Functional interaction of diphenols with polyphenol oxidase - Molecular determinants of substrate/inhibitor specificity SO FEBS JOURNAL

Polyphenol oxidase (PPO) catalyzes the oxidation of o-diphenols to their respective quinones. The quinones autopolymerize to form dark pigments, an undesired effect. PPO is therefore the target for the development of antibrowning and antimelanization agents. A series of phenolic compounds experimentally evaluated for their binding affinity and inhibition constants were computationally docked to the active site of catechol oxidase. Docking studies suggested two distinct modes of binding, dividing the docked ligands into two groups. Remarkably, the first group corresponds to ligands determined to be substrates and the second group corresponds to reversible inhibitors. Analyses of the complexes provide structural explanations for correlating subtle changes in the position and nature of the substitutions on o-diphenols to their functional properties as substrates and inhibitors. Higher reaction rates and binding are reckoned by additional interactions of the substrates with key residues that line the hydrophobic cavity. The docking results suggest that inhibition of oxidation stems from an interaction between the aromatic carboxylic acid group and the apical His 109 of the four coordinates of the trigonal pyramidal coordination polyhedron of CuA. The spatial orientation of the hydroxyl in relation to the carboxylic group either allows a perfect fit in the substrate cavity, leading to inhibition, or because of a steric clash flips the molecule vertically, facilitating oxidation. This is the first study to explain, at the molecular level, the determinants Of substrate and inhibitor specificity of a catechol oxidase, thereby providing a platform for the design of selective inhibitors useful to both the food and pharmaceutical industries.

Experimental Demonstration of H{infty} Control based Active Vibration Suppression in Composite Fin-tip of Aircraft using Optimally Placed Piezoelectric Patch Actuators

The goal of this study is the multi-mode structural vibration control in the composite fin-tip of an aircraft. Structural model of the composite fin-tip with surface bonded piezoelectric actuators is developed using the finite element method. The finite element model is updated experimentally to reflect the natural frequencies and mode shapes accurately. A model order reduction technique is employed for reducing the finite element structural matrices before developing the controller. Particle swarm based evolutionary optimization technique is used for optimal placement of piezoelectric patch actuators and accelerometer sensors to suppress vibration. H{infty} based active vibration controllers are designed directly in the discrete domain and implemented using dSpace® (DS-1005) electronic signal processing boards. Significant vibration suppression in the multiple bending modes of interest is experimentally demonstrated for sinusoidal and band limited white noise forcing functions.

The profile of psychiatric symptoms exacerbated by methamphetamine use

Background Methamphetamine use can produce symptoms almost indistinguishable from schizophrenia. Distinguishing between the two conditions has been hampered by the lack of a validated symptom profile for methamphetamine-induced psychiatric symptoms. We use data from a longitudinal cohort study to examine the profile of psychiatric symptoms that are acutely exacerbated by methamphetamine use. Methods 164 methamphetamine users, who did not meet DSM-IV criteria for a lifetime primary psychotic disorder, were followed monthly for one year to assess the relationship between days of methamphetamine use and symptom severity on the 24-item Brief Psychiatric Rating Scale. Exacerbation of psychiatric symptoms with methamphetamine use was quantified using random coefficient models. The dimensions of symptom exacerbation were examined using principal axis factoring and a latent profile analysis. Results Symptoms exacerbated by methamphetamine loaded on three factors: positive psychotic symptoms (suspiciousness, unusual thought content, hallucinations, bizarre behavior); affective symptoms (depression, suicidality, guilt, hostility, somatic concern, self-neglect); and psychomotor symptoms (tension, excitement, distractibility, motor hyperactivity). Methamphetamine use did not significantly increase negative symptoms. Vulnerability to positive psychotic and affective symptom exacerbation was shared by 28% of participants, and this vulnerability aligned with a past year DSM-IV diagnosis of substance-induced psychosis (38% vs. 22%, _2 (df1) = 3.66, p = 0.056). Conclusion Methamphetamine use produced a symptom profile comprised of positive psychotic and affective symptoms, which aligned with a diagnosis of substance-induced psychosis, with no evidence of a negative syndrome.

