The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis.

The ability of pollutants to affect human health is a major concern, justified by the wide demonstration that reproductive functions are altered by endocrine disrupting chemicals. The definition of endocrine disruption is today extended to broader endocrine regulations, and includes activation of metabolic sensors, such as the peroxisome proliferator-activated receptors (PPARs). Toxicology approaches have demonstrated that phthalate plasticizers can directly influence PPAR activity. What is now missing is a detailed molecular understanding of the fundamental basis of endocrine disrupting chemical interference with PPAR signaling. We thus performed structural and functional analyses that demonstrate how monoethyl-hexyl-phthalate (MEHP) directly activates PPARgamma and promotes adipogenesis, albeit to a lower extent than the full agonist rosiglitazone. Importantly, we demonstrate that MEHP induces a selective activation of different PPARgamma target genes. Chromatin immunoprecipitation and fluorescence microscopy in living cells reveal that this selective activity correlates with the recruitment of a specific subset of PPARgamma coregulators that includes Med1 and PGC-1alpha, but not p300 and SRC-1. These results highlight some key mechanisms in metabolic disruption but are also instrumental in the context of selective PPAR modulation, a promising field for new therapeutic development based on PPAR modulation.

Surface-functionalized ultrasmall superparamagnetic nanoparticles as magnetic delivery vectors for camptothecin.

Drug-nanoparticle conjugates: The anticancer drug camptothecin (CPT) was covalently linked at the surface of ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) via a linker, allowing drug release by cellular esterases. Nanoparticles were hierarchically built to achieve magnetically-enhanced drug delivery to human cancer cells and antiproliferative activity.The linking of therapeutic drugs to ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) allowing intracellular release of the active drug via cell-specific mechanisms would achieve tumor-selective magnetically-enhanced drug delivery. To validate this concept, we covalently attached the anticancer drug camptothecin (CPT) to biocompatible USPIOs (iron oxide core, 9-10 nm; hydrodynamic diameter, 52 nm) coated with polyvinylalcohol/polyvinylamine (PVA/aminoPVA). A bifunctional, end-differentiated dicarboxylic acid linker allowed the attachment of CPT to the aminoPVA as a biologically labile ester substrate for cellular esterases at one end, and as an amide at the other end. These CPT-USPIO conjugates exhibited antiproliferative activity in vitro against human melanoma cells. The intracellular localization of CPT-USPIOs was confirmed by transmission electron microscopy (iron oxide core), suggesting localization in lipid vesicles, and by fluorescence microscopy (CPT). An external static magnetic field applied during exposure increased melanoma cell uptake of the CPT-USPIOs.

Evolution of a polymineralic mantle shear zone and the role of second phases in the localization of deformation

The influence of second phases (e.g., pyroxenes) on olivine grain size was studied by quantitative microfabric analyses of samples of the Hilti massif mantle shear zone (Semail ophiolite, Oman). The microstructures range from porphyroclastic tectonites to ultramylonites, from outside to the center of the shear zone. Starting at conditions of ridge-related flow, they formed under continuous cooling leading to progressive strain localization. The dependence of the average olivine grain size on the second-phase content can be split into a second-phase controlled and a dynamic recrystallization-controlled field. In the former, the olivine grain size is related to the ratio between the second-phase grain size and volume fraction (Zener parameter). In the latter, dynamic recrystallization manifested by a balance between grain growth and grain size reduction processes yields a stable olivine grain size. In both fields the average olivine and second-phase grain size decreases with decreasing temperature. Combining the microstructural information with deformation mechanism maps suggests that the porphyroclastic tectonites (similar to 1100 degrees C) and mylonites (similar to 800 degrees C) formed under the predominance of dislocation creep. Since olivine-rich layers are intercalated with layer parallel, polymineralic bands in the mylonites, nearly equiviscous conditions can be assumed. In the ultramylonites, diffusion creep represents the major deformation mechanism in the polymineralic layers. It is this switch in deformation mechanism from dislocation creep to diffusion creep that forces strain to localize in the fine-grained polymineralic domains at low temperatures (<similar to 700 degrees C), underlining the role of the second phases on strain localization in cooling mantle rocks.

