19, 2018: PLoS Pathogens
Fen Huang, Bo Wang, Jiangzheng Zeng, Shenggang Sang, Junhua Lei, Yanda Lu
Programmed cell death-1 (PD-1) is an oncogene associated with suppressing proliferation and cytokine production of T cells in the progression of liver cancer. microRNAs (miRs) regulate gene expression via specific binding to the target 3'untranslated region of mRNA. In the present study, miR-374b was indicated to interact with PD-1 and affect the tumor-targeting capacity of cytokine-induced killer (CIK) cells. miR-374b inhibitor significantly increased PD-1 expression in CIK cells. A synthetic small interfering (si)RNA targeting PD-1 was employed to silence the expression level of PD-1 in CIK cells...
April 2018: Oncology Letters
Chenju Yi, Jérémy Theillon, Annette Koulakoff, Hugues Berry, Christian Giaume
Intercellular communication through gap junction channels plays a key role in cellular homeostasis and in synchronizing physiological functions, a feature that is modified in number of pathological situations. In the brain, astrocytes are the cell population that expresses the highest amount of gap junction proteins, named connexins. Several techniques have been used to assess the level of gap junctional communication in astrocytes, but so far they remain very difficult to apply in adult brain tissue. Here, using specific loading of astrocytes with sulforhodamine 101, we adapted the gap-FRAP (Fluorescence Recovery After Photobleaching) to acute hippocampal slices from 9 month-old adult mice...
March 15, 2018: Journal of Neuroscience Methods
Chao Dong, Ji-Chun Zhang, Qian Ren, Min Ma, Youge Qu, Kai Zhang, Wei Yao, Tamaki Ishima, Hisashi Mori, Kenji Hashimoto
The N-methyl-D-aspartate receptor (NMDAR) plays a key role in the pathophysiology of depression. Serine racemase (SRR, encoded by Srr) converts L-serine to D-serine, an endogenous co-agonist at the glycine site of the NMDAR. Knock-out (KO) of Srr did not alter behavioral signs of depression compared with wild-type (WT) mice as evaluated by locomotion, tail suspension, forced swimming, and 1% sucrose preference tests. However, chronic social defeat stress (CSDS: 10 days) caused a depression-like phenotype as measured by these same tests in WT mice but not in Srr KO mice, suggesting that decreased D-serine co-agonist activity confers resilience against CSDS...
March 14, 2018: Neurochemistry International
Chaofan Zhang, Kwong Yuen Chiu, Boris Pok Man Chan, Teng Li, Chunyi Wen, Aimin Xu, Chun Hoi Yan
OBJECTIVES: Adipokines play roles in the pathogenesis of osteoarthritis (OA). Fatty acid binding protein 4 (FABP4) is a novel adipokine that is closely associated with obesity and metabolic diseases. The aim of this study was to discover the potential role of FABP4 in OA. METHODS: Seventy-two FABP4 knockout mice (KO) in C57BL/6N background and wild-type littermates (WT) (male, 6-week-old) were fed with a high-fat diet (HFD, 60% calorie) or standard diet (STD, 11...
March 13, 2018: Osteoarthritis and Cartilage
Nicholas Beazley-Long, Catherine Elizabeth Moss, William Robert Ashby, Samuel Marcus Bestall, Fatimah Almahasneh, Alexandra Margaret Durrant, Andrew Vaughan Benest, Zoe Blackley, Kurt Ballmer-Hofer, Masanori Hirashima, Richard Phillip Hulse, David Owen Bates, Lucy Frances Donaldson
Chronic pain can develop in response to conditions such as inflammatory arthritis. The central mechanisms underlying the development and maintenance of chronic pain in humans are not well elucidated although there is evidence for a role of microglia and astrocytes. However in pre-clinical models of pain, including models of inflammatory arthritis, there is a wealth of evidence indicating roles for pathological glial reactivity within the CNS. In the spinal dorsal horn of rats with painful inflammatory arthritis we found both a significant increase in CD11b+ microglia-like cells and GFAP+ astrocytes associated with blood vessels, and the number of activated blood vessels expressing the adhesion molecule ICAM-1, indicating potential glio-vascular activation...
March 13, 2018: Brain, Behavior, and Immunity
Ji-Eun Kang, Hyun-Do Kim, Soo-Young Park, Jae-Gu Pan, Jeong Hyun Kim, Do-Young Yum
Background and Aims: Commercial superoxide dismutase (SOD) is derived from melon extract and has a potential as a dietary supplement due to its beneficial anti-oxidative effects. We aimed to improve the productivity of SOD compared with plant SOD by using a generally-regarded-as-safe (GRAS) microorganism, Bacillus amyloliquefaciens, and assess its anti-oxidative effect using γ-radiation- and dextransulfate sodium (DSS)-induced oxidative models in mice. Methods: We identified the sodA gene encoding manganese-containing SODs (Mn-SOD) in B...
March 14, 2018: Journal of Crohn's & Colitis
Pan Pan, Hongmin Zhang, Longxiang Su, Xiaoting Wang, Dawei Liu
To explore the mechanism of mitochondrial uncoupling protein 2 (UCP2) mediating the protective of melatonin when septic cardiomyopathy. UCP2 knocked out mice and cardiomyocytes were used to study the effect of melatonin in response to LPS. Indicators of myocardial and mitochondria injury including mitochondrial membrane potential, mitochondrial permeability transition pore, calcium loading, ROS, and ATP detection were assessed. In addition cell viability and apoptosis as well as autophagy-associated proteins were evaluated...
March 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
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