Localization of the succinate receptor in the distal nephron and its signaling in polarized MDCK cells

When the succinate receptor (SUCNR1) is activated in the afferent arterioles of the glomerulus it increases renin release and induces hypertension. To study its location in other nephron segments and its role in kidney function, we performed immunohistochemical analysis and found that SUCNR1 is located in the luminal membrane of macula densa cells of the juxtaglomerular apparatus in close proximity to renin-producing granular cells, the cortical thick ascending limb, and cortical and inner medullary collecting duct cells. In order to study its signaling, SUCNR1 was stably expressed in Madin-Darby Canine Kidney (MDCK) cells, where it localized to the apical membrane. Activation of the cells by succinate caused Gq and Gi-mediated intracellular calcium mobilization, transient phosphorylation of extracellular regulated kinase (ERK)1/2 and the release of arachidonic acid along with prostaglandins E2 and I2. Signaling was desensitized without receptor internalization but rapidly resensitized upon succinate removal. Immunohistochemical evidence of phosphorylated ERK1/2 was found in cortical collecting duct cells of wild type but not SUCNR1 knockout streptozotocin-induced diabetic mice, indicating in vivo relevance. Since urinary succinate concentrations in health and disease are in the activation range of the SUCNR1, this receptor can sense succinate in the luminal fluid. Our study suggests that changes in the luminal succinate concentration may regulate several aspects of renal function

Synthesis and biological characterization of organoruthenium complexes with 8-hydroxyquinolines

In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium–8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells.Centro de Química Inorgánic

Synthesis and biological characterization of organoruthenium complexes with 8-hydroxyquinolines

In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium–8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells.Centro de Química Inorgánic

Synthesis and biological characterization of organoruthenium complexes with 8-hydroxyquinolines

In this study we report the synthesis, characterization and a thorough biological evaluation of twelve organoruthenium–8-hydroxyquinolinato (Ru-hq) complexes. The chosen hqH ligands bear various halogen atoms in different positions which enables to study effect of the substituents on physico-chemical and biological properties. The determined crystal structures of novel complexes expectedly show the cymene ring, a bidentately coordinated deprotonated hq and a halide ligand (chlorido or iodido) coordinated to the ruthenium central ion. In previous studies the anticancer potential of organoruthenium complex with 8-hydroxyquinoline ligand clioquinol was well established and we have decided to perform an extended biological evaluation (antibacterial and antitumor activity) of the whole series of halo-substituted analogs. Beside the cytotoxic potential of studied compounds also the effect of two selected complexes (9 and 10) on apoptosis induction in MG-63 and A549 cells was also studied via externalization of phosphatidylserine at the outer plasma membrane leaflet. Both selected complexes that gave best preliminary cytotoxicity results contain bromo substituted hq ligands. Apoptosis induction results are in agreement with the cell viability assays suggesting the higher and more selective anticancer activity of complex 10 in comparison to complex 9 on MG-63 cells.Centro de Química Inorgánic

Examining Asphaltene Solubility on Deposition in Model Porous Media

Asphaltenes are known to cause severe flow assurance problems in the near-wellbore region of oil reservoirs. Understanding the mechanism of asphaltene deposition in porous media is of great significance for the development of accurate numerical simulators and effective chemical remediation treatments. Here, we present a study of the dynamics of asphaltene deposition in porous media using microfluidic devices. A model oil containing 5 wt % dissolved asphaltenes was mixed with n-heptane, a known asphaltene precipitant, and flowed through a representative porous media microfluidic chip. Asphaltene deposition was recorded and analyzed as a function of solubility, which was directly correlated to particle size and Péclet number. In particular, pore-scale visualization and velocity profiles, as well as three stages of deposition, were identified and examined to determine the important convection−diffusion effects on deposition

Explicit factorization of external coordinates in constrained Statistical Mechanics models

If a macromolecule is described by curvilinear coordinates or rigid constraints are imposed, the equilibrium probability density that must be sampled in Monte Carlo simulations includes the determinants of different mass-metric tensors. In this work, we explicitly write the determinant of the mass-metric tensor G and of the reduced mass-metric tensor g, for any molecule, general internal coordinates and arbitrary constraints, as a product of two functions; one depending only on the external coordinates that describe the overall translation and rotation of the system, and the other only on the internal coordinates. This work extends previous results in the literature, proving with full generality that one may integrate out the external coordinates and perform Monte Carlo simulations in the internal conformational space of macromolecules. In addition, we give a general mathematical argument showing that the factorization is a consequence of the symmetries of the metric tensors involved. Finally, the determinant of the mass-metric tensor G is computed explicitly in a set of curvilinear coordinates specially well-suited for general branched molecules.Comment: 22 pages, 2 figures, LaTeX, AMSTeX. v2: Introduccion slightly extended. Version in arXiv is slightly larger than the published on

