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Conditional knock-out

Manan Khan, Nazish Jabeen, Teka Khan, Hafiz Muhammad Jafar Hussain, Asim Ali, Ranjha Khan, Long Jiang, Tao Li, Qizhao Tao, Xingxia Zhang, Hao Yin, Changping Yu, Xiaohua Jiang, Qinghua Shi
There are more than 2300 genes that are predominantly expressed in mouse testes. The role of hundreds of these genes has been studied in mouse spermatogenesis but still there are many genes whose function is unknown. Gene knockout (KO) strategy in mice is widely used for in vivo study of gene function. The present study was designed to explore the function of the four genes: Tex37, Ccdc73, Prss55 and Nxt2, which were evolutionarily conserved in eutherians. We found that these genes had a testis-enriched expression pattern in mice except Nxt2...
March 21, 2018: Scientific Reports
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
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
Mengyao Wu, Senquan Liu, Yongxing Gao, Hao Bai, Vasiliki Machairaki, Gang Li, Tong Chen, Linzhao Cheng
Precise genome editing in human induced pluripotent stem cells (iPSCs) significantly enhances our capability to use human iPSCs for disease modeling, drug testing and screening as well as investigation of human cell biology. In this study, we seek to achieve conditional expression of the CD55 gene in order to interrogate its functions. We used two human iPSC lines that have unique genotypes, and constructed an inducible Cas9 gene expression system that is integrated at the AAVS1 safe harbor site in the human genome...
March 10, 2018: Stem Cell Research
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
Shiqi Luo, Feng He, Junjie Luo, Shengqian Dou, Yirong Wang, Annan Guo, Jian Lu
Transfer RNA-derived small RNAs (tsRNAs) are an emerging class of small RNAs, yet their regulatory roles have not been well understood. Here we studied the molecular mechanisms and consequences of tsRNA-mediated regulation in Drosophila. By analyzing 495 public small RNA libraries, we demonstrate that most tsRNAs are conserved, prevalent and abundant in Drosophila. By carrying out mRNA sequencing and ribosome profiling of S2 cells transfected with single-stranded tsRNA mimics and mocks, we show that tsRNAs recognize target mRNAs through conserved complementary sequence matching and suppress target genes by translational inhibition...
March 14, 2018: Nucleic Acids Research
Tong Liu, Dong-Wei Tian, Li-Juan Zou, Fang-Yu Liu, Qi-Yan Can, Jin-Kui Yang, Jian-Ping Xu, Xiao-Wei Huang, Jia-Qin Xi, Ming-Liang Zhu, Ming-He Mo, Ke-Qin Zhang
Ammonia is one of the fungistatic factors in soil that can suppress conidial germination, but the molecular mechanism underlying the suppression is unknown. In this study, the proteomes of fungistatic conidia, fresh conidia and germinated conidia of Arthrobotrys oligospora ATCC24927 were determined and quantified. The protein expression profile of fungistatic conidia was significantly different from those in the other two conditions. 281 proteins were down expressed in fungistatic conidia and characterized by GO annotation...
March 12, 2018: International Journal of Biochemistry & Cell Biology
Frank Tüttelmann, Christian Ruckert, Albrecht Röpke
Infertility is a common condition estimated to affect 10-15% of couples. The clinical causes are attributed in equal parts to the male and female partners. Diagnosing male infertility mostly relies on semen (and hormone) analysis, which results in classification into the two major phenotypes of oligo- and azoospermia. The clinical routine analyses have not changed over the last 20 years and comprise screening for chromosomal aberrations and Y‑chromosomal azoospermia factor deletions. These tests establish a causal genetic diagnosis in about 4% of unselected men in infertile couples and 20% of azoospermic men...
2018: Medizinische Genetik: Mitteilungsblatt des Berufsverbandes Medizinische Genetik E.V
Alexis Roman, Soraya Meftah, Sébastien Arthaud, Pierre-Hervé Luppi, Christelle Peyron
Narcolepsy type 1 is a disabling disorder with four primary symptoms: excessive-daytime-sleepiness, cataplexy, hypnagogic hallucinations and sleep paralysis. The three latter symptoms together with a short REM sleep latency have suggested impairment in REM sleep homeostatic regulation with an enhanced propensity for (i.e. tendency to enter) REM sleep. To test this hypothesis, we challenged REM sleep homeostatic regulation in a recognized model of narcolepsy, the orexin knock-out (Orex-KO) mice and their wild-type (WT) littermates...