Turbulent vertical fluxes and air quality measured in urban air in Helsinki

There is a growing need to understand the exchange processes of momentum, heat and mass between an urban surface and the atmosphere as they affect our quality of life. Understanding the source/sink strengths as well as the mixing mechanisms of air pollutants is particularly important due to their effects on human health and climate. This work aims to improve our understanding of these surface-atmosphere interactions based on the analysis of measurements carried out in Helsinki, Finland. The vertical exchange of momentum, heat, carbon dioxide (CO2) and aerosol particle number was measured with the eddy covariance technique at the urban measurement station SMEAR III, where the concentrations of ultrafine, accumulation mode and coarse particle numbers, nitrogen oxides (NOx), carbon monoxide (CO), ozone (O3) and sulphur dioxide (SO2) were also measured. These measurements were carried out over varying measurement periods between 2004 and 2008. In addition, black carbon mass concentration was measured at the Helsinki Metropolitan Area Council site during three campaigns in 1996-2005. Thus, the analyzed dataset covered far, the most comprehensive long-term measurements of turbulent fluxes reported in the literature from urban areas. Moreover, simultaneously measured urban air pollution concentrations and turbulent fluxes were examined for the first time. The complex measurement surrounding enabled us to study the effect of different urban covers on the exchange processes from a single point of measurement. The sensible and latent heat fluxes closely followed the intensity of solar radiation, and the sensible heat flux always exceeded the latent heat flux due to anthropogenic heat emissions and the conversion of solar radiation to direct heat in urban structures. This urban heat island effect was most evident during winter nights. The effect of land use cover was seen as increased sensible heat fluxes in more built-up areas than in areas with high vegetation cover. Both aerosol particle and CO2 exchanges were largely affected by road traffic, and the highest diurnal fluxes reached 109 m-2 s-1 and 20 µmol m-2 s-1, respectively, in the direction of the road. Local road traffic had the greatest effect on ultrafine particle concentrations, whereas meteorological variables were more important for accumulation mode and coarse particle concentrations. The measurement surroundings of the SMEAR III station served as a source for both particles and CO2, except in summer, when the vegetation uptake of CO2 exceeded the anthropogenic sources in the vegetation sector in daytime, and we observed a downward median flux of 8 µmol m-2 s-1. This work improved our understanding of the interactions between an urban surface and the atmosphere in a city located at high latitudes in a semi-continental climate. The results can be utilised in urban planning, as the fraction of vegetation cover and vehicular activity were found to be the major environmental drivers affecting most of the exchange processes. However, in order to understand these exchange and mixing processes on a city scale, more measurements above various urban surfaces accompanied by numerical modelling are required.

Unlocking the potential of bile acids in synthesis, supramolecular/materials chemistry and nanoscience

The Maitra group has explored a variety of chemistry with bile acids during the past 15 years and these experiments have covered a wide variety of chemistry - asymmetric synthesis, molecular recognition, ion receptors/sensors, dendrimers, low molecular mass organo and hydrogelators, gel-nanoparticle composites, etc. Some of what excites us in this field is highlighted in this perspective article.

Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial

Background The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting. Methods This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660. Findings Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3–33·9). Progression-free survival (median 11·0 months [95% CI 10·6–12·9] with afatinib vs 10·9 months [9·1–11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57–0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9–15·0] with afatinib vs 11·5 months [10·1–13·1] with gefitinib; HR 0·73 [95% CI 0·58–0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure. Interpretation Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.

Exfoliation of alpha-hydroxides of nickel and cobalt in water

p-Aminobenzoate ion intercalated alpha-hydroxides of nickel/cobalt were synthesized by precipitation using ammonia (pH = similar to 12). Aqueous colloidal suspension of alpha-hydroxide of nickel/cobalt was obtained on washing the precipitate as the pH was reduced to similar to 7. The development of partial positive charge on the amine end of the intercalated anion causes repulsion between the layers leading to exfoliation and colloidal suspension of monolayers in water. While theb layers could be restacked from the colloidal suspension in the presenceof other anions in the case of alpha-cobalt hydroxide, the exfoliation could not be reversed easily in the case of the nickel analog. (C) 2010 Elsevier Inc. All rights reserved.

