Ab-Initio-Based Kinetic Modeling to Understand RAFT Exchange: The Case of 2-Cyano-2-Propyl Dodecyl Trithiocarbonate and Styrene.

Ab-initio-calculated rate coefficients for addition and fragmentation in reversible-addition fragmentation chain transfer (RAFT) polymerization of styrene with 2-cyano-2-propyl dodecyl trithiocarbonate initiated by azobisisobutyronitrile allow the reliable simulation of the experimentally observed conversion, number average chain length, and dispersity. The rate coefficient for addition of a macroradical Ri to the macroRAFT agent Ri X at 333 K (6.8 104 L mol-1 s-1 ) is significantly lower than to the initial RAFT agent R0 X (3.2 106 L mol-1 s-1 ), mainly due to a difference in activation energy (15.4 vs 3.0 kJ mol-1 ), which causes the dispersity to spike in the beginning of the polymerization.

Essential medicines for cancer: WHO recommendations and national priorities.

OBJECTIVE: To examine, for essential anti-cancer medicines, the alignment of national lists of essential medicines and national reimbursable medicines lists with the World Health Organization's (WHO's) Model Lists. METHODS: National medicine lists for 135 countries with per-capita gross national incomes below 25 000 United States dollars in 2015 were compared with WHO's 2013 and 2015 Model Lists of Essential Medicines. Correlations between numbers of anti-cancer medicines included in national lists and gross national income (GNI), government health expenditure and number of physicians per 1000 population were evaluated. FINDINGS: Of the 25 anti-cancer medicines on the 2013 Model List and the 16 added via the 2015 revision of the Model List, 0-25 (median: 17) and 0-15 (median: 3) appeared in national lists, respectively. There was considerable variability in these numbers within and between World Bank income groups. Of the 16 new medicines included in the 2015 Model List, for example, 0-10 (median: 1) and 2-15 (median: 10) were included in the national lists of low-income and high-income countries, respectively. The numbers of these new medicines included in national lists were significantly correlated (P ≤ 0.0001) with per-capita GNI (r = 0.45), per-capita annual government health expenditure (r = 0.33) and number of physicians per 1000 population (r = 0.48). Twenty-one countries (16%) included the targeted anti-cancer medicines imatinib, rituximab and trastuzumab in their national lists. CONCLUSION: Substantial numbers of anti-cancer medicines are included in national lists of low- and middle-income countries but the availability, affordability, accessibility and administration feasibility of these medicines, at country-level, need assessment.

Computational Investigation of the Aminolysis of RAFT Macromolecules.

This work presents a detailed computational study and kinetic analysis of the aminolysis of dithioates, dithiobenzoates, trithiocarbonates, xanthates, and thiocarbamates, which are frequently used as chain-transfer agents for reversible addition-fragmentation chain-transfer (RAFT) polymerization. Rate coefficients were obtained from ab initio calculations, taking into account a diffusional contribution according to the encounter pair model. A kinetic model was constructed and reveals a reaction mechanism of four elementary steps: (i) formation of a zwitterionic intermediate, (ii) formation of a complex intermediate in which an assisting amine molecule takes over the proton from the zwitterionic intermediate, (iii) breakdown of the complex into a neutral tetrahedral intermediate with release of the assisting amine molecule, and (iv) amine-assisted breakdown of the neutral intermediate to the products. Furthermore, a comparative analysis indicates that the alkanedithioates and dithiobenzoates react the fastest, followed, respectively, by xanthates and trithiocarbonates, which react almost equally fast, and dithiocarbamates, which are not reactive at typical experimentally used conditions.

Quantitative First-Principles Kinetic Modeling of the Aza-Michael Addition to Acrylates in Polar Aprotic Solvents.

