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Peripheral viral transduction

Coralea Stephanou, Panayiota Papasavva, Myria Zachariou, Petros Patsali, Marilena Epitropou, Petros Ladas, Ruba Al-Abdulla, Soteroulla Christou, Michael N Antoniou, Carsten W Lederer, Marina Kleanthous
BACKGROUND AIMS: Primary hematopoietic stem and progenitor cells (HSPCs) are key components of cell-based therapies for blood disorders and are thus the authentic substrate for related research. We propose that ubiquitous small-volume diagnostic samples represent a readily available and as yet untapped resource of primary patient-derived cells for cell- and gene-therapy studies. METHODS: In the present study we compare isolation and storage methods for HSPCs from normal and thalassemic small-volume blood samples, considering genotype, density-gradient versus lysis-based cell isolation and cryostorage media with different serum contents...
February 2017: Cytotherapy
Thanh Kim Nguyen, Sarah J Morse, Angela G Fleischman
Transduction-transplantation is a quick and efficient way to model human hematologic malignancies in mice. This technique results in expression of the gene of interest in hematopoietic cells and can be used to study the gene's role in normal and/or malignant hematopoiesis. This protocol provides a detailed description on how to perform transduction-transplantation using calreticulin (CALR) mutations recently identified in myeloproliferative neoplasm (MPN) as an example. In this protocol whole bone marrow cells from 5-flurouracil (5-FU) treated donor mice are transduced with a retrovirus encoding mutant CALR and transplanted into lethally irradiated syngeneic hosts...
December 22, 2016: Journal of Visualized Experiments: JoVE
Siddappa Manjunath, Bishnu Prasad Mishra, Bina Mishra, Aditya Prasad Sahoo, Ashok K Tiwari, Kaushal Kishore Rajak, D Muthuchelvan, Shikha Saxena, Lakshman Santra, Amit Ranjan Sahu, Sajad Ahmad Wani, R P Singh, Y P Singh, Aruna Pandey, Sonam Kanchan, R K Singh, Gandham Ravi Kumar, Sarath Chandra Janga
Peste des petits ruminanats virus (PPRV), a morbillivirus causes an acute, highly contagious disease - peste des petits ruminants (PPR), affecting goats and sheep. Sungri/96 vaccine strain is widely used for mass vaccination programs in India against PPR and is considered the most potent vaccine providing long-term immunity. However, occurrence of outbreaks due to emerging PPR viruses may be a challenge. In this study, the temporal dynamics of immune response in goat peripheral blood mononuclear cells (PBMCs) infected with Sungri/96 vaccine virus was investigated by transcriptome analysis...
February 2, 2017: Virus Research
Narasimhan J Venkatachari, Siddhartha Jain, Leah Walker, Shalmali Bivalkar-Mehla, Ansuman Chattopadhyay, Ziv Bar-Joseph, Charles Rinaldo, Ann Ragin, Eric Seaberg, Andrew Levine, James Becker, Eileen Martin, Ned Sacktor, Velpandi Ayyavoo
OBJECTIVE: HIV-1 viral proteins and host inflammatory factors have a direct role in neuronal toxicity in vitro; however, the contribution of these factors in vivo in HIV-1-associated neurocognitive disorder (HAND) is not fully understood. We applied novel Systems Biology approaches to identify specific cellular and viral factors and their related pathways that are associated with different stages of HAND. DESIGN: A cross-sectional study of individuals enrolled in the Multicenter AIDS Cohort Study including HIV-1-seronegative (N = 36) and HIV-1-seropositive individuals without neurocognitive symptoms (N = 16) or with mild neurocognitive disorder (MND) (N = 8) or HIV-associated dementia (HAD) (N = 16)...
March 13, 2017: AIDS
Lourdes Lopez-Onieva, Candela Machuca, Mar Lamolda, Rosa Montes, Maria Luisa Lozano, Vicente Vicente, José Rivera, Verónica Ramos-Mejía, Pedro J Real
Bernard Soulier Syndrome (BSS) is an inherited rare platelet disorder characterized by mutations in the platelet glycoprotein complex GPIb-IX-V. We generated an induced pluripotent stem cell (iPSC) line from a BSS patient with a mutation p.Asn45Ser in the GPIX locus (BSS2-PBMC-iPS4F24). Peripheral blood mononuclear cells were reprogrammed using non-integrative viral transduction. Characterization of BSS2-PBMC-iPS4F24 included mutational analysis of GPIX locus, analysis of conventional pluripotency-associated factors at mRNA and protein level and in vitro and in vivo differentiation studies...
November 8, 2016: Stem Cell Research
Marie Humbert-Claude, D Duc, D Dwir, L Thieren, J Sandström von Tobel, C Begka, F Legueux, D Velin, M H Maillard, K Q Do, F Monnet-Tschudi, L Tenenbaum
BACKGROUND: Tollip is a ubiquitously expressed protein, originally described as a modulator of the IL-1R/TLR-NF-κB signaling pathways. Although this property has been well characterized in peripheral cells, and despite some evidence of its expression in the central nervous system, the role of Tollip in neuroinflammation remains poorly understood. The present study sought to explore the implication of Tollip in inflammation in the substantia nigra pars compacta, the structure affected in Parkinson's disease...
