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https://www.readbyqxmd.com/read/28727987/associations-of-autoimmunity-immunodeficiency-lymphomagenesis-and-gut-microbiota-in-mice-with-knockins-for-a-pathogenic-autoantibody
#1
Shweta Jain, Jerrold M Ward, Dong-Mi Shin, Hongsheng Wang, Zohreh Naghashfar, Alexander L Kovalchuk, Herbert C Morse
A number of mouse strains transgenic for B-cell receptors specific for nucleic acids or other autoantigens have been generated to understand how autoreactive B cells are regulated in normal and autoimmune mice. Previous studies of nonautoimmune C57BL/6 mice heterozygous for both the IgH and IgL knockins of the polyreactive autoantibody, 564, produced high levels of autoantibodies in a largely Toll-like receptor 7-dependent manner. Herein, we describe studies of mice homozygous for the knockins that also expressed high levels of autoantibodies but, unlike the heterozygotes, exhibited a high incidence of mature B-cell lymphomas and enhanced susceptibility to bacterial infections...
July 17, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28727940/intestinal-transit-time-and-cortisol-mediated-stress-in-zebrafish
#2
Clayton Brady, Maxwell Denora, Ian Shannon, Karl J Clark, Adam Rich
Intestinal motility, the spontaneous and rhythmic smooth muscle contraction, is a complex process that is regulated by overlapping and redundant regulatory mechanisms. Primary regulators intrinsic to the gastrointestinal tract include interstitial cells of Cajal, enteric neurons, and smooth muscle cells. Extrinsic primary regulators include the autonomic nervous system, immune system, and the endocrine system. Due to this complexity, a reductionist approach may be inappropriate if the ultimate goal is to understand motility regulation in vivo...
July 20, 2017: Zebrafish
https://www.readbyqxmd.com/read/28727785/novel-crispr-cas9-gene-drive-constructs-reveal-insights-into-mechanisms-of-resistance-allele-formation-and-drive-efficiency-in-genetically-diverse-populations
#3
Jackson Champer, Riona Reeves, Suh Yeon Oh, Chen Liu, Jingxian Liu, Andrew G Clark, Philipp W Messer
A functioning gene drive system could fundamentally change our strategies for the control of vector-borne diseases by facilitating rapid dissemination of transgenes that prevent pathogen transmission or reduce vector capacity. CRISPR/Cas9 gene drive promises such a mechanism, which works by converting cells that are heterozygous for the drive construct into homozygotes, thereby enabling super-Mendelian inheritance. Although CRISPR gene drive activity has already been demonstrated, a key obstacle for current systems is their propensity to generate resistance alleles, which cannot be converted to drive alleles...
July 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28726522/steerable-induction-of-the-thymosin-%C3%A3-4-mrtf-a-pathway-via-aav-based-overexpression-induces-therapeutic-neovascularization
#4
Tilman Ziegler, Markus Kraus, Wira Husada, Florian Gesenhues, Qui Jiang, Olaf Pinkenburg, Teresa Trenkwalder, Karl-Ludwig Laugwitz, Ferdinand le Noble, Christian Weber, Christian Kupatt, Rabea Hinkel
Viral vectors have been frequently used in a variety of preclinical animal models to deliver genetic constructs into tissues. Among the vectors used, adeno-associated viral vectors (AAVs) may be targeted to specific tissues, depending on the serotype used. Moreover, they show robust expression for prolonged periods of time and have a low immunogenic potential. Furthermore, AAVs, unlike other vector systems, only display a low rate of genomic integration. However, to ensure efficient transgene production, expression is typically driven by constitutively active promoters, such as the CMV promotor...
July 20, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28726016/amyloid-%C3%AE-derived-from-the-brain-of-the-alzheimer-s-disease-transgenic-mouse-is-resistant-to-proteolytic-digestion-due-to-its-conformation
#5
Baian Chen, Jing Zhang, Shubo Wang, Wen Wang, Zitong Yao, Quan Sun, Yi Wu, Jing Lu
The main pathological feature of Alzheimer's disease (AD) is the formation of abundant amyloid-β (Aβ) plaques in the human brain. Studies have reported that Aβ from the AD brain is resistant to proteolytic digestion, which may explain why Aβ cannot be readily eliminated from this organ. However, there are only a few studies that address this important question. We used the AD transgenic mouse (APP/PS1) model to show that Aβ derived from the brain of the old mouse is resistant to proteolytic digestion. This was in contrast to the proteinase K-sensitive human Aβ peptide, whose amino acid sequence was identical to that of AD mouse-derived Aβ but whose conformation was different (i...