In situ fluorescence imaging of glutamate-evoked mitochondrial Na+ responses in astrocytes.

Astrocytes can experience large intracellular Na+ changes following the activation of the Na+-coupled glutamate transport. The present study investigated whether cytosolic Na+ changes are transmitted to mitochondria, which could therefore influence their function and contribute to the overall intracellular Na+ regulation. Mitochondrial Na+ (Na+(mit)) changes were monitored using the Na+-sensitive fluorescent probe CoroNa Red (CR) in intact primary cortical astrocytes, as opposed to the classical isolated mitochondria preparation. The mitochondrial localization and Na+ sensitivity of the dye were first verified and indicated that it can be safely used as a selective Na+(mit) indicator. We found by simultaneously monitoring cytosolic and mitochondrial Na+ using sodium-binding benzofuran isophthalate and CR, respectively, that glutamate-evoked cytosolic Na+ elevations are transmitted to mitochondria. The resting Na+(mit) concentration was estimated at 19.0 +/- 0.8 mM, reaching 30.1 +/- 1.2 mM during 200 microM glutamate application. Blockers of conductances potentially mediating Na+ entry (calcium uniporter, monovalent cation conductances, K+(ATP) channels) were not able to prevent the Na+(mit) response to glutamate. However, Ca2+ and its exchange with Na+ appear to play an important role in mediating mitochondrial Na+ entry as chelating intracellular Ca2+ with BAPTA or inhibiting Na+/Ca2+ exchanger with CGP-37157 diminished the Na+(mit) response. Moreover, intracellular Ca2+ increase achieved by photoactivation of caged Ca2+ also induced a Na+(mit) elevation. Inhibition of mitochondrial Na/H antiporter using ethylisopropyl-amiloride caused a steady increase in Na+(mit) without increasing cytosolic Na+, indicating that Na+ extrusion from mitochondria is mediated by these exchangers. Thus, mitochondria in intact astrocytes are equipped to efficiently sense cellular Na+ signals and to dynamically regulate their Na+ content.

Thrombin-sensitive photodynamic agents: a novel strategy for selective synovectomy in rheumatoid arthritis.

Protease-sensitive macromolecular prodrugs have attracted interest for bio-responsive drug delivery to sites with up-regulated proteolytic activities such as inflammatory or cancerous lesions. Here we report the development of a novel polymeric photosensitizer prodrug (T-PS) to target thrombin, a protease up-regulated in synovial tissues of rheumatoid arthritis (RA) patients, for minimally invasive photodynamic synovectomy. In T-PS, multiple photosensitizer units are tethered to a polymeric backbone via short, thrombin-cleavable peptide linkers. Photoactivity of the prodrug is efficiently impaired due to energy transfer between neighbouring photosensitizer units. T-PS activation by exogenous and endogenous thrombin induced an increase in fluorescence emission by a factor of 16 after in vitro digestion and a selective fluorescence enhancement in arthritic lesions in vivo, in a collagen-induced arthritis mouse model. In vitro studies on primary human synoviocytes showed a phototoxic effect only after enzymatic digestion of the prodrug and light irradiation, thus demonstrating the functionality of T-PS induced PDT. The developed photosensitizer prodrugs combine the passive targeting capacity of macromolecular drug delivery systems with site-selective photosensitizer release and activation. They illuminate lesions with pathologically enhanced proteolytic activity and induce cell death, subsequent to irradiation.