Basalt derived from highly refractory mantle sources during early Izu-Bonin-Mariana arc development

The magmatic character of early subduction zone and arc development is unlike mature systems. Low-Ti-K tholeiitic basalts and boninites dominate the early Izu-Bonin-Mariana (IBM) system. Basalts recovered from the Amami Sankaku Basin (ASB), underlying and located west of the IBM’s oldest remnant arc, erupted at ~49 Ma. This was 3 million years after subduction inception (51-52 Ma) represented by forearc basalt (FAB), at the tipping point between FAB-boninite and typical arc magmatism. We show ASB basalts are low-Ti-K, aluminous spinel-bearing tholeiites, distinct compared to mid-ocean ridge (MOR), backarc basin, island arc or ocean island basalts. Their upper mantle source was hot, reduced, refractory peridotite, indicating prior melt extraction. ASB basalts transferred rapidly from pressures (~0.7-2 GPa) at the plagioclase-spinel peridotite facies boundary to the surface. Vestiges of a polybaric-polythermal mineralogy are preserved in this basalt, and were not obliterated during persistent recharge-mix-tap-fractionate regimes typical of MOR or mature arcs

Is age a risk factor for Candida glabrata colonisation?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86861/1/j.1439-0507.2010.01941.x.pd

Protocol for the Foot in Juvenile Idiopathic Arthritis trial (FiJIA): a randomised controlled trial of an integrated foot care programme for foot problems in JIA

<b>Background</b>: Foot and ankle problems are a common but relatively neglected manifestation of juvenile idiopathic arthritis. Studies of medical and non-medical interventions have shown that clinical outcome measures can be improved. However existing data has been drawn from small non-randomised clinical studies of single interventions that appear to under-represent the adult population suffering from juvenile idiopathic arthritis. To date, no evidence of combined therapies or integrated care for juvenile idiopathic arthritis patients with foot and ankle problems exists. <b>Methods/design</b>: An exploratory phase II non-pharmacological randomised controlled trial where patients including young children, adolescents and adults with juvenile idiopathic arthritis and associated foot/ankle problems will be randomised to receive integrated podiatric care via a new foot care programme, or to receive standard podiatry care. Sixty patients (30 in each arm) including children, adolescents and adults diagnosed with juvenile idiopathic arthritis who satisfy the inclusion and exclusion criteria will be recruited from 2 outpatient centres of paediatric and adult rheumatology respectively. Participants will be randomised by process of minimisation using the Minim software package. The primary outcome measure is the foot related impairment measured by the Juvenile Arthritis Disability Index questionnaire's impairment domain at 6 and 12 months, with secondary outcomes including disease activity score, foot deformity score, active/limited foot joint counts, spatio-temporal and plantar-pressure gait parameters, health related quality of life and semi-quantitative ultrasonography score for inflammatory foot lesions. The new foot care programme will comprise rapid assessment and investigation, targeted treatment, with detailed outcome assessment and follow-up at minimum intervals of 3 months. Data will be collected at baseline, 6 months and 12 months from baseline. Intention to treat data analysis will be conducted. A full health economic evaluation will be conducted alongside the trial and will evaluate the cost effectiveness of the intervention. This will consider the cost per improvement in Juvenile Arthritis Disability Index, and cost per quality adjusted life year gained. In addition, a discrete choice experiment will elicit willingness to pay values and a cost benefit analysis will also be undertaken

Quantum mechanical calculation of the effects of stiff and rigid constraints in the conformational equilibrium of the Alanine dipeptide

If constraints are imposed on a macromolecule, two inequivalent classical models may be used: the stiff and the rigid one. This work studies the effects of such constraints on the Conformational Equilibrium Distribution (CED) of the model dipeptide HCO-L-Ala-NH2 without any simplifying assumption. We use ab initio Quantum Mechanics calculations including electron correlation at the MP2 level to describe the system, and we measure the conformational dependence of all the correcting terms to the naive CED based in the Potential Energy Surface (PES) that appear when the constraints are considered. These terms are related to mass-metric tensors determinants and also occur in the Fixman's compensating potential. We show that some of the corrections are non-negligible if one is interested in the whole Ramachandran space. On the other hand, if only the energetically lower region, containing the principal secondary structure elements, is assumed to be relevant, then, all correcting terms may be neglected up to peptides of considerable length. This is the first time, as far as we know, that the analysis of the conformational dependence of these correcting terms is performed in a relevant biomolecule with a realistic potential energy function.Comment: 37 pages, 4 figures, LaTeX, BibTeX, AMSTe