July 19, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28724797/increasing-the-level-of-peroxisome-proliferator-activated-receptor-%C3%AE-coactivator-1%C3%AE-in-podocytes-results-in-collapsing-glomerulopathy
#6
Szu-Yuan Li, Jihwan Park, Chengxiang Qiu, Seung Hyeok Han, Matthew B Palmer, Zoltan Arany, Katalin Susztak
Inherited and acquired mitochondrial defects have been associated with podocyte dysfunction and chronic kidney disease (CKD). Peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α) is one of the main transcriptional regulators of mitochondrial biogenesis and function. We hypothesized that increasing PGC1α expression in podocytes could protect from CKD. We found that PGC1α and mitochondrial transcript levels are lower in podocytes of patients and mouse models with diabetic kidney disease (DKD)...
July 20, 2017: JCI Insight
https://www.readbyqxmd.com/read/28724608/erbb4-deletion-accelerates-renal-fibrosis-following-renal-injury
#7
Fenghua Zeng, Tomoki Miyazawa, Lance A Kloepfer, Raymond C Harris
Tubulointerstitial fibrosis (TIF) is a prominent factor in the progression of chronic kidney disease (CKD) regardless of etiology. ErbB4 expression levels were inversely correlated to renal fibrosis in human fibrotic kidneys. In both unilateral ureteral obstruction (UUO) and ischemia reperfusion injury followed by uninephrectomy (IRI/UNx) mouse models, expression levels of ErbB4 were elevated in the early stage of renal injury. Using mice with global ErbB4 deletion except for transgenic rescue in cardiac tissue (ErbB4-/-ht+), we determined that UUO induced similar injury in proximal tubules compared to wild-type mice but more severe injury in distal nephrons...
July 19, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28724203/huprine-x-attenuates-the-neurotoxicity-induced-by-kainic-acid-especially-brain-inflammation
#8
J Relat, B Pérez, P Camps, D Muñoz-Torrero, A Badia, M V Clos
Huprine X (HX) is a synthetic anticholinesterasic compound that exerts a potent inhibitory action on acetylcholinesterase (AChE) activity, an agonist effect on cholinergic receptors, neuroprotective activity in different neurotoxicity models in vivo and in vitro and cognition enhancing effects in non-transgenic (C57BL/6) and transgenic (3xTg-AD, APPswe) mice. In the present study, we assessed the ability of HX (0.8 mg/kg, 21 days) to prevent the damage induced by kainic acid (KA; 28 mg/kg) regarding apoptosis, glia reactivity and neurogenesis in mouse brain...
July 19, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28723387/sigma-1-receptor-activation-modifies-intracellular-calcium-exchange-in-the-g93a-hsod1-als-model
#9
Vedrana Tadić, Ayse Malci, Nadine Goldhammer, Beatrice Stubendorff, Saikata Sengupta, Tino Prell, Silke Keiner, Jingyu Liu, Madlen Guenther, Christiane Frahm, Otto W Witte, Julian Grosskreutz
Aberrations in intracellular calcium (Ca(2+)) have been well established within amyotrophic lateral sclerosis (ALS), a severe motor neuron disease. Intracellular Ca(2+) concentration is controlled in part through the endoplasmic reticulum (ER) mitochondria Ca(2+) cycle (ERMCC). The ER supplies Ca(2+) to the mitochondria at close contacts between the two organelles, i.e. the mitochondria-associated ER membranes (MAMs). The Sigma 1 receptor (Sig1R) is enriched at MAMs, where it acts as an inter-organelle signalling modulator...
July 16, 2017: Neuroscience
https://www.readbyqxmd.com/read/28721684/pharmacokinetics-microscale-distribution-and-dosimetry-of-alpha-emitter-labeled-anti-pd-l1-antibodies-in-an-immune-competent-transgenic-breast-cancer-model
#10
Jessie R Nedrow, Anders Josefsson, Sunju Park, Tom Bäck, Robert F Hobbs, Cory Brayton, Frank Bruchertseifer, Alfred Morgenstern, George Sgouros
BACKGROUND: Studies combining immune checkpoint inhibitors with external beam radiation have shown a therapeutic advantage over each modality alone. The purpose of these works is to evaluate the potential of targeted delivery of high LET radiation to the tumor microenvironment via an immune checkpoint inhibitor. METHODS: The impact of protein concentration on the distribution of (111)In-DTPA-anti-PD-L1-BC, an (111)In-antibody conjugate targeted to PD-L1, was evaluated in an immunocompetent mouse model of breast cancer...