Selective ablation of photovoltaic materials with UV laser sources for monolithic interconnection of devices based on a-Si:H

Lasers are essential tools for cell isolation and monolithic interconnection in thin-film-silicon photovoltaic technologies. Laser ablation of transparent conductive oxides (TCOs), amorphous silicon structures and back contact removal are standard processes in industry for monolithic device interconnection. However, material ablation with minimum debris and small heat affected zone is one of the main difficulty is to achieve, to reduce costs and to improve device efficiency. In this paper we present recent results in laser ablation of photovoltaic materials using excimer and UV wavelengths of diode-pumped solid-state (DPSS) laser sources. We discuss results concerning UV ablation of different TCO and thin-film silicon (a-Si:H and nc-Si:H), focussing our study on ablation threshold measurements and process-quality assessment using advanced optical microscopy techniques. In that way we show the advantages of using UV wavelengths for minimizing the characteristic material thermal affection of laser irradiation in the ns regime at higher wavelengths. Additionally we include preliminary results of selective ablation of film on film structures irradiating from the film side (direct writing configuration) including the problem of selective ablation of ZnO films on a-Si:H layers. In that way we demonstrate the potential use of UV wavelengths of fully commercial laser sources as an alternative to standard backscribing process in device fabrication.

Pancréatite aiguë clinique après chimio-embolisation sélective d'un carcinome hépatocellulaire [Acute clinical pancreatitis following selective transcatheter arterial chemoembolization of hepatocellular carcinoma]

Acute pancreatitis can complicate non-selective transcatheter arterial embolization of hepatocellular carcinoma with an incidence ranging from 1,7% (acute clinical pancreatitis) to 40% (biological pancreatitis). This complication is thought to be related to embolization of extrahepatic arterial collaterals.We report herein a case of acute clinical pancreatitis developing within 24 hours after a second course of selective transcatheter arterial chemo-embolization into the proper hepatic artery. Neither anatomical arterial variation nor particular risk factor for acute pancreatitis could be identified. This complication is unusual after selective arterial embolization. Because it may clinically mimick a postembolization syndrome, dosage of serum pancreatic enzymes should be performed systematically in case of abdominal pain following chemoembolization.

Collective bargaining in U.S. higher education, 1960-1971 : a selective bibliography, 1972.

This document represents a substantial attempt to survey the literature of labor negotiations as it relates to the faculty in higher education.

Growth and recruitment after mountain forest selective cutting in irregular spruce forest : a case study in northern Norway

Abstract

The design and characterization of receptor-selective APRIL variants.

A proliferation-inducing ligand (APRIL), a member of the TNF ligand superfamily with an important role in humoral immunity, is also implicated in several cancers as a prosurvival factor. APRIL binds two different TNF receptors, B cell maturation antigen (BCMA) and transmembrane activator and cylclophilin ligand interactor (TACI), and also interacts independently with heparan sulfate proteoglycans. Because APRIL shares binding of the TNF receptors with B cell activation factor, separating the precise signaling pathways activated by either ligand in a given context has proven quite difficult. In this study, we have used the protein design algorithm FoldX to successfully generate a BCMA-specific variant of APRIL, APRIL-R206E, and two TACI-selective variants, D132F and D132Y. These APRIL variants show selective activity toward their receptors in several in vitro assays. Moreover, we have used these ligands to show that BCMA and TACI have a distinct role in APRIL-induced B cell stimulation. We conclude that these ligands are useful tools for studying APRIL biology in the context of individual receptor activation.

Cross validation of experts versus registration methods for target localization in deep brain stimulation.

In the last five years, Deep Brain Stimulation (DBS) has become the most popular and effective surgical technique for the treatent of Parkinson's disease (PD). The Subthalamic Nucleus (STN) is the usual target involved when applying DBS. Unfortunately, the STN is in general not visible in common medical imaging modalities. Therefore, atlas-based segmentation is commonly considered to locate it in the images. In this paper, we propose a scheme that allows both, to perform a comparison between different registration algorithms and to evaluate their ability to locate the STN automatically. Using this scheme we can evaluate the expert variability against the error of the algorithms and we demonstrate that automatic STN location is possible and as accurate as the methods currently used.