Vaikeavammaisen nuoren aikuistuminen : Yksilöllinen ja erilainen elämänkulku

Transition to adulthood of severely disabled adolescents. Diversity in individual life courses. The focus of this study is to examine the transition to adulthood of severely disabled adolescents as part of their life course. The data for this study were gathered through interviews with nine severely disabled adolescents, who were interviewed several times over a period of eight years. At the beginning of the study the adolescents were between 18 and 24 years old. The informants had severe disabilities manifesting themselves as physical incapacity, cerebral palsy, vision or hearing impairment, neurological disease, or developmental disability. One of the adolescents communicated with symbols. All except one used a wheelchair. As severely disabled adolescents, they received benefits from Kela for persons with severe disabilities, such as the higher-rate or special disability allowance or disability pension, the higher-rate or special pensioners' care allowance, or medical rehabilitation services. The interviews focused on a number of selected themes such as relationships, family, education, work, leisure-time activities, dating, decision-making, independence, happiness, and one s self-image and identity. Data were also derived from interviews with five experts. Two of the experts interviewed were severely disabled themselves. The theoritical foundation of the study lies in perviuos research on the severly disabled, the transition to adulthood and the life course. The method of analysis and interpretation is qualitative and based on interviews with the adolescents. In terms of the analytical process, the focus is on recognizing individual events in the transition process to adulthood and identifying the meanings assigned to them by the adolescents. The narratives also provide a method to shed light on the individuality of the transition. The individual situations of severely disabled adolescents vary, and their disability impacts the range of options available to them as they plan their life course. The medical and social models of disability also have an effect on life courses. Although severely disabled adolescents are able to attain some goals, they remain outsiders in many respects. Key words: Disabled person, severely disabled person, adolescent, transition to adulthood, identity, life course.

Studies on structural and electrical properties of sprayed SnO2 : Sb films

Thin films of antimony-doped tin oxide (SnO2:Sb) were prepared by spray pyrolysis using stannous chloride (SnCl2) and antimony trichloride (SbCl3) as precursors. The antimony doping was varied from 0 to 4 wt%. Scanning electron microscopy (SEM) revealed the surface morphology to be very smooth, yet grainy in nature. X-ray diffraction (XRD) shows films to have preferred orientation, which varies with the extent of antimony doping: undoped films prefer the (2 1 1) orientation, while the (3 0 1) orientation is preferred for doping levels of 0.5 and 1.0 wt%. For higher doping levels, the (2 0 0) orientation is preferred. This difference in preferred orientations is reflected in the SEM of the films. Atomic force microscopy (AFM) reveals that film roughness is not affected by antimony doping. The minimum sheet resistance (2.17 ohm/square) achieved in the present study is lower than values reported to date in SnO2:Sb films prepared from SnCl2 precursor. The Hall mobility of undoped SnO2 films was found to be 109.52 cm(2)/V s, which reduces to 2.55 cm(2)/ Vs for the films doped with 4 wt% of Sb. On the other hand, the carrier concentration, which is 1.23 x 10(19) cm(-3) in undoped films, increases to 2.89 x 10(21) cm(-3) for the films doped with 4 wt% of Sb. (c) 2004 Elsevier B.V. All rights reserved.

Conformation of di-n-propylglycine residues (Dpg) in peptides: crystal structures of a type I 'beta-turn forming tetrapeptide and an alpha-helical tetradecapeptide

The crystal structures of two oligopeptides containing di-n-propylglycine (Dpg) residues, Boc-Gly-Dpg-Gly-Leu-OMe (1) and Boc-Val-Ala-Leu-Dpg-Val-Ala-Leu-Val-Ala-Leu-Dpg-Val-Ala-Leu-OMe (2) are presented. Peptide 1 adopts a type I' beta-turn conformation with Dpg(2)-Gly(3) at the corner positions. The 14-residue peptide 2 crystallizes with two molecules in the asymmetric unit, both of which adopt alpha-helical conformations stabilized by 11 successive 5 -> 1 hydrogen bonds. In addition, a single 4 -> 1 hydrogen bond is also observed at the N-terminus. All live Dpg residues adopt backbone torsion angles (phi, psi) in the helical region of conformational space. Evaluation of the available structural data on Dpg peptides confirm the correlation between backbone bond angle N-C-alpha-C' (tau) and the observed backbone phi,psi values. For tau > 106 degrees, helices are observed, while fully extended structures are characterized by tau < 106 degrees. The mean r values for extended and folded conformations for the Dpg residue are 103.6 degrees +/- 1.7 degrees and 109.9 degrees +/- 2.6 degrees, respectively. Copyright (C) 2007 European Peptide Society and John Wiley & Sons, Ltd.