This work presents a detailed computational study and kinetic analysis of the aza-Michael addition of primary and secondary amines to acrylates in an aprotic solvent. Accurate rate coefficients for all elementary steps in the various competing mechanisms are calculated using an ONIOM-based approach in which the full system is calculated with M06-2X/6-311+G(d,p) and the core system with CBS-QB3 corrected for solvation using COSMO-RS. Diffusional contributions are taken into account using the coupled encounter pair model with diffusion coefficients calculated based on molecular dynamics simulations. The calculated thermodynamic and kinetic parameters for all forward and reverse elementary reactions are fed to a microkinetic model giving excellent agreement with experimental data obtained using GC analysis. Rate analysis reveals that for primary and secondary amines, the aza-Michael addition to ethyl acrylate occurs preferentially according to a 1,2-addition mechanism, consisting of the pseudoequilibrated formation of a zwitterion followed by a rate controlling amine assisted proton transfer toward the singly substituted product. The alternative 1,4-addition becomes competitive if substituents are present on the amine or double bond of the acrylate. Primary amines react faster than secondary amines due to increased solvation of the zwitterionic intermediate and less sterically hindered proton transfer.

Mechanism and function of monoclonal antibodies targeting siglec-15 for therapeutic inhibition of osteoclastic bone resorption.

The use of monoclonal antibodies to target functionally important cell-surface proteins on bone-resorbing osteoclasts represents a promising approach for treatment of cancer-associated bone loss and other skeletal pathologies. Previously, we identified Siglec-15, a little studied sialic acid-binding receptor, as a candidate target that is highly up-regulated during osteoclast differentiation induced by the cytokine receptor activator of NF-κB ligand (RANKL). In this report, we confirm that Siglec-15 is localized to the plasma membrane where it can be targeted by monoclonal antibodies to inhibit differentiation of functional osteoclasts in vitro. Furthermore, we found that treatment of mice with these antibodies led to a marked increase in bone mineral density, consistent with inhibition of osteoclast activity. Interestingly, osteoblast numbers were maintained despite the anti-resorptive activity. At the molecular level, Siglec-15 interacts with the adapter protein DAP12 and can induce Akt activation when clustered on the osteoclast cell surface, which likely represents its normal signaling function. Importantly, we discovered that monoclonal antibodies induce rapid internalization, lysosomal targeting, and degradation of Siglec-15 by inducing receptor dimerization. This study defines a key regulatory node that controls osteoclast differentiation and activity downstream of RANKL and supports further development of Siglec-15 antibodies as a novel class of bone loss therapeutics.

Conservatism and novelty in the genetic architecture of adaptation in Heliconius butterflies.

Understanding the genetic architecture of adaptive traits has been at the centre of modern evolutionary biology since Fisher; however, evaluating how the genetic architecture of ecologically important traits influences their diversification has been hampered by the scarcity of empirical data. Now, high-throughput genomics facilitates the detailed exploration of variation in the genome-to-phenotype map among closely related taxa. Here, we investigate the evolution of wing pattern diversity in Heliconius, a clade of neotropical butterflies that have undergone an adaptive radiation for wing-pattern mimicry and are influenced by distinct selection regimes. Using crosses between natural wing-pattern variants, we used genome-wide restriction site-associated DNA (RAD) genotyping, traditional linkage mapping and multivariate image analysis to study the evolution of the architecture of adaptive variation in two closely related species: Heliconius hecale and H. ismenius. We implemented a new morphometric procedure for the analysis of whole-wing pattern variation, which allows visualising spatial heatmaps of genotype-to-phenotype association for each quantitative trait locus separately. We used the H. melpomene reference genome to fine-map variation for each major wing-patterning region uncovered, evaluated the role of candidate genes and compared genetic architectures across the genus. Our results show that, although the loci responding to mimicry selection are highly conserved between species, their effect size and phenotypic action vary throughout the clade. Multilocus architecture is ancestral and maintained across species under directional selection, whereas the single-locus (supergene) inheritance controlling polymorphism in H. numata appears to have evolved only once. Nevertheless, the conservatism in the wing-patterning toolkit found throughout the genus does not appear to constrain phenotypic evolution towards local adaptive optima.

Computational Study and Kinetic Analysis of the Aminolysis of Thiolactones.