Knot localization in proteins.

The backbones of proteins form linear chains. In the case of some proteins, these chains can be characterized as forming linear open knots. The knot type of the full chain reveals only limited information about the entanglement of the chain since, for example, subchains of an unknotted protein can form knots and subchains of a knotted protein can form different types of knots than the entire protein. To understand fully the entanglement within the backbone of a given protein, a complete analysis of the knotting within all of the subchains of that protein is necessary. In the present article, we review efforts to characterize the full knotting complexity within individual proteins and present a matrix that conveys information about various aspects of protein knotting. For a given protein, this matrix identifies the precise localization of knotted regions and shows the knot types formed by all subchains. The pattern in the matrix can be considered as a knotting fingerprint of that protein. We observe that knotting fingerprints of distantly related knotted proteins are strongly conserved during evolution and discuss how some characteristic motifs in the knotting fingerprints are related to the structure of the knotted regions and their possible biological role.

Selective inhibition of JNK with a peptide inhibitor attenuates pain hypersensitivity and tumor growth in a mouse skin cancer pain model.

Cancer pain significantly affects the quality of cancer patients, and current treatments for this pain are limited. C-Jun N-terminal kinase (JNK) has been implicated in tumor growth and neuropathic pain sensitization. We investigated the role of JNK in cancer pain and tumor growth in a skin cancer pain model. Injection of luciferase-transfected B16-Fluc melanoma cells into a hindpaw of mouse induced robust tumor growth, as indicated by increase in paw volume and fluorescence intensity. Pain hypersensitivity in this model developed rapidly (<5 days) and reached a peak in 2 weeks, and was characterized by mechanical allodynia and heat hyperalgesia. Tumor growth was associated with JNK activation in tumor mass, dorsal root ganglion (DRG), and spinal cord and a peripheral neuropathy, such as loss of nerve fibers in the hindpaw skin and induction of ATF-3 expression in DRG neurons. Repeated systemic injections of D-JNKI-1 (6 mg/kg, i.p.), a selective and cell-permeable peptide inhibitor of JNK, produced an accumulative inhibition of mechanical allodynia and heat hyperalgesia. A bolus spinal injection of D-JNKI-1 also inhibited mechanical allodynia. Further, JNK inhibition suppressed tumor growth in vivo and melanoma cell proliferation in vitro. In contrast, repeated injections of morphine (5 mg/kg), a commonly used analgesic for terminal cancer, produced analgesic tolerance after 1 day and did not inhibit tumor growth. Our data reveal a marked peripheral neuropathy in this skin cancer model and important roles of the JNK pathway in cancer pain development and tumor growth. JNK inhibitors such as D-JNKI-1 may be used to treat cancer pain.

Nuclear localization of mouse fibroblast growth factor 2 requires N-terminal and C-terminal sequences.

In vertebrates, different isoforms of fibroblast growth factor 2 (FGF2) exist, which differ by their N-terminal extension. They show different localization and expression levels and exert distinct biological effects. Nevertheless, genetic inactivation of all FGF2 isoforms in the mouse results in only mild phenotypes. Here, we analyzed mouse FGF2, and show that, as in the human, mouse FGF2 contains CTG-initiated high molecular-weight (HMW) isoforms, which contain a nuclear localization signal, and which mediate localization of this isoform to the nucleus. Using green fluorescent protein-FGF2 fusions, we furthermore observed, that C-terminal deletions disable nuclear localization of the short low-molecular-weight (LMW) 18-kDa isoform. This loss of specific localization is accompanied by a loss in heparin binding. We therefore suggest that, first, localization of mouse FGF2 is comparable to that in other vertebrates and, second, FGF2 contains at least two sequences important for nuclear localization, a nuclear localization sequence at the N terminus which is only contained in the HMW isoform, and another sequence at the C terminus, which is only required for localization of the LMW 18-kDa isoform.