March 7, 2018: Sleep
Akshaya Tatke, Karthik Yadav Janga, Bharathi Avula, XiangDi Wang, Monica M Jablonski, Ikhlas A Khan, Soumyajit Majumdar
The current research was undertaken to determine the existence and magnitude of P-glycoprotein (P-gp) expression on the blood-ocular barriers by studying the ocular penetration of loperamide, a specific P-gp substrate, in P-gp (Mdr1a) knock-out (KO) and wild type (WT) Sprague Dawley rats. A clear, stable, sterile solution of loperamide (1 mg/mL), for intravenous administration, was formulated and evaluated. Ocular distribution was studied in P-gp KO and WT rats following intravenous administration of loperamide (at two doses)...
March 8, 2018: AAPS PharmSciTech
Kaitryn E Ronning, Gabriel Peinado Allina, Eric B Miller, Robert J Zawadzki, Edward N Pugh, Rolf Hermann, Marie E Burns
Rods and cones mediate visual perception over 9 log units of light intensities, with both photoreceptor types contributing to a middle 3-log unit range that comprises most night-time conditions. Rod function in this mesopic range has been difficult to isolate and study in vivo because of the paucity of mutants that abolish cone signaling without causing photoreceptor degeneration. Here we describe a novel Gnat2 knockout mouse line (Gnat2-/- ) ideal for dissecting rod and cone function. In this line, loss of Gnat2 expression abolished cone phototransduction, yet there was no loss of cones, disruption of the photoreceptor mosaic, nor change in general retinal morphology up to at least 9 months of age...
March 5, 2018: Experimental Eye Research
S Mu, Y Cui, W Wang, L Wang, H Xu, O Zhu, D Zhu
OBJECTIVES: The aim of this study was to characterise a novel mutation in the gene encoding RhAG in order to elucidate a molecular mechanism for Rh antigen expression and spherocytosis. BACKGROUND: Rhesus-associated glycoprotein (RhAG) is critical for maintaining the structure and stability of erythrocytes. Single missense mutations in the gene encoding RhAG are sufficient to induce spherocytosis and deficiencies in Rh complex formation. We report a novel missense mutation that incompletely disrupts Rh antigen expression and selectively knocks out RhD antigen expression...
March 6, 2018: Transfusion Medicine
Bin Zhang, Le Xuan Truong Nguyen, Ling Li, Dandan Zhao, Bijender Kumar, Herman Wu, Allen Lin, Francesca Pellicano, Lisa Hopcroft, Yu-Lin Su, Mhairi Copland, Tessa L Holyoake, Calvin J Kuo, Ravi Bhatia, David S Snyder, Haris Ali, Anthony S Stein, Casey Brewer, Huafeng Wang, Tinisha McDonald, Piotr Swiderski, Estelle Troadec, Ching-Cheng Chen, Adrienne Dorrance, Vinod Pullarkat, Yate-Ching Yuan, Danilo Perrotti, Nadia Carlesso, Stephen J Forman, Marcin Kortylewski, Ya-Huei Kuo, Guido Marcucci
Leukemia stem cells (LSCs) in individuals with chronic myelogenous leukemia (CML) (hereafter referred to as CML LSCs) are responsible for initiating and maintaining clonal hematopoiesis. These cells persist in the bone marrow (BM) despite effective inhibition of BCR-ABL kinase activity by tyrosine kinase inhibitors (TKIs). Here we show that although the microRNA (miRNA) miR-126 supported the quiescence, self-renewal and engraftment capacity of CML LSCs, miR-126 levels were lower in CML LSCs than in long-term hematopoietic stem cells (LT-HSCs) from healthy individuals...
March 5, 2018: Nature Medicine
Lubin Chen, Jianying Huang, Peng Zhao, Anna-Karin Persson, Fadia B Dib-Hajj, Xiaoyang Cheng, Andrew Tan, Stephen G Waxman, Sulayman D Dib-Hajj
Voltage-gated sodium channels NaV 1.7, NaV 1.8 and NaV 1.9 have been the focus for pain studies because their mutations are associated with human pain disorders, but the role of NaV 1.6 in pain is less understood. In this study, we selectively knocked out NaV 1.6 in dorsal root ganglion (DRG) neurons, using NaV 1.8-Cre directed or adeno-associated virus (AAV)-Cre mediated approaches, and examined the specific contribution of NaV 1.6 to the tetrodotoxin-sensitive (TTX-S) current in these neurons and its role in neuropathic pain...
March 1, 2018: Scientific Reports
Dionysios V Chartoumpekis, Dushani L Palliyaguru, Nobunao Wakabayashi, Marco Fazzari, Nicholas Kh Khoo, Francisco J Schopfer, Ian Sipula, Yoko Yagishita, George K Michalopoulos, Robert M O'Doherty, Thomas W Kensler
Nrf2 is a canonical regulator of cytoprotective gene expression but evidence of its crosstalk with other pathways, including metabolic ones, is ever increasing. Pharmacologic or systemic genetic activation of the Nrf2 pathway partially protects from obesity in mice and ameliorates fasting hyperglycemia in mice and humans. However, systemic Nrf2 deletion also protected from diet-induced obesity and insulin resistance in mice. To further investigate the effect of the disruption of Nrf2 on obesity in a tissue-specific manner, we focused on adipocytes and hepatocytes with targeted deletion of Nrf2...