The aminolysis of three differently α-substituted γ-thiolactones (C4H5OSX, X = H, NH2, and NH(CO)CH3) is modeled based on CBS-QB3 calculated free energies corrected for solvation using COSMO-RS. For the first time, quantitative kinetic and thermodynamic data are provided for the concerted path and the stepwise path over a neutral tetrahedral intermediate. These paths can take place via an unassisted, an amine-assisted, or a thiol-assisted mechanism. Amine assistance lowers the free energy barriers along both paths, while thiol assistance only lowers the formation of the neutral tetrahedral intermediate. Based on the ab initio calculated rate coefficients, a kinetic model is constructed that is able to reliably describe experimental observations for the aminolysis of N-acetyl-dl-homocysteine thiolactone with n-butylamine in THF and CHCl3. Reaction path analysis shows that for all conditions relevant for applications in polymer synthesis and postpolymer modification, an assisted stepwise mechanism is operative in which the formation of the neutral tetrahedral intermediate is rate-determining and which is mainly amine-assisted at low conversions and thiol-assisted at high conversions.

Induced superconductivity in graphene grown on rhenium.

We report a new way to strongly couple graphene to a superconductor. The graphene monolayer has been grown directly on top of a superconducting Re(0001) thin film and characterized by scanning tunneling microscopy and spectroscopy. We observed a moiré pattern due to the mismatch between Re and graphene lattice parameters that we have simulated with ab initio calculations. The density of states around the Fermi energy appears to be position dependent on this moiré pattern. Tunneling spectroscopy performed at 50 mK shows that the superconducting behavior of graphene on Re is well described by the Bardeen-Cooper-Schrieffer theory and stands for a very good interface between the graphene and its metallic substrate.

Extracellular acidification enhances osteoclast survival through an NFAT-independent, protein kinase C-dependent pathway.

Systemic acidosis has detrimental effects on the skeleton and local acidosis is associated with bone destruction in inflammatory and neoplastic diseases. However, the mechanisms by which acidosis enhances osteoclastic bone resorption are poorly understood. Our aim was to examine the effects of acid on osteoclast survival and the involvement of cytosolic Ca(2+) in mediating these effects. Osteoclasts were isolated from long bones of newborn rats, and multinucleated osteoclast-like cells were generated from RAW 264.7 cells. Cytosolic free Ca(2+) concentration ([Ca(2+)](i)) was monitored using fura-2. Survival of rat osteoclasts over a period of 18 h was significantly enhanced by acidification of the medium from 40+/-10% at pH 7.6 to 83+/-4% at pH 7.0. Consistent with its effects on survival, acidosis suppressed osteoclast apoptosis at 6 h. We examined the possible involvement of the proton-sensing receptor ovarian cancer G protein-coupled receptor 1 (OGR1) in mediating the effects of acid. Acid-induced rise of [Ca(2+)](i) was inhibited by the OGR1 antagonist Cu(2+) and was suppressed in osteoclast-like cells in which OGR1 transcripts were depleted using RNA interference. These findings support an essential role for OGR1 in acid-induced Ca(2+) signaling in osteoclasts. Addition of Cu(2+) or chelation of cytosolic Ca(2+) with BAPTA abolished the ability of acidification to enhance osteoclast survival. Inhibition of NFAT activation with the cell-permeable peptide 11R-VIVIT did not alter the ability of acid to promote survival; however, it suppressed the increase in survival induced by RANKL. In contrast, inhibition of protein kinase C (PKC) blocked the effect of acid on osteoclast survival. Thus, this study reveals that extracellular acidification enhances osteoclast survival through an NFAT-independent, PKC-dependent pathway. Increased osteoclast survival may contribute to bone loss in systemic and local acidosis.

Lifting the mirror symmetry of metal surfaces: decoupling the electronic and physical manifestations of surface chirality.

Naturally occurring metal surfaces possess planes of mirror symmetry on the nanometer-length scale. This mirror symmetry can be lifted and chirality "physically" conveyed onto a surface by adsorbing a chiral molecule. Until now, it has not been known whether the conveying of chirality is limited to just the physical structure or whether it goes deeper and permeates the electronic structure of the underlying surface. By using optically active second harmonic generation (OA-SHG), it is demonstrated that the adsorption of some, but not all, chiral molecules can reversibly, and without significant structural rearrangement, measurably lift the mirror symmetry of the surface electronic structure of a metal. It is proposed that the ability of a chiral molecule to place a significant "chiral perturbation" on the electronic structure of a surface is correlated to its adsorption geometry. The microscopic origins of the observed optical activity are also discussed in terms of classical models of chirality. The results of the study challenge current models of how chiral adsorbates induce enantioselectivity in the chemical/physical behavior of heterogeneous systems, which are based on geometric/stereochemical arguments, by suggesting that chiral electronic perturbations could play a role.