Vaikuttavuusyhteiskunta : Sosiaalisten olojen arvostelusta vaikutusten todentamiseen

Evaluation practices have pervaded the Finnish society and welfare state. At the same time the term effectiveness has become a powerful organising concept in welfare state activities. The aim of the study is to analyse how the outcome-oriented society came into being through historical processes, to answer the question of how social policy and welfare state practices were brought under the governance of the concept of effectiveness . Discussions about social imagination, Michel Foucault s conceptions of the history of the present and of governmentality, genealogy and archaeology, along with Ian Hacking s notions of dynamic nominalism and styles of reasoning, are used as the conceptual and methodological starting points for the study. In addition, Luc Boltanski s and Laurent Thévenot s ideas of orders of worth , regimes of evaluation in everyday life, are employed. Usually, evaluation is conceptualised as an autonomous epistemic culture and practice (evaluation as epistemic practice), but evaluation is here understood as knowledge-creation processes elementary to different epistemic practices (evaluation in epistemic practices). The emergence of epistemic cultures and styles of reasoning about the effectiveness or impacts of welfare state activities are analysed through Finnish social policy and social work research. The study uses case studies which represent debates and empirical research dealing with the effectiveness and quality of social services and social work. While uncertainty and doubts over the effects and consequences of welfare policies have always been present in discourses about social policy, the theme has not been acknowledged much in social policy research. To resolve these uncertainties, eight styles of reasoning about such effects have emerged over time. These are the statistical, goal-based, needs-based, experimental, interaction-based, performance measurement, auditing and evidence-based styles of reasoning. Social policy research has contributed in various ways to the creation of these epistemic practices. The transformation of the welfare state, starting at the end of 1980s, increased market-orientation and trimmed public welfare responsibilities, and led to the adoption of the New Public Management (NPM) style of leadership. Due to these developments the concept of effectiveness made a breakthrough, and new accountabilities with their knowledge tools for performance measurement and auditing and evidence-based styles of reasoning became more dominant in the ruling of the welfare state. Social sciences and evaluation have developed a heteronomous relation with each other, although there still remain divergent tendencies between them. Key words: evaluation, effectiveness, social policy, welfare state, public services, sociology of knowledge

Kelan järjestämän kuntoutuksen kohdentuminen ja vaikutukset työkykyyn kunnallisilla työpaikoilla

Tutkimuksessa selvitettiin Kansaneläkelaitoksen (Kelan) järjestämän kuuden yleisimmän työssä käyvälle väestölle tarkoitetun kuntoutusmuodon kohdentumista kuntatyöntekijöille (n = 67 106 henkilöä). Lisäksi selvitettiin Kelan järjestämän tuki- ja liikuntaelinkuntoutuksen ja ASLAKkurssien vaikutuksia työkykyyn sekä verrattiin kahta fibromyalgiaa sairastaville tarkoitettua kuntoutusmuotoa. Muuttujatiedot kerättiin työnantajien omista ja kansallisista rekistereistä. Naiset olivat Kelan järjestämässä kuntoutuksessa yliedustettuina ja määräaikaisessa työsuhteessa työskentelevät aliedustettuina. Selkäkipukuntoutukseen osallistuneiden ja työnantajien palveluksessa seurannan loppuun saakka olleiden vuosittaiset hyvin pitkät sairauspoissaolot vähenivät kolmen kuntoutuksen jälkeisen vuoden ajaksi. Niskakipukuntoutukseen osallistuneilla ei todettu tätä muutosta. ASLAK-kuntoutukseen osallistuneiden sairauspoissaolopäivät ja hyvin pitkät sairauspoissaolokerrat vähenivät kuntoutusvuonna ja kolmena sen jälkeisenä vuonna samalle tasolle kuin kuntoutukseen osallistumattomilla kaltaistetuilla verrokeilla. Työkyvyttömyyseläkkeen riski oli kuntoutujilla neljän kuntoutuksen jälkeisen vuoden aikana verrokkeja pienempi. Fibromyalgiaa sairastavien kahden kuntoutusmuodon (fibromyalgiakurssi ja epäspesifinen tules-kuntoutus) vertailussa ei kuntoutuksen vaikutuksissa työkykykyyn todettu eroa. Kelan järjestämän kuntoutuksen sisällössä tarvitaan kriittistä arviointia, tutkimusta ja kehitystyötä, jotta yhteiskunnan odotus vaikuttavuudesta toteutuu.