December 7, 2016: Journal of Neuroinflammation
Brenden Van Wyk, Marlene Snider, Erin Scruten, Sylvia van Drunen Littel-van den Hurk, Scott Napper
As a part of their pathogenic mechanism, many pathogens causing persistent infections, including bovine viral diarrhea virus (BVDV), immunosuppress their hosts, often by limiting the ability to either produce, or respond to, interferon. The objective of this study was to quantify the extent to which an acute infection of cattle with a non-cytopathic strain of BVDV induces interferon responses and to establish the functionality of these responses. Functionality of responses was investigated using a bovine specific peptide array to monitor kinase-mediated signal transduction activity within peripheral blood mononuclear cells (PBMCs) at time points corresponding to the interferon gamma (IFN-γ) and alpha (IFN-α) responsive phases of acute BVDV infection...
November 15, 2016: Veterinary Microbiology
Melissa R Andrews, Sara Soleman, Menghon Cheah, David A Tumbarello, Matthew R J Mason, Elizabeth Moloney, Joost Verhaagen, Jean-Charles Bensadoun, Bernard Schneider, Patrick Aebischer, James W Fawcett
The regenerative ability of CNS axons decreases with age, however, this ability remains largely intact in PNS axons throughout adulthood. These differences are likely to correspond with age-related silencing of proteins necessary for axon growth and elongation. In previous studies, it has been shown that reintroduction of the α9 integrin subunit (tenascin-C receptor, α9) that is downregulated in adult CNS can improve neurite outgrowth and sensory axon regeneration after a dorsal rhizotomy or a dorsal column crush spinal cord lesion...
July 2016: ENeuro
Md Aminul Islam, Christine Große-Brinkhaus, Maren Julia Pröll, Muhammad Jasim Uddin, Sharmin Aqter Rony, Dawit Tesfaye, Ernst Tholen, Michael Hölker, Karl Schellander, Christiane Neuhoff
BACKGROUND: Porcine reproductive and respiratory syndrome (PRRS) is one of the most economically important viral diseases affecting swine industry worldwide. Despite routine farm vaccination, effective control strategies for PRRS remained elusive which underscores the need for in-depth studies to gain insight into the host immune response to vaccines. The current study aimed to investigate transcriptional responses to PRRS Virus (PRRSV) vaccine in the peripheral blood mononuclear cells (PBMCs) within 3 days following vaccination in German Landrace pigs...
2016: BMC Genomics
Andrew E Sloan, Hua Fung, Jane Reese, Lisa R Rogers, Christopher Murphay, Hillard Lazrus, Boro Dropulic, Stan L Gerson
INTRODUCTION: Glioblastoma (GBM) is the most common malignant brain tumor with a median survival of 15 months despite surgery and aggressive radiochemotherapy. The most important mechanism of temozolomide (TMZ) resistance is the O-methylguanine-DNA methyltransferase (MGMT) gene that repairs temozolomide-induced DNA methylation. The MGMT inhibitor O-benzylguanine (BG) has demonstrated efficacy in depleting MGMT and maximizing tumor response in early-phase clinical trials. However, because MGMT expression is also low in hematopoietic cells, this has resulted in unacceptable bone marrow toxicity, and this approach has been abandoned...
August 2016: Neurosurgery
Zachary L Watson, Monica K Ertel, Alfred S Lewin, Sonal S Tuli, Gregory S Schultz, Donna M Neumann, David C Bloom
UNLABELLED: Following infection of epithelial tissues, herpes simplex virus 1 (HSV-1) virions travel via axonal transport to sensory ganglia and establish a lifelong latent infection within neurons. Recent studies have revealed that, following intraganglionic or intrathecal injection, recombinant adeno-associated virus (rAAV) vectors can also infect sensory neurons and are capable of stable, long-term transgene expression. We sought to determine if application of rAAV to peripheral nerve termini at the epithelial surface would allow rAAV to traffic to sensory ganglia in a manner similar to that seen with HSV...
September 1, 2016: Journal of Virology
Saloni T Mehta, Xueting Luo, Kevin K Park, John L Bixby, Vance P Lemmon
Axonal regeneration after spinal cord injury (SCI) is intrinsically and extrinsically inhibited by multiple factors. One major factor contributing to intrinsic regeneration failure is the inability of mature neurons in the central nervous system (CNS) to activate regeneration-associated transcription factors (TFs) post-injury. A prior study identified TFs overexpressed in neurons of the peripheral nervous system (PNS) compared to the CNS; some of these could be involved in the ability of PNS neurons to regenerate...
June 2016: Experimental Neurology
Koen Vercauteren, Brad E Hoffman, Irene Zolotukhin, Geoffrey D Keeler, Jing W Xiao, Etiena Basner-Tschakarjan, Katherine A High, Hildegund Cj Ertl, Charles M Rice, Arun Srivastava, Ype P de Jong, Roland W Herzog
Adeno-associated viral (AAV) vectors are currently being tested in multiple clinical trials for liver-directed gene transfer to treat the bleeding disorders hemophilia A and B and metabolic disorders. The optimal viral capsid for transduction of human hepatocytes has been under active investigation, but results across various models are inconsistent. We tested in vivo transduction in "humanized" mice. Methods to quantitate percent AAV transduced human and murine hepatocytes in chimeric livers were optimized using flow cytometry and confocal microscopy with image analysis...
