Grain in a Plasma in the Presence of External Electric Field: Kinetic Calculation of Effective Potential and Ionic Drag Force

Kinetic calculations of the effective grain potential are presented for the case of weakly-ionized plasma in the external electric field. The drag force associated with the ionic drift in the external field is found. It is shown that the absorption of electrons and ions by the grain can cause the change of the direction of the drag force.Представлено кiнетичнi розрахунки ефективного потенцiалу порошинки для випадку слабоiонiзованої плазми у зовнiшньому електричному полi. Знайдено силу опору, яка пов’язана з дрейфом iонiв у зовнiшньому полi. Показано, що поглинання електронiв та iонiв порошинкою може привести до змiни напрямку сили опору

Caractérisation fonctionnelle des facteurs intermédiaires de transcription TIF1alpha et TIF1delta chez la souris

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Trim24 (Tif1 alpha): an essential 'brake' for retinoic acid-induced transcription to prevent liver cancer.

International audienceRetinoic acid (RA), the active derivative of vitamin A, is an important signaling molecule that controls various developmental processes and influence the proliferation and differentiation of a variety of cell types. RA exerts its biological functions primarily through binding to and activating nuclear RA receptors (RARs, which include the RAR alpha, beta and gamma isotypes RARA, RARB and RARC). Aberrant expression or impaired function of these nuclear receptors has been linked to diverse types of cancer. RARs are RA-dependent transcription factors that regulate gene expression through the recruitment of different co-regulators (co-activators and co-repressors). TRIM24 (formerly known as TIF1 alpha) was among the first co-regulators identified as interacting with RARs in a ligand-dependent fashion, and it was recently shown to function in mice as a potent liver-specific tumor suppressor by attenuating Rara-mediated transcription. The fact that Trim24(-/-), but not Trim24(-/-)Rara(+/-), mutant mice are highly predisposed to the development of hepatocellular carcinoma (HCC) has significant implications in cancer research. This result, along with the observation that in response to pharmacological inhibition of the RA signaling, hepatocytes lacking Trim24 loose their ability to proliferate, strongly implicates Rara as a proto-oncogene in hepatocytes and demonstrates that overactivated RA signaling is deleterious to liver homeostasis

TIF1delta, a novel HP1-interacting member of the transcriptional intermediary factor 1 (TIF1) family expressed by elongating spermatids

TIF1 (transcriptional intermediary factor 1) proteins are encoded by an expanding family of developmental and physiological control genes that are conserved from flies to man. These proteins are characterized by an N-terminal RING-B box-coiled-coil (RBCC) motif and a C-terminal PHD finger/bromodomain unit, and have been implicated in epigenetic mechanisms of transcriptional repression involving histone modifiers and heterochromatin-binding proteins. We describe here the isolation and functional characterization of a fourth murine TIF1 gene, TIF1delta. The predicted TIF1delta protein displays all the structural hallmarks of a bona fide TIF1 family member and resembles the other TIF1s in that it can exert a deacetylase-dependent silencing effect when tethered to a promoter region. Moreover, like TIF1alpha and TIF1beta, TIF1delta can homodimerize and contains a PXVXL motif necessary and sufficient for HP1 (heterochromatin protein 1) binding. Although TIF1alpha and TIF1beta also bind nuclear receptors and Kruppel-associated boxes specifically and respectively, TIF1delta appears to lack nuclear receptor- and Kruppel-associated box binding activity. Furthermore, TIF1delta is unique among the TIF1 family proteins in that its expression is largely restricted to the testis and confined to haploid elongating spermatids, where it associates preferentially with HP1 isotype gamma (HP1gamma) and forms discrete foci dispersed within the centromeric chromocenter and the surrounding nucleoplasm. Collectively, these data are consistent with specific, nonredundant functions for the TIF1 family members in vivo and suggest a role for TIF1delta in heterochromatin-mediated gene silencing during postmeiotic phases of spermatogenesis

Additional file 4: of Development of a methodology for in vivo follow-up of hepatocellular carcinoma in hepatocyte specific Trim24-null mice treated with myo-inositol trispyrophosphate

Follow-up of hepatocellular carcinoma (HCC) growth by 3D reconstruction. Follow-up of hepatocellular carcinoma (HCC) growth by 3D reconstruction of micro-CT rendering. Micro-CT imaging was performed at 12, 15, and 21 months of age respectively in hepatocyte specific Trim24-null mice. A, B, C Exponential growth of unifocal HCC. A. Micro-CT-scan rendering in coronal slides (strips indicate vertical diameter of HCC). B. 3D reconstruction of the micro-CT-scan (HCC is depicted in green). C. Macroscopic appearance of the liver and HCC at dissection at 22 months old (black arrow indicates tumor). D, E, F. Multifocal growth of HCC. D. Micro-CT scan rendering in coronal slides (strips indicate vertical diameters of the HCCs). E. 3D reconstruction of the micro-CT-scan (HCCs are depicted in green). F. Macroscopic appearance of the liver and HCCs at dissection at 23 months old (black arrows indicate tumors). (JPG 4259 kb

Loss of Trim24 (Tif1alpha) gene function confers oncogenic activity to retinoic acid receptor alpha.

Hepatocellular carcinoma (HCC) is a major cause of death worldwide. Here, we provide evidence that the ligand-dependent nuclear receptor co-regulator Trim24 (also known as Tif1alpha) functions in mice as a liver-specific tumor suppressor. In Trim24-null mice, hepatocytes fail to execute proper cell cycle withdrawal during the neonatal-to-adult transition and continue to cycle in adult livers, becoming prone to a continuum of cellular alterations that progress toward metastatic HCC. Using pharmacological approaches, we show that inhibition of retinoic acid signaling markedly reduces hepatocyte proliferation in Trim24-/- mice. We further show that deletion of a single retinoic acid receptor alpha (Rara) allele in a Trim24-null background suppresses HCC development and restores wild-type expression of retinoic acid-responsive genes in the liver, thus demonstrating that in this genetic background Rara expresses an oncogenic activity correlating with a dysregulation of the retinoic acid signaling pathway. Our results not only provide genetic evidence that Trim24 and Rara co-regulate hepatocarcinogenesis in an antagonistic manner but also suggest that aberrant activation of Rara is deleterious to liver homeostasis

Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.

International audienceDAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated. We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies. Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFΚB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC). We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function