February 27, 2018: American Journal of Physiology. Endocrinology and Metabolism
Steven D Schutt, Yongxia Wu, Chih-Hang Anthony Tang, David Bastian, Hung Nguyen, M Hanief Sofi, MengMeng Zhang, Chen Liu, Kris Helke, Carole Wilson, Lynn M Schnapp, Juan R Del Valle, Chih-Chi Andrew Hu, Xue-Zhong Yu
Hematopoietic stem cell transplantation (HCT) is a curative procedure for hematological malignancies, but chronic graft-versus-host disease (cGVHD) remains a major complication after allogeneic HCT. Because donor B cells are essential for cGVHD development and B cells are sensitive to endoplasmic reticulum (ER) stress, we hypothesized that the IRE-1α/XBP-1 pathway is required for B-cell activation and function and for the development of cGVHD. To test this hypothesis, we used conditional knock-out mice deficient of XBP-1 specifically in B cells...
February 27, 2018: Blood Advances
Naris Nilubol, ZiQiang Yuan, Giulio F Paciotti, Lawrence Tamarkin, Carmen Sanchez, Kelli Gaskins, Esther M Freedman, Shugeng Cao, Jielu Zhao, David G I Kingston, Steven K Libutti, Electron Kebebew
Background: The advantages of nanomedicines include preferential delivery of the payload directly to tumor tissues. CYT-21625 is the novel, first-in-class gold nanomedicine designed to target tumor vasculature and cancer cells by specifically delivering recombinant human tumor necrosis factor alpha (rhTNF) and a paclitaxel prodrug. Methods: We analyzed TNF receptor expression in publicly available gene expression profiling data and in thyroid tissue samples. Mice with metastatic FTC-133 and 8505C xenografts and the MEN1 conditional knock-out mice were treated weekly with CYT-21625 and gold nanoparticles with rhTNF only (CYT-6091); controls included mice treated with either paclitaxel or saline...
February 22, 2018: Journal of the National Cancer Institute
Ana Gutiérrez-Rodríguez, Itziar Bonilla-Del Río, Nagore Puente, Sonia M Gómez-Urquijo, Christine J Fontaine, Jon Egaña-Huguet, Izaskun Elezgarai, Sabine Ruehle, Beat Lutz, Laurie M Robin, Edgar Soria-Gómez, Luigi Bellocchio, Jalindar D Padwal, Mario van der Stelt, Juan Mendizabal-Zubiaga, Leire Reguero, Almudena Ramos, Inmaculada Gerrikagoitia, Giovanni Marsicano, Pedro Grandes
Astroglial type-1 cannabinoid (CB1 ) receptors are involved in synaptic transmission, plasticity and behavior by interfering with the so-called tripartite synapse formed by pre- and post-synaptic neuronal elements and surrounding astrocyte processes. However, little is known concerning the subcellular distribution of astroglial CB1 receptors. In particular, brain CB1 receptors are mostly localized at cells' plasmalemma, but recent evidence indicates their functional presence in mitochondrial membranes. Whether CB1 receptors are present in astroglial mitochondria has remained unknown...
February 26, 2018: Glia
Allison M Wilkin, Amber Harnett, Michael Underschultz, Cheryl Cragg, Kelly A Meckling
The protein disulfide isomerase ERp57 (GRp58/PDIA3/1,25D3-MARRS) has been implicated in a multitude of signaling pathways throughout the entire body. Most thoroughly studied for its protein-folding role, ERp57 has also been found to have multiple binding partners, and have significant effects on cellular growth. ERp57 has been studied n the context of several neurodegenerative disorders, metabolic conditions, and can be used as a prognosis marker in certain cancers. One role, as an alternate vitamin D binding receptor, has prompted research in tissues with known vitamin D activity, such as the intestine and bone...
February 22, 2018: Steroids
Nabeel Abdulrahman, Béatrice Jaspard Vinassa, Larry Fliegel, Ayesha Jabeen, Sadaf Riaz, Alain-Pierre Gadeau, Fatima Mraiche
Cardiovascular diseases are the leading cause of death worldwide. One in three cases of heart failure is due to dilated cardiomyopathy. The Na+ /H+ exchanger isoform 1 (NHE1), a multifunctional protein and the key pH regulator in the heart, has been demonstrated to be increased in this condition. We have previously demonstrated that elevated NHE1 activity induced cardiac hypertrophy in vivo. Furthermore, the overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an upregulation of myocardial osteopontin (OPN) expression...
February 23, 2018: Physiological Genomics
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