Preselection of retrovirally transduced bone marrow avoids subsequent stem cell gene silencing and age-dependent extinction of expression of human β-globin in engrafted mice

Transcriptional silencing of genes transferred into hematopoietic stem cells poses one of the most significant challenges to the success of gene therapy. If the transferred gene is not completely silenced, a progressive decline in gene expression as the mice age often is encountered. These phenomena were observed to various degrees in mouse transplant experiments using retroviral vectors containing a human β-globin gene, even when cis-linked to locus control region derivatives. Here, we have investigated whether ex vivo preselection of retrovirally transduced stem cells on the basis of expression of the green fluorescent protein driven by the CpG island phosphoglycerate kinase promoter can ensure subsequent long-term expression of a cis-linked β-globin gene in the erythroid lineage of transplanted mice. We observed that 100% of mice (n = 7) engrafted with preselected cells concurrently expressed human β-globin and the green fluorescent protein in 20–95% of their RBC for up to 9.5 mo posttransplantation, the longest time point assessed. This expression pattern was successfully transferred to secondary transplant recipients. In the presence of β-locus control region hypersensitive site 2 alone, human β-globin mRNA expression levels ranged from 0.15% to 20% with human β-globin chains detected by HPLC. Neither the proportion of positive blood cells nor the average expression levels declined with time in transplanted recipients. Although suboptimal expression levels and heterocellular position effects persisted, in vivo stem cell gene silencing and age-dependent extinction of expression were avoided. These findings support the further investigation of this type of vector for the gene therapy of human hemoglobinopathies.

The TTIP negotiations: a Pirandello play

Notre Europe – Jacques Delors Institute and the European Policy Centre during which experts, including Pascal Lamy, honorary president of Notre Europe – Jacques Delors Institute and former Director of the WTO explored the key issues of the current Transatlantic Trade and Investment Partnership (TTIP) negotiations. What are the geoeconomic and geostrategic goals of the negotiations? What are the rules of the negotiations? Who are the main players? What impact might TTIP have on world trade?

TTIP: une negociation a la pirandello = The TTIP: A Pirandello play

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Frequency of MELAS main mutation in a phenotype-targeted young ischemic stroke patient population

Mitochondrial diseases, predominantly mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), may occasionally underlie or coincide with ischemic stroke (IS) in young and middle-aged individuals. We searched for undiagnosed patients with MELAS in a target subpopulation of unselected young IS patients enrolled in the Stroke in Young Fabry Patients study (sifap1). Among the 3291 IS patients aged 18-55 years recruited to the sifap1 study at 47 centers across 14 European countries, we identified potential MELAS patients with the following phenotypic features: (a) diagnosed cardiomyopathy or (b) presence of two of the three following findings: migraine, short stature (≤165 cm for males; ≤155 cm for females), and diabetes. Identified patients' blood samples underwent analysis of the common MELAS mutation, m.3243A>G in the MTTL1 gene of mitochondrial DNA. Clinical and cerebral MRI features of the mutation carriers were reviewed. We analyzed blood samples of 238 patients (177 with cardiomyopathy) leading to identification of four previously unrecognized MELAS main mutation carrier-patients. Their clinical and MRI characteristics were within the expectation for common IS patients except for severe hearing loss in one patient and hyperintensity of the pulvinar thalami on T1-weighted MRI in another one. Genetic testing for the m.3243A>G MELAS mutation in young patients with IS based on phenotypes suggestive of mitochondrial disease identifies previously unrecognized carriers of MELAS main mutation, but does not prove MELAS as the putative cause.

Vertical profiles of environmental parameters measured on discrete water samples collected with Niskin bottles during the Tara Oceans expedition 2009-2013

The present data publication provides permanent links to original and updated versions of validated data files. The data files include properties of seawater, particulate matter and dissolved matter that were measured from discrete water samples collected with Niskin bottles during the 2009-2013 Tara Oceans expedition. Properties include pigment concentrations from HPLC analysis (10 depths per vertical profile, 25 pigments per depth), the carbonate system (Surface and 400m; pH (total scale), CO2, pCO2, fCO2, HCO3, CO3, Total alkalinity, Total carbon, OmegaAragonite, OmegaCalcite, and dosage Flags), nutrients (10 depths per vertical profile; NO2, PO4, N02/NO3, SI, quality Flags), DOC, CDOM, and dissolved oxygen isotopes. The Service National d'Analyse des Paramètres Océaniques du CO2, at the Université Pierre et Marie Curie, determined CT and AT potentiometrically (Edmond 1970; DOE 1994) on samples preserved according to Dickson et al. (2007). More than 250 vertical profiles of these properties were made across the world ocean. DOC, CDOM and dissolved oxygen isotopes are available only for the Arctic Ocean and Arctic Seas (2013).

Les missionnaires de 93,

Mode of access: Internet.

Tratado de lanas /

Mode of access: Internet.

Compendiosa demostracion de los crecidos adelantamientos, que pudiera lograr la Real Hacienda de su Magestad mediante la rebaja en el precio del azogue, que se consume para el laborio de las minas de este Reyno, ó del aumento tan considerable, que se avia de experimentar en el producto annual de sus reales rentas, en beneficio no menos grande, que universal de esta mineria, de ambos comercios, y por consiguiente de todo el comun de la Republica ... /

Mode of access: Internet.

Traité de mathématiques générales : a l'usage des chimistes, physiciens, ingénieurs et des élèves des facultés des sciences /

Mode of access: Internet.

Campagne de l'armée d'Italie, 1796-1797 /

"Les Tomes I et II ont paru en 1900 sous le titre 'Histoire de l'armée d'Italie'."--Catalogue général de la Librairie Française, t.18, 1908.

Problèmes de mecanique rationnelle. A l'usage des candidats aux certificats de licence et a l'agrégation.

At head of title: E. Fabry.

Itinéraire de Buonaparte de l'île d'Elbe à l'île Sainte-Hélène, ou, Mémoires pour servir à l'histoire des événemens de 1815 : avec le recueil des principales pièces officielles de cette époque /

Mode of access: Internet.

Mémoires du Cardinal de Retz,

Mode of access: Internet.

La régence à Blois, ou Le derniers momens du gouvernement impérial.

Mode of access: Internet.

Formal opening the new Michigan Stadium Ann Arbor

View from the south of the stadium during the Ohio State-Michigan game. On image: KAUFMANN & FABRY CO. COMMERCIAL PHOTOGRAPHERS 425 South Wabash Ave. CHICAGO TELEPHONE HARRISON 3135 MOST THOROUGHLY EQUIPPED PHOTOGRAPHIC PLANT IN AMERICA. Verso: Rotary Club of Chicago 10/25/27