June 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Daniel O Griffin, Stephen P Goff
BACKGROUND: Gene therapy is currently being attempted using a number of delivery vehicles including lentiviral-based vectors. The delivery and insertion of a gene using lentiviral-based vectors involves multiple discrete steps, including reverse transcription of viral RNA into DNA, nuclear entry, integration of viral DNA into the host genome and expression of integrated genes. Transduction of murine stem cells by the murine leukemia viruses is inefficient because the expression of the integrated DNA is profoundly blocked...
March 5, 2016: Retrovirology
Vikram Thakur, Mayra Gonzalez, Kristen Pennington, Munmun Chattopadhyay
Painful diabetic neuropathy is a common and difficult to treat complication of diabetes. A growing body of evidence implicates the role of inflammatory mediators in the damage to the peripheral axons and in the pathogenesis of neuropathic pain. Increased expression of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the peripheral nervous system suggests the possibility of change in pain perception in diabetes. In this study we investigated that continuous delivery of IL10 in the nerve fibers achieved by HSV vector mediated transduction of dorsal root ganglion (DRG) in animals with Type 1 diabetes, blocks the nociceptive and stress responses in the DRG neurons by reducing IL1β expression along with inhibition of phosphorylation of p38 MAPK (mitogen-activated protein kinase) and protein kinase C (PKC)...
April 2016: Molecular and Cellular Neurosciences
Florian Douam, Louis-Marie Bobay, Guillemette Maurin, Judith Fresquet, Noémie Calland, Carine Maisse, Tony Durand, François-Loïc Cosset, Cyrille Féray, Dimitri Lavillette
UNLABELLED: Hepatitis C virus (HCV) productively infects hepatocytes. Virion surface glycoproteins E1 and E2 play a major role in this restricted cell tropism by mediating virus entry into particular cell types. However, several pieces of evidence have suggested the ability of patient-derived HCV particles to infect peripheral blood mononuclear cells. The viral determinants and mechanisms mediating such events remain poorly understood. Here, we aimed at isolating viral determinants of HCV entry into B lymphocytes...
January 2016: Journal of Virology
Mitsuhiro Enomoto, Takashi Hirai, Hidetoshi Kaburagi, Takanori Yokota
RNA interference is a powerful tool used to induce loss-of-function phenotypes through post-transcriptional gene silencing. Small interfering RNA (siRNA) molecules have been used to target the central nervous system (CNS) and are expected to have clinical utility against refractory neurodegenerative diseases. However, siRNA is characterized by low transduction efficiency, insufficient inhibition of gene expression, and short duration of therapeutic effects, and is thus not ideal for treatment of neural tissues and diseases...
2016: Methods in Molecular Biology
Brett D Dufour, Jodi L McBride
Viral vector delivery of RNA silencing constructs, when administered into vasculature, typically results in poor central nervous system (CNS) transduction due to the inability of the vector to cross the blood-brain barrier (BBB). However, adeno-associated virus serotype 9 (AAV9) has the ability to cross the BBB and robustly transduce brain parenchyma and peripheral tissues at biologically meaningful levels when injected intravenously. Recent work by our lab has shown that this method can be used to deliver RNA silencing constructs, resulting in significant reductions in gene expression in multiple brain regions and in peripheral tissues...
2016: Methods in Molecular Biology
Sujata Halder, Kim Van Vliet, J Kennon Smith, Thao Thi Phuong Duong, Robert McKenna, James M Wilson, Mavis Agbandje-McKenna
Adeno-associated virus rhesus isolate 8 (AAVrh.8) is a leading vector for the treatment of neurological diseases due to its efficient transduction of neuronal cells and reduced peripheral tissue tropism. Toward identification of the capsid determinants for these properties, the structure of AAVrh.8 was determined by X-ray crystallography to 3.5 Å resolution and compared to those of other AAV isolates. The capsid viral protein (VP) structure consists of an αA helix and an eight-stranded anti-parallel β-barrel core conserved in parvoviruses, and large insertion loop regions between the β-strands form the capsid surface topology...
October 2015: Journal of Structural Biology
Andrew M Tan, Omar A Samad, Sulayman D Dib-Hajj, Stephen G Waxman
Diabetic neuropathic pain affects a substantial number of people and represents a major public health problem. Available clinical treatments for diabetic neuropathic pain remain only partially effective and many of these treatments carry the burden of side effects or the risk of dependence. The misexpression of sodium channels within nociceptive neurons contributes to abnormal electrical activity associated with neuropathic pain. Voltage-gated sodium channel Nav1.3 produces tetrodotoxin-sensitive sodium currents with rapid repriming kinetics and has been shown to contribute to neuronal hyperexcitability and ectopic firing in injured neurons...
2015: Molecular Medicine
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