Length functions of Hitchin representations

Given a Hitchin representation \rho \colon \pi_1(S) \to \PSL_n(\mathbb{R}), we construct $n$ continuous functions \ell_i^\rho \colon \mathcal \CH(S) \to \mathbb{R} defined on the space of H\"older geodesic currents \CH(S) such that, for a closed, oriented curve $\gamma$ in $S$, the $i$--th eigenvalue of the matrix \rho(\gamma)\in \PSL_n(\mathbb{R}) is of the form $\pm \mathrm{exp}\, \ell_i^\rho(\gamma)$: such functions generalize to higher rank Thurston's length function of Fuchsian re\presentations. Identities, diffe\rentiability properties of these lengths $\ell_i^\rho$, as well as applications to eigenvalue estimates, are also considered.Comment: 16 pages, 2 figures, final version to appear in Algebraic and Geometric Topolog

Chem. Sci.

The isobutyl side chain is a highly prevalent hydrophobic group in drugs, and it notably constitutes the side chain of leucine. Its replacement by a hexafluorinated version containing two CF3 groups may endow the target compound with new and advantageous properties, yet this modification remains overlooked due to the absence of a general and practical synthetic methodology. Herein, we report the first general method to introduce the hexafluoroisobutyl group into ketoesters, malonates, 1,3-diketones, Schiff base esters and malononitrile. We demonstrated that the reaction occurs through an elimination/allylic shift/hydrofluorination cascade process which efficiently overcomes the usual fluoride β-elimination observed with α-CF3-vinyl groups. We showed that with alkali metal bases, a pentafluorinated alkene is obtained predominantly, whereas the use of tetrabutylammonium fluoride (TBAF) allows hydrofluorination to occur. This tandem process represents a conceptually new pathway to synthesize bis-trifluoromethylated compounds. This methodology was applied to the multigram-scale synthesis of enantiopure (S)-5,5,5,5′,5′,5′-hexafluoroleucine.Interactions supramoléculaires sélectives et directionnelles à base de synthons fluorés hautement polaire

Cultures visuelles et révolutions : enjeux et nouvelles problématiques

Parce que la question des liens entre les cultures visuelles et les révolutions est aujourd’hui en profond renouvellement, nous avons souhaité présenter quelques-uns des débats qui traversent un champ en pleine expansion mais qui reste pourtant encore très méconnu ou sujet à de nombreux malentendus, notamment en France. Méconnues des historiens, les images de « la » Révolution ? Cette affirmation peut surprendre. Depuis les années 1980, de nombreux travaux ont en effet totalement transformé l..

Nonlinear compression of high energy fiber amplifier pulses in air-filled hypocycloid-core Kagome fiber

International audienceWe report on the generation of 34 fs and 50 µJ pulses from a high energy fiber amplifier system with nonlinear compression in an air-filled hypocycloid-core Kagome fiber. The unique properties of such fibers allow bridging the gap between solid core fibers-based and hollow capillary-based post-compression setups, thereby operating with pulse energies obtained with current state-of-the-art fiber systems. The overall transmission of the compression setup is over 70%. Together with Yb-doped fiber amplifier technologies, Kagome fibers therefore appear as a promising tool for efficient generation of pulses with durations below 50 fs, energies ranging from 10 to several hundreds of µJ, and high average powers

Regulation and novel action of thymidine phosphorylase in non-small cell lung cancer : crosstalk with Nrf2 and HO-1

Proangiogenic enzyme thymidine phosphorylase (TP) is a promising target for anticancer therapy, yet its action in non-small cell lung carcinoma (NSCLC) is not fully understood. To elucidate its role in NSCLC tumor growth, NCI-H292 lung mucoepidermoid carcinoma cells and endothelial cells were engineered to overexpress TP by viral vector transduction. NSCLC cells with altered expression of transcription factor Nrf2 or its target gene heme oxygenase-1 (HO-1) were used to study the regulation of TP and the findings from pre-clinical models were related to gene expression data from clinical NSCLC specimens. Overexpression of Nrf2 or HO-1 resulted in upregulation of TP in NCI-H292 cells, an effect mimicked by treatment with an antioxidant N-acetylcysteine and partially reversed by HO-1 knockdown. Overexpression of TP attenuated cell proliferation and migration in vitro, but simultaneously enhanced angiogenic potential of cancer cells supplemented with thymidine. The latter was also observed for SK-MES-1 squamous cell carcinoma and NCI-H460 large cell carcinoma cells. TP-overexpressing NCI-H292 tumors in vivo exhibited better oxygenation and higher expression of IL-8, IL-1β and IL-6. TP overexpression in endothelial cells augmented their angiogenic properties which was associated with enhanced generation of HO-1 and VEGF. Correlation of TP with the expression of HO-1 and inflammatory cytokines was confirmed in clinical samples of NSCLC. Altogether, the increased expression of IL-1β and IL-6 together with proangiogenic effects of TP-expressing NSCLC on endothelium can contribute to tumor growth, implying TP as a target for antiangiogenesis in NSCLC

Identification of Restricted Subsets of Mature microRNA Abnormally Expressed in Inactive Colonic Mucosa of Patients with Inflammatory Bowel Disease

