RelA/NF-kappaB recruitment on the bax gene promoter antagonizes p73-dependent apoptosis in costimulated T cells

The balance between antiapoptotic and proapoptotic proteins of the Bcl-2 family is critical in determining the fate of T cells in response to death stimuli. Proapoptotic genes, such as bax, are generally regulated by the p53 family of transcription factors, whereas NF-kappaB subunits can activate the transcription of antiapoptotic Bcl-2 members. Here, we show that CD28 activation protects memory T cells from irradiation-induced apoptosis by both upregulating bcl-xL and inhibiting bax gene expression. We found that p73, but not p53, binds to and trans-activates the bax gene promoter in irradiated T cells. The activation of RelA/NF-kappaB subunit in CD28 costimulated T cells and its binding onto the bax gene promoter results in suppression of bax transcription and decrease in both p73 and RNA polymerase II recruitment in vivo. RelA recruitment on the bax gene promoter is also accompanied by the lost of p300 binding and the parallel appearance of histone deacetylase-1-containing complexes. These findings identify RelA/NF-kappaB as a critical regulator of T-cell survival by affecting the balance of Bcl-2 family members

Revisiting G3BP1 as a RasGAP binding protein: sensitization of tumor cells to chemotherapy by the RasGAP 317-326 sequence does not involve G3BP1.

RasGAP is a multifunctional protein that controls Ras activity and that is found in chromosomal passenger complexes. It also negatively or positively regulates apoptosis depending on the extent of its cleavage by caspase-3. RasGAP has been reported to bind to G3BP1 (RasGAP SH3-domain-binding protein 1), a protein regulating mRNA stability and stress granule formation. The region of RasGAP (amino acids 317-326) thought to bind to G3BP1 corresponds exactly to the sequence within fragment N2, a caspase-3-generated fragment of RasGAP, that mediates sensitization of tumor cells to genotoxins. While assessing the contribution of G3BP1 in the anti-cancer function of a cell-permeable peptide containing the 317-326 sequence of RasGAP (TAT-RasGAP₃₁₇₋₃₂₆), we found that, in conditions where G3BP1 and RasGAP bind to known partners, no interaction between G3BP1 and RasGAP could be detected. TAT-RasGAP₃₁₇₋₃₂₆ did not modulate binding of G3BP1 to USP10, stress granule formation or c-myc mRNA levels. Finally, TAT-RasGAP₃₁₇₋₃₂₆ was able to sensitize G3BP1 knock-out cells to cisplatin-induced apoptosis. Collectively these results indicate that G3BP1 and its putative RasGAP binding region have no functional influence on each other. Importantly, our data provide arguments against G3BP1 being a genuine RasGAP-binding partner. Hence, G3BP1-mediated signaling may not involve RasGAP

2D continuous spectrum of shear Alfven waves in the presence of a magnetic island

The radial structure of the continuous spectrum of shear Alfven modes is calculated in the presence of a magnetic island in tokamak plasmas. Modes with the same helicity of the magnetic island are considered in a slab model approximation. In this framework, with an appropriate rotation of the coordinates the problem reduces to 2 dimensions. Geometrical effects due to the shape of the flux surface's cross section are retained to all orders. On the other hand, we keep only curvature effects responsible of the beta induced gap in the low-frequency part of the continuous spectrum. New continuum accumulation points are found at the O-point of the magnetic island. The beta-induced Alfven Eigenmodes (BAE) continuum accumulation point is found to be positioned at the separatrix flux surface. The most remarkable result is the nonlinear modification of the BAE continuum accumulation point frequency

Tumor sensitizing function and mechanism of action of a RasGAP derived peptide

Cancer is the second cause of death after cardio-vascular diseases in economically developed countries. Two of the most commonly used anti-cancer therapies are chemo and radiotherapy. Despite the remarkable advances made in term of delivery and specificity of these two anti-tumor regimens, their toxicity towards healthy tissue remains a limitation. A promising approach to overcome this obstacle would be the utilization of therapeutic peptides that specifically augment the sensitivity of tumoral cells to treatments. Lower therapeutical doses would then be required to kill malignant cells, limiting toxic effects on healthy tissues. It was previously shown in our laboratory that the caspase-3 generated fragment N2 of RasGAP is able to potentiate the genotoxin-induced apoptosis selectively in cancer cells. In this work we show that fragment N2 strictly requires a cytoplasmic localization to deliver its pro-apoptotic effect in genotoxin-treated cancer cells. The tumor sensitizing capacity of fragment N2 was found to reside within the 10 amino acid sequence 317-326. Our laboratory earlier demonstrated that a peptide corresponding to amino acids 317 to 326 of RasGAP fused to the TAT cell permeable moiety, called TAT-RasGAP317.326, is able to sensitize cancer cells, but not normal cells, to genotoxin-induced apoptosis. In the present study we describe the capacity of TAT-RasGAP 317.326 to sensitize tumors to both chemo and radiotherapy in an in vivo mouse model. The molecular mechanism underlying the TAT-RasGAP 317.326-mediated sensitization starts now to be elucidated. We demonstrate that G3BP1, an endoribonuclease binding to amino acids 317-326 of RasGAP, is not involved in the sensitization mechanism. We also provide evidence showing that TAT-RasGAP3 17-326 potentiates the genotoxin-mediated activation of Bax in a tBid-dependent manner. Altogether our results show that TAT-RasGAP 317.326 could be potentially used in cancer therapy as sensitizer, in order to improve the efficacy of chemo and radiotherapy and prolong the life expectancy of cancer patients. Moreover, the understanding of the TAT-RasGAP317.326 mode of action might help to unravel the mechanisms by which cancer cells resist to chemo and radiotherapy and therefore to design more targeted and efficient anti-tumoral strategies