Coregulators of estrogen receptor action.

The estrogen receptors are members of a large family of transcription factors, which include receptors for steroid hormones, retinoids, vitamin D and thyroid hormone, as well as several orphan receptors with yet undiscovered ligands. The process by which small lipophilic molecules signal in target tissues is complex and involves nuclear receptor associations with a multitude of coregulator proteins. These proteins participate in and recruit many enzymatic and structural activities that allow modulation of chromatin structure to facilitate stimulation or repression of gene expression. This review will present an overview of those regulatory factors that interact with the estrogen receptors and participate in the transmission of the estrogenic signal.

Synthesis and evaluation of a novel nonsteroidal-specific endothelial cell proliferation inhibitor.

The identification of agents with specific antiproliferative or cytostatic activity against endothelial cells has significant value for the treatment of pathologies associated with angiogenesis, including solid tumors. Here, we describe a novel substituted dibenzo[b,d]pyran-6-one scaffold, exemplified by structures 9a and 10, and report preliminary in vitro activity data indicating that this scaffold is a promising lead for the development of specific inhibitors of endothelial cell proliferation.

De novo design, synthesis, and evaluation of novel nonsteroidal phenanthrene ligands for the estrogen receptor.

Although there are many estrogen receptor antagonists with improved tissue selectivity profiles compared with tamoxifen, optimal tissue selectivity has not yet been demonstrated. As such there is still a need for additional diversity and new chemical scaffolds to allow for exploration of improved tissue selectivity. Here, we describe the discovery of a novel phenanthrene scaffold for estrogen receptor ligands utilizing a ligand based de novo design approach. The nanomolar binding of phenanthrenes, 12b,c, 14b,c, and 15 against human recombinant ER(alpha) indicates that our ligand based de novo design approach was successful. From a gene transfection assay, 12b,c, 14b,c, and 15 displayed only antagonistic activity with no observable agonistic activity. The alkyl 9,10-dihydrophenanthrene 16 (presumably a racemic mixture) was a substantially more potent ER binder than the phenanthrenes. It also displayed only antagonistic activity and was effective at inhibiting estradiol stimulated MCF-7 cell proliferation. These results demonstrate that this phenanthrene (and 9,10-dihydrophenanthrene) scaffold warrants further study as potential selective estrogen receptor modulators and/or pure antiestrogens.

Metered dose inhalers for bronchodilator delivery in intubated, mechanically ventilated patients.

We determined the relative efficacy of two bronchodilator aerosol delivery methods in 18 intubated mechanically ventilated patients with airways obstruction. Two treatment arms, consisting of albuterol 270 micrograms (three puffs) from a metered dose inhaler and albuterol 2.5 mg from a saline solution nebulized with an updraft inhaler, were compared in a single blind, randomized crossover design. Pulmonary function was evaluated using an interrupter technique. Changes in passive expiratory flow at respiratory system recoil pressures between 6 and 10 cm H2O provided the therapeutic endpoints. Paired measurements were made before and 30 minutes after drug delivery. The MDI and NEB resulted in similar improvements in iso-recoil flow (mean increase for both groups = 0.1 L/s). Treatment sequence, severity of obstruction, and bronchodilator responsiveness had no effect on relative efficacy. Albuterol caused a small but significant increase in heart rate that was similar following both delivery methods. We conclude that bronchodilator aerosol delivery with metered dose inhalers provides a viable alternative to nebulizer therapy in intubated mechanically ventilated patients and may result in a cost savings to hospitals and patients.

Chiral discrimination within disordered adlayers on metal surfaces.

Using a novel non-linear optical technique enantiomeric excess within a translationally disordered overlayer on a metal surface has been monitored for the first time.

[Significance of ST segment depression in the precordial leads during the acute phase of inferior myocardial infarction]. / Signification du sous-décalage du segment ST dans les dérivations précordiales à la phase aiguë de l'infarctus du myocarde inférieur.