December 2017: EJNMMI Research
https://www.readbyqxmd.com/read/28721361/role-of-endoplasmic-reticulum-stress-in-learning-and-memory-impairment-and-alzheimer-s-disease-like-neuropathology-in-the-ps19-and-app-swe-mouse-models-of-tauopathy-and-amyloidosis
#11
Denise Isabelle Briggs, Erwin Defensor, Pooneh Memar Ardestani, Bitna Yi, Michelle Halpain, Guy Seabrook, Mehrdad Shamloo
Emerging evidence suggests that endoplasmic reticulum (ER) stress may be involved in the pathogenesis of Alzheimer's disease (AD). Recently, pharmacological modulation of the eukaryotic translation initiation factor-2 (eIF2α) pathway was achieved using an integrated stress response inhibitor (ISRIB). While members of this signaling cascade have been suggested as potential therapeutic targets for neurodegeneration, the biological significance of this pathway has not been comprehensively assessed in animal models of AD...
July 2017: ENeuro
https://www.readbyqxmd.com/read/28720848/the-natural-disc1-deletion-present-in-several-inbred-mouse-strains-does-not-affect-sleep
#12
Lars Dittrich, Alessandro Petese, Walker S Jackson
The gene Disrupted in Schizophrenia-1 (DISC1) is linked to a range of psychiatric disorders. Two recent transgenic studies suggest DISC1 is also involved in homeostatic sleep regulation. Several strains of inbred mice commonly used for genome manipulation experiments, including several Swiss and likely all 129 substrains, carry a natural deletion mutation of Disc1. This constitutes a potential confound for studying sleep in genetically modified mice. Since disturbed sleep can also influence psychiatric and neurodegenerative disease models, this putative confound might affect a wide range of studies in several fields...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28720577/lysyl-oxidase-like-protein-loxl2-promotes-lung-metastasis-of-breast-cancer
#13
Fernando Salvador, Alberto Martin, Celia López-Menéndez, Gema Moreno-Bueno, Vanesa Santos, Alberto Vazquez-Naharro, Patricia G Santamaría, Saleta Morales, Pierre Dubus, Laura Muinelo-Romay, Rafael López López, Jason C Tung, Valerie M Weaver, Francisco Portillo, Amparo Cano
The lysyl oxidase-like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but in vivo evidence has been lacking. Here we provide functional evidence that LOXL2 is a key driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 independent of its conventional role in extracellular matrix remodeling...
July 18, 2017: Cancer Research
https://www.readbyqxmd.com/read/28720467/intradermal-immunization-with-raav1-vector-induces-robust-memory-cd8-t-cell-responses-independently-of-transgene-expression-in-dcs
#14
Alexandre Ghenassia, David-Alexandre Gross, Stéphanie Lorain, Fabiola Tros, Dominique Urbain, Sofia Benkhelifa-Ziyyat, Alain Charbit, Jean Davoust, Pascal Chappert
Recombinant adeno-associated viral (rAAV) vectors exhibit interesting properties as vaccine carriers for their ability to induce long-lasting antibody responses. However, rAAV-based vaccines have been suggested to trigger functionally impaired long-term memory CD8(+) T cell responses, in part due to poor dendritic cell (DC) transduction. Such results, albeit limited to intramuscular immunization, undermined the use of rAAV as vaccine vehicles against intracellular pathogens. We report here that intradermal immunization with a model rAAV2/1-based vaccine drives the development of bona fide long-term memory CD8(+) T cell responses...
July 15, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28719075/fibrosis-in-small-syngeneic-rat-liver-grafts-due-to-damaged-bone-marrow-stem-cells-from-chronic-alcohol-consumption
#15
Masayuki Hisada, Xiuying Zhang, Yoshihiro Ota, Andrew M Cameron, James Burdick, Bin Gao, George Melville Williams, Zhaoli Sun
A patient with liver failure due to chronic and acute alcohol abuse under consideration for an urgent liver transplant shortly after stopping alcohol may have residual abnormalities that threaten transplant success, particularly for a small graft. To address this, we studied a model in which reduced size (50%) Lewis rat livers are transplanted into green fluorescence protein (GFP) transgenic Lewis recipients after they are fed alcohol or a control diet for 5 weeks. Here we show that normal small Lewis grafts transplanted to alcohol fed Lewis hosts developed fibrosis whereas no fibrosis was observed in control fed recipients...