Reconstructing historical changes in the macroalgal vegetation of a central Mediterranean coastal area based on herbarium collections

Well-conserved herbarium specimens of marine macroalgae represent a valuable resource for multiple types of investigation. When algal herbaria host specimens collected over long time spans from a certain geographic area, they have the potential to document historical changes in the benthic vegetation of that area. In this study, historical changes in the macroalgal vegetation of a central Mediterranean coast (Conero Riviera, Adriatic Sea) were assessed based on a critical re-examination of the herbarium of Irma Pierpaoli (collection period 1925–1951) and the phycological herbarium of the Polytechnic University of Marche (ANC ALG, collections made mostly in the period 1999–2024). For both herbaria, the identifications of many specimens were revised based on the current species circumscriptions. The comparison indicates that some major changes occurred between the two collection periods: a switch in the morphological functional structure of the vegetation (increase in the number of filamentous species, decrease in leathery macrophytes, and the near disappearance of calcareous articulated algae), local extinction of some species (at least 23, possibly more), and introduction of 11 species of non-indigenous seaweeds. Anthropogenic impacts (habitat destruction, increase in sediment load, and impacts of port activities and maritime traffic) are considered the main factors responsible for these changes

Acute primary repair of the anterior cruciate ligament with anterolateral ligament augmentation

Acute injuries of the anterior cruciate ligament are often associated with concurrent injuries to the structures of the anterolateral complex, specifically the anterolateral ligament. Some injury patterns of the anterior cruciate ligament involve tearing of the majority of the ligament from the femoral origin, leaving a large, viable ligament remnant. In these patients, a repair of the anterior cruciate ligament back to the femoral origin can be undertaken. Subsequently, percutaneous repair of the anterolateral ligament can be performed through anatomical, percutaneous suture tape augmentation. The combined technique of anterior cruciate ligament repair with anterolateral ligament reinforcement is presented

Combined acl and segond repair in combined acute proximal acl tears and segond fracture

A renewed interest in anterior cruciate ligament preservation has been noted using arthroscopic primary repair in patients with proximal tears, but the main concern remained the control of the rotational instability. Segond fracture occurs in less than 10% of cases of acute anterolateral instability, but it can result in continued rotation instability. The aim of this study is to describe the surgical technique to acutely repair both the anterior cruciate ligament and Segond fracture in the acute setting

In-situ trace metal (Cd, Pb, Cu) speciation along the Po River plume (Northern Adriatic Sea) using submersible systems

Information on the distribution and speciation of trace metals is of critical importance for our ability to interpret the links between the bioavailability and uptake of an element, and its biogeochemical cycle in coastal environments. Within the framework of the European Project “In-situ automated Monitoring of Trace metal speciation in Estuaries and Coastal zones in relation with the biogeochemical processes (IMTEC)”, the chemical speciation of Cd, Pb and Cu was carried out along the Po River plume in the period 27 October – 2 November 2002. During the cruise, five Voltammetric In-situ Profiling systems and one Multi Physical Chemical Profiler, as well as conventional voltammetric instruments, were successfully applied in order to evaluate the distribution of Cd, Pb and Cu between different fractions (free ion, dynamic, colloidal, dissolved and particulate fractions) and to assess the evolution of these fractions during estuarine mixing and in the water column. Dynamic concentrations were 0.05–0.2 nmol L-1 Cd, 0.02–0.2 nmol L-1 Pb, and 0.15–4.0 nmol L-1Cu. Cd was mainly present as dynamic fraction (40–100% of the dissolved Cd). High proportions of Pb (~70%) and Cu (~80%) were present as colloids probably of biogenic origin. Principal components analysis reveals a strong influence of the Po River discharge on the spatial and vertical distributions of metal species. Almost all the metal fractions globally decreased following the salinity gradient. Metal concentrations are far below (at least one order of magnitude lower) the Environmental Quality Standard established by the Italian law. However, the Cu dynamic fraction showed concentrations likely to be toxic to sensitive phytoplankton community and to have negative effects on larva development of coastal macroinvertebrate species (toxicity data extracted from literature)