Reciprocal changes of the ST segment in the acute phase of inferior myocardial infarction are common but their significance remain controversial. We studied this problem by comparing the ECG on admission of 83 patients with acute inferior myocardial infarction, with the clinical outcome and haemodynamic and angiographic data obtained on average 3 weeks after the onset of symptoms. Fifty nine patients (Group I) had ST depression greater than or equal to 1 mm in at least one of the leads V1 to V4; 24 patients (Group II) had no ST depression in this territory. The patients in Group I were older (59.6 +/- 6.4 vs 54 +/- 5.3 years, p less than 0.01), had higher total CPK (1 835 +/- 940 vs 875 +/- 305, p less than 0.01) and MB fractions (269 +/- 102 vs 95 +/- 35), more complications during the hospital period (80%, mainly haemodynamic vs 38%, p less than 0.01) and more severe left ventricular dysfunction: ejection fraction 52.2 +/- 6% vs 59.2 +/- 7%, p less than 0.05; cardiac index 2.75 +/- 0.4 l/min/m2 vs 3.25 +/- 0.3 l/min/m2, p less than 0.005). There was no difference in left ventricular wall motion between the groups on biplane angiography. However, coronary angiography showed left coronary disease to be more common in Group I (84%) than in Group II (37%), p less than 0.005. Left anterior descending and left circumflex disease was equally common. Patients with persistent ST depression after 48 hours had lower ejection fractions than those in whom it regressed within 48 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of facial burns on the family.

At the University Burn Unit in Leuven (Belgium), we have been working for 4 years now with a multidisciplinary reintegration program. Our team consists of a plastic surgeon (head of the unit), a physical therapist, a social worker and a child psychiatrist. We set up family, context-oriented counselling for the families of seriously burned patients. In this paper, we would like to illustrate some aspects of the importance of facial scars in our society as well as the consequences of such scars for the families of patients. These are 2 essential aspects which have to be taken into account so that the counsellors and family do not reach a deadlock. We discuss how this therapy can be applied. Cooperation with the school is a keystone in the application of such therapy. The teacher is involved as a reflection of the feelings of the parents. Via this intermediary they learn how to cope with their feelings and to talk about them. The team has experienced this as an important step in the construction of family therapy.

[Marchiafava-Bignani disease of good prognosis. Two cases]. / Maladie de Marchiafava-Bignami d'évolution favorable. Deux observations.

BACKGROUND: Marchiafava-Bignami disease or corpus callosum necrosis, is an uncommon complication of chronic alcoholism. Prognosis is severe. CASE REPORTS: Two young adults with chronic alcoholism who developed Marchiafava-Bignami disease initially improved clinically. DISCUSSION: Diagnosis has been facilitated with MRI. An MRI exploration should be performed in chronic alcoholic patients presenting chronic encephalopathy with dementia, dysarthria, hypertonia, and ataxia, or acute encephalopathy with confusion, dumbness, seizures, and hypertonia. Necrosis of the corpus callosum gives the diagnosis of Marchiafava-Bignami disease.

[A severe form of external otitis: necrosing diabetic otitis]. / Une forme grave d'otite externe: l'otite nécrosante des diabétiques.

Otitis externa are of usual observation in inter-tropical regions. Pseudomonas aeruginosa is responsible generally. But, when immunodeficiency is associated or on diabetic diathesis, such an otitis externa can be extremely dangerous: extensive osteitis of the base of the skull, paralysis of the last pairs of cervical nerves rapidly creeping, built a clinical identity called malignant external otitis, leading to death in 50% of the cases.

A portable transfer chamber for electrochemical measurements on electrodes prepared in ultra-high vacuum.

This paper describes a versatile, light weight, and portable chamber dedicated to the transfer of electrodes from ultra-high vacuum (UHV) to atmospheric pressure and the liquid phase. This chamber can be connected to a liquid-phase reaction cell to perform electrochemical measurements and transfer back the electrode to the UHV environment. The experimental set-up can also be turned in order to make the electrode the bottom of the electrochemical cell. The validity and the efficiency of the experimental set-up were tested with a Pt(111) surface that provides unique electrochemical features in acidic sulphate-containing solution. This transfer chamber concept provides the surface science community with a new and versatile tool, complementary to existing systems, which allows fast electrolyte purging or electrochemical measurements under well-controlled mass transport conditions.