July 18, 2017: Liver Transplantation
https://www.readbyqxmd.com/read/28718799/zebrafish-as-a-model-organism-for-the-development-of-drugs-for-skin-cancer
#16
REVIEW
Fatemeh Bootorabi, Hamed Manouchehri, Reza Changizi, Harlan Barker, Elisabetta Palazzo, Annalisa Saltari, Mataleena Parikka, Carlo Pincelli, Ashok Aspatwar
Skin cancer, which includes melanoma and squamous cell carcinoma, represents the most common type of cutaneous malignancy worldwide, and its incidence is expected to rise in the near future. This condition derives from acquired genetic dysregulation of signaling pathways involved in the proliferation and apoptosis of skin cells. The development of animal models has allowed a better understanding of these pathomechanisms, with the possibility of carrying out toxicological screening and drug development. In particular, the zebrafish (Danio rerio) has been established as one of the most important model organisms for cancer research...
July 18, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28718508/development-of-ifox-hunting-as-a-functional-genomics-tool-and-demonstration-of-its-use-to-identify-early-senescence-related-genes-in-the-polyploid-brassica-napus
#17
Juan Ling, Renjie Li, Chinedu Charles Nwafor, Junluo Cheng, Maoteng Li, Qing Xu, Jian Wu, Lu Gan, Qingyong Yang, Chao Liu, Ming Chen, Yongming Zhou, Edgar B Cahoon, Chunyu Zhang
Functional genomics studies of many polyploid crops, including rapeseed (Brassica napus) are constrained by limited tool sets. Here we report development of a gain-of-function platform, termed "iFOX (inducible Full-length cDNA OvereXpressor gene)-Hunting", for inducible expression of B. napus seed cDNAs in Arabidopsis. A Gateway-compatible plant gene expression vector containing a methoxyfenozide-inducible constitutive promoter for transgene expression was developed. This vector was used for cloning of random cDNAs from developing B...
July 17, 2017: Plant Biotechnology Journal
https://www.readbyqxmd.com/read/28717161/development-and-characterization-of-a-novel-prox1-egfp-lymphatic-and-schlemm-s-canal-reporter-rat
#18
Eunson Jung, Daniel Gardner, Dongwon Choi, Eunkyung Park, Young Jin Seong, Sara Yang, Jorge Castorena-Gonzalez, Antoine Louveau, Zhao Zhou, Gene K Lee, David P Perrault, Sunju Lee, Maxwell Johnson, George Daghlian, Maria Lee, Yeo Jin Hong, Yukinari Kato, Jonathan Kipnis, Michael J Davis, Alex K Wong, Young-Kwon Hong
The lymphatic system plays a key role in tissue fluid homeostasis, immune cell trafficking, and fat absorption. We previously reported a bacterial artificial chromosome (BAC)-based lymphatic reporter mouse, where EGFP is expressed under the regulation of the Prox1 promoter. This reporter line has been widely used to conveniently visualize lymphatic vessels and other Prox1-expressing tissues such as Schlemm's canal. However, mice have a number of experimental limitations due to small body size. By comparison, laboratory rats are larger in size and more closely model the metabolic, physiological, and surgical aspects of humans...
July 17, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28716990/proof-of-principle-for-a-novel-class-of-antihypertensives-that-target-the-oxidative-activation-of-protein-kinase-g-i%C3%AE
#19
Joseph R Burgoyne, Oleksandra Prysyazhna, Daniel A Richards, Philip Eaton
Arterial hypertension continues to be a major health burden. Development of new antihypertensive drugs that engage vasodilatory mechanisms not harnessed by available therapies offer therapeutic potential. Oxidants induce an interprotein disulfide in protein kinase G Iα (PKG Iα) at C42, which is associated with its targeting and activation, resulting in vasodilation and blood pressure lowering. Consequently, we developed an assay and screened for electrophilic drugs that activate PKG Iα by selectively targeting C42, as such compounds have potential as novel antihypertensives with a mechanism of action that differs from current therapies...
July 17, 2017: Hypertension
https://www.readbyqxmd.com/read/28716964/a-glun2b-selective-nmdar-antagonist-reverses-synapse-loss-and-cognitive-impairment-produced-by-the-hiv-1-protein-tat
#20
Jonathan D Raybuck, Nicholas J Hargus, Stanley A Thayer
HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV-infected patients. Loss of synaptic connections is a hallmark of many neurocognitive disorders, including HAND. The HIV-1 protein transactivator of transcription (Tat) disrupts synaptic connections both in vitro and in vivo and has been linked to impaired neurocognitive function in humans. In vitro studies have shown that ifenprodil, an antagonist selective for GluN2B-containing NMDARs, reverses synapse loss when applied after Tat...
July 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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