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Shyh-Chang N.,Agency for Science, Technology and Research Singapore | Daley G.Q.,Dana-Farber Cancer Institute | Daley G.Q.,Harvard Stem Cell Institute | Daley G.Q.,Harvard University | And 2 more authors.
Cell Metabolism | Year: 2015

Embryonic stem cells (ESCs) manifest a unique metabolism that is intimately linked to their pluripotent state. In this issue, Moussaieff et al. (2015) find that ESCs utilize glycolysis to fuel high rates of cytosolic acetyl-CoA synthesis to maintain the histone acetylation required for pluripotency. © 2015 Elsevier Inc. Source

Sankaran V.G.,Manton Center for Orphan Disease Research | Sankaran V.G.,Dana-Farber Cancer Institute | Sankaran V.G.,The Broad Institute of MIT and Harvard | Sankaran V.G.,St Jude Childrens Research Hospital | Weiss M.J.,St Jude Childrens Research Hospital
Nature Medicine | Year: 2015

Anemia is a major source of morbidity and mortality worldwide. Here we review recent insights into how red blood cells (RBCs) are produced, the pathogenic mechanisms underlying various forms of anemia, and novel therapies derived from these findings. It is likely that these new insights, mainly arising from basic scientific studies, will contribute immensely to both the understanding of frequently debilitating forms of anemia and the ability to treat affected patients. Major worldwide diseases that are likely to benefit from new advances include the hemoglobinopathies (β-thalassemia and sickle cell disease); rare genetic disorders of RBC production; and anemias associated with chronic kidney disease, inflammation, and cancer. Promising new approaches to treatment include drugs that target recently defined pathways in RBC production, iron metabolism, and fetal globin-family gene expression, as well as gene therapies that use improved viral vectors and newly developed genome editing technologies. © 2015 Nature America, Inc. All rights reserved. Source

Notarangelo L.D.,Manton Center for Orphan Disease Research
Annual Review of Immunology | Year: 2013

Severe combined immunodeficiency (SCID) comprises a group of disorders that are fatal owing to genetic defects that abrogate T cell development. Numerous related defects have recently been identified that allow T cell development but that compromise T cell function by affecting proximal or distal steps in intracellular signaling. These functional T cell immunodeficiencies are characterized by immune dysregulation and increased risk of malignancies, in addition to infections. The study of patients with these rare conditions, and of corresponding animal models, illustrates the importance of intracellular signaling to maintain T cell homeostasis. © Copyright 2013 by Annual Reviews. All rights reserved. Source

Pessach I.M.,Sheba Medical Center | Pessach I.M.,Harvard University | Notarangelo L.D.,Harvard University | Notarangelo L.D.,Manton Center for Orphan Disease Research
Journal of Allergy and Clinical Immunology | Year: 2011

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for severe primary immunodeficiencies (PIDs). For patients lacking an HLA-identical donor, gene therapy is an attractive therapeutic option. Approaches based on insertion of a functional gene by using viral vectors have provided proof of concept for the ability of gene therapy to cure PIDs. However, leukemic transformation as a result of insertional mutagenesis has been observed, prompting development of novel approaches based on introduction of DNA double-strand breaks into the endogenous locus to achieve gene correction, or into a safe genomic location ("safe harbor"). Homing endonucleases and zinc finger nucleases are target-specific endonucleases that induce site-specific DNA double-strand breaks, facilitating homologous recombination around their target sites to achieve gene correction or gene insertion into safe harbors. An alternative approach to achieve site-specific insertion of functional genes is based on transposons, DNA elements that spontaneously translocate from a specific chromosomal location to another. These novel tools may lead to efficient and safer strategies to achieve gene therapy for PIDs and other disorders. © 2011 American Academy of Allergy, Asthma & Immunology. Source

Campbell S.L.,University of Alabama at Birmingham | Robel S.,University of Alabama at Birmingham | Cuddapah V.A.,University of Alabama at Birmingham | Robert S.,University of Alabama at Birmingham | And 4 more authors.
GLIA | Year: 2015

Seizures frequently accompany gliomas and often escalate to peritumoral epilepsy. Previous work revealed the importance of tumor-derived excitatory glutamate (Glu) release mediated by the cystine-glutamate transporter (SXC) in epileptogenesis. We now show a novel contribution of GABAergic disinhibition to disease pathophysiology. In a validated mouse glioma model, we found that peritumoral parvalbumin-positive GABAergic inhibitory interneurons are significantly reduced, corresponding with deficits in spontaneous and evoked inhibitory neurotransmission. Most remaining peritumoral neurons exhibit elevated intracellular Cl- concentration ([Cl-]i) and consequently depolarizing, excitatory gamma-aminobutyric acid (GABA) responses. In these neurons, the plasmalemmal expression of KCC2, which establishes the low [Cl-]i required for GABAAR-mediated inhibition, is significantly decreased. Interestingly, reductions in inhibition are independent of Glu release, but the presence of both decreased inhibition and decreased SXC expression is required for epileptogenesis. We suggest GABAergic disinhibition renders peritumoral neuronal networks hyper-excitable and susceptible to seizures triggered by excitatory stimuli, and propose KCC2 as a therapeutic target. © 2014 Wiley Periodicals, Inc. Source

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