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HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice.

Mastrogiannaki, Maria Matak, Pavle Keith, Brian Simon, M Celeste Sophie Vaulont Carole Peyssonnaux

Published in Journal of Clinical Investigation

HIF transcription factors (HIF-1 and HIF-2) are central mediators of cellular adaptation to hypoxia. Because the resting partial pressure of oxygen is low in the intestinal lumen, epithelial cells are believed to be mildly hypoxic. Having recently established a link between HIF and the iron-regulatory hormone hepcidin, we hypothesized that HIFs, st...

HIF-1alpha expression regulates the bactericidal capacity of phagocytes.

Carole Peyssonnaux Datta, Vivekanand Cramer, Thorsten Doedens, Andrew Theodorakis, Emmanuel A Gallo, Richard L Hurtado-Ziola, Nancy Nizet, Victor Johnson, Randall S

Published in Journal of Clinical Investigation

Hypoxia is a characteristic feature of the tissue microenvironment during bacterial infection. Here we report on our use of conditional gene targeting to examine the contribution of hypoxia-inducible factor 1, alpha subunit (HIF-1alpha) to myeloid cell innate immune function. HIF-1alpha was induced by bacterial infection, even under normoxia, and r...

Constitutively active Akt1 expression in mouse pancreas requires S6 kinase 1 for insulinoma formation.

Alliouachene, Samira Tuttle, Robyn L Boumard, Stephanie Lapointe, Thomas Berissi, Sophie Germain, Stephane Jaubert, Francis Tosh, David Birnbaum, Morris J Pende, Mario ...

Published in Journal of Clinical Investigation

Factors that promote pancreatic beta cell growth and function are potential therapeutic targets for diabetes mellitus. In mice, genetic experiments suggest that signaling cascades initiated by insulin and IGFs positively regulate beta cell mass and insulin secretion. Akt and S6 kinase (S6K) family members are activated as part of these signaling ca...

AIRE deficiency in thymus of 2 patients with Omenn syndrome.

Cavadini, Patrizia Vermi, William Facchetti, Fabio Fontana, Stefania Nagafuchi, Seiho Mazzolari, Evelina Sediva, Anna Marrella, Veronica Villa, Anna Fischer, Alain ...

Published in Br J Dermatol

Omenn syndrome is a severe primary immunodeficiency with putative autoimmune manifestations of the skin and gastrointestinal tract. The disease is caused by hypomorphic mutations in recombination-activating genes that impair but do not abolish the process of VDJ recombination, leading to the generation of autoreactive T cells with a highly restrict...

AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons.

Claret, Marc Smith, Mark A Batterham, Rachel L Selman, Colin Choudhury, Agharul I Fryer, Lee G D Clements, Melanie Al-Qassab, Hind Heffron, Helen Xu, Allison W ...

Published in Journal of Clinical Investigation

Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are ...

Acceleration of type 1 diabetes mellitus in proinsulin 2-deficient NOD mice.

Thébault-Baumont, Karine Dubois-Laforgue, Danielle Krief, Patricia Briand, Jean-Paul Halbout, Philippe Vallon-Geoffroy, Karine Morin, Joëlle Laloux, Véronique Agnès Lehuen Carel, Jean-Claude ...

Published in Journal of Clinical Investigation

Accumulating evidence favors a role for proinsulin as a key autoantigen in diabetes. In the mouse, two proinsulin isoforms coexist. Most studies point to proinsulin 2 as the major isoform recognized by T cells in the NOD mouse. We studied mice in which a null proinsulin 2 mutation was transferred from proinsulin 2-deficient 129 mice onto the NOD ba...

Hyper-IgM syndrome type 4 with a B lymphocyte-intrinsic selective deficiency in Ig class-switch recombination.

Imai, Kohsuke Catalan, Nadia Plebani, Alessandro Maródi, László Sanal, Ozden Kumaki, Satoru Nagendran, Vasantha Wood, Philip Glastre, Catherine Sarrot-Reynauld, Françoise ...

Published in Journal of Clinical Investigation

Hyper-IgM syndrome (HIGM) is a heterogeneous condition characterized by impaired Ig class-switch recombination (CSR). The molecular defects that have so far been associated with this syndrome - which affect the CD40 ligand in HIGM type 1 (HIGM1), CD40 in HIGM3, and activation-induced cytidine deaminase (AID) in HIGM2 - do not account for all cases....

Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1.

Hacein-Bey-Abina, Salima Garrigue, Alexandrine Wang, Gary P Jean Soulier Lim, Annick Morillon, Estelle Clappier, Emmanuelle Caccavelli, Laure Delabesse, Eric Beldjord, Kheira ...

Published in Journal of Clinical Investigation

Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blas...

Cooperativity of imprinted genes inactivated by acquired chromosome 20q deletions.

Aziz, Athar Baxter, E Joanna Edwards, Carol Cheong, Clara Yujing Ito, Mitsuteru Bench, Anthony Kelley, Rebecca Silber, Yvonne Beer, Philip A Chng, Keefe ...

Published in Journal of Clinical Investigation

Large regions of recurrent genomic loss are common in cancers; however, with a few well-characterized exceptions, how they contribute to tumor pathogenesis remains largely obscure. Here we identified primate-restricted imprinting of a gene cluster on chromosome 20 in the region commonly deleted in chronic myeloid malignancies. We showed that a sing...

Adaptive human regulatory T cells: myth or reality?

Chatenoud, Lucienne Bach, Jean-François

Published in Br J Dermatol

It is now well established that a distinct subset of T lymphocytes is essential for downregulating immune responses to both endogenous (self) and exogenous antigens. These Tregs are CD4+ and express high levels of CD25 (the alpha chain of the IL-2 receptor) and the transcription factor Foxp3. The mechanisms determining the lifespan, homeostasis, an...

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