International audienceBACKGROUND: Ulcerative Colitis (UC) and Crohn's Disease (CD) are two chronic Inflammatory Bowel Diseases (IBD) affecting the intestinal mucosa. Current understanding of IBD pathogenesis points out the interplay of genetic events and environmental cues in the dysregulated immune response. We hypothesized that dysregulated microRNA (miRNA) expression may contribute to IBD pathogenesis. miRNAs are small, non-coding RNAs which prevent protein synthesis through translational suppression or mRNAs degradation, and regulate several physiological processes. METHODOLOGY/FINDINGS: Expression of mature miRNAs was studied by Q-PCR in inactive colonic mucosa of patients with UC (8), CD (8) and expressed relative to that observed in healthy controls (10). Only miRNAs with highly altered expression (>5 or 100 -fold and 0.05-0.19 -fold for over- and under- expression, respectively; 0.00

Stable tumor vessel normalization with pO_{2} increase and endothelial PTEN activation by inositol trispyrophosphate brings novel tumor treatment

Tumor hypoxia is a characteristic of cancer cell growth and invasion, promoting angiogenesis, which facilitates metastasis. Oxygen delivery remains impaired because tumor vessels are anarchic and leaky, contributing to tumor cell dissemination. Counteracting hypoxia by normalizing tumor vessels in order to improve drug and radio therapy efficacy and avoid cancer stem-like cell selection is a highly challenging issue. We show here that inositol trispyrophosphate (ITPP) treatment stably increases oxygen tension and blood flow in melanoma and breast cancer syngeneic models. It suppresses hypoxia-inducible factors (HIFs) and proangiogenic/glycolysis genes and proteins cascade. It selectively activates the tumor suppressor phosphatase and tensin homolog (PTEN) in vitro and in vivo at the endothelial cell (EC) level thus inhibiting PI3K and reducing tumor AKT phosphorylation. These mechanisms normalize tumor vessels by EC reorganization, maturation, pericytes attraction, and lowering progenitor cells recruitment in the tumor. It strongly reduces vascular leakage, tumor growth, drug resistance, and metastasis. ITPP treatment avoids cancer stem-like cell selection, multidrug resistance (MDR) activation and efficiently enhances chemotherapeutic drugs activity. These data show that counteracting tumor hypoxia by stably restoring healthy vasculature is achieved by ITPP treatment, which opens new therapeutic options overcoming hypoxia-related limitations of antiangiogenesis-restricted therapies. By achieving long-term vessels normalization, ITPP should provide the adjuvant treatment required in order to overcome the subtle definition of therapeutic windows for in vivo treatments aimed by the current strategies against angiogenesis-dependent tumors

Optimal anchoring of a foldamer inhibitor of ASF1 histone chaperone through backbone plasticity

Sequence-specific oligomers with predictable folding patterns, i.e., foldamers, provide new opportunities to mimic.-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may notably contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as. helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a notable plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with nonpeptide oligourea segments is the resistance to proteolysis in human plasma, which was highly improved compared to the cognate alpha-helical peptide

Evolution of Surface Hydrology in the Sahelo-Sudanian Strip: An Updated Review

In the West African Sahel, two paradoxical hydrological behaviors have occurred during the last five decades. The first paradox was observed during the 1968–1990s ‘Great Drought’ period, during which runoff significantly increased. The second paradox appeared during the subsequent period of rainfall recovery (i.e., since the 1990s), during which the runoff coefficient continued to increase despite the general re-greening of the Sahel. This paper reviews and synthesizes the literature on the drivers of these paradoxical behaviors, focusing on recent works in the West African Sahelo/Sudanian strip, and upscaling the hydrological processes through an analysis of recent data from two representative areas of this region. This paper helps better determine the respective roles played by Land Use/Land Cover Changes (LULCC), the evolution of rainfall intensity and the occurrence of extreme rainfall events in these hydrological paradoxes. Both the literature review and recent data converge in indicating that the first Sahelian hydrological paradox was mostly driven by LULCC, while the second paradox has been caused by both LULCC and climate evolution, mainly the recent increase in rainfall intensity

N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death.

APO2L/TRAIL (TNF-related apoptosis-inducing ligand) induces death of tumor cells through two agonist receptors, TRAIL-R1 and TRAIL-R2. We demonstrate here that N-linked glycosylation (N-glyc) plays also an important regulatory role for TRAIL-R1-mediated and mouse TRAIL receptor (mTRAIL-R)-mediated apoptosis, but not for TRAIL-R2, which is devoid of N-glycans. Cells expressing N-glyc-defective mutants of TRAIL-R1 and mouse TRAIL-R were less sensitive to TRAIL than their wild-type counterparts. Defective apoptotic signaling by N-glyc-deficient TRAIL receptors was associated with lower TRAIL receptor aggregation and reduced DISC formation, but not with reduced TRAIL-binding affinity. Our results also indicate that TRAIL receptor N-glyc impacts immune evasion strategies. The cytomegalovirus (CMV) UL141 protein, which restricts cell-surface expression of human TRAIL death receptors, binds with significant higher affinity TRAIL-R1 lacking N-glyc, suggesting that this sugar modification may have evolved as a counterstrategy to prevent receptor inhibition by UL141. Altogether our findings demonstrate that N-glyc of TRAIL-R1 promotes TRAIL signaling and restricts virus-mediated inhibition