Orientational melting and reorientational motion in a cubane molecular crystal: A molecular simulation study

Detailed molecular simulations are carried out to investigate the effect of temperature on orientational order in cubane molecular crystal. We report a transition from an orientationally ordered to an orientationally disordered plastic crystalline phase in the temperature range 425-450 K. This is similar to the experimentally reported transition at 395 K. The nature of this transition is first order and is associated with a 4.8% increase in unit Cell volume that is comparable to the experimentally reported unit cell volume change of 5.4% (Phys. Rev. Lett. 1997, 78, 4938). An orientational order parameter, eta(T), has been defined in terms of average angle of libration of a molecular 3-fold axis and the orientational melting has been characterized by using eta(T). The orientational melting is associated with an anomaly in specific heat at constant pressure (C-p) and compressibility (kappa). The enthalpy of transition and entropy of transition associated with this orientational melting are 20.8 J mol(-1) and 0.046 J mol(-1) K-1, respectively. The structure of crystalline as well as plastic crystalline phases is characterized by using various radial distribution functions and orientational distribution functions. The coefficient of thermal expansion of the plastic crystalline phase is more than twice that of the crystalline phase.

Suomalaiset lääkärit ja Suomen Lääkäriliitto osana hyvinvointivaltiota ja sen terveyspolitiikkaa

Tässä julkaisussa selvitetään Suomen Lääkäriliiton ideoita (makrotaso) ja lääkäreiden (mikrotaso) mielipiteitä hyvinvointivaltiosta ja sen terveyspolitiikasta. Makrotason aineiston muodostavat erilaiset julkiset dokumentit. Aineistot ovat pääosin vuosilta 1970–2007. Dokumentteja analysoidaan sekä määrällisen että laadullisen sisällönanalyysin tai erittelyn keinoin. Mikrotason aineiston muodostaa vuonna 2007 kerätty kyselyaineisto (n = 1 092). Sitä analysoidaan kuvailevin tilastollisin menetelmin ja logistisen regressioanalyysin keinoin. Tulosten perusteella Suomen Lääkäriliitto koki julkisen vallan puuttumisen uhkaksi rakennettaessa universaalia terveydenhuoltojärjestelmää. Uhka kuitenkin väheni julkisen sektorin jatkuvasti laajentuessa. Toisaalta jatkuvana vaatimuksena Lääkäriliiton dokumenteissa esiintyy 1970-luvulta lähtien yksityisen sektorin roolin lisäämisvaateet. 1990-luvun laman jälkeisenä aikana yksityiseen sektoriin liittyvät ideat ovat tulleet yhä selkeämmiksi ja konkreettisemmiksi. Argumenteissaan Lääkäriliitto ei tuo juurikaan esille omia taloudellisia intressejään vaan vetoaa useammin yleiseen hyvään. Kyselyaineistosta tehtyjen analyysien mukaan lääkärit kokevat sosiaaliturvan muuta väestöä useammin liian laajaksi. Lääkärit eivät kuitenkaan halua erityisen voimakkaasti markkinoistaa terveydenhuoltoa, jopa verrattaessa muuhun väestöön. Parhaiten lääkäreiden mielipiteitä sosiaaliturvasta ja terveydenhuoltojärjestelmästä selittävät poliittinen orientaatio ja työskentelysektori. Nuorten lääkäreiden mielipiteet sosiaaliturvasta ja terveydenhuoltojärjestelmästä eivät ole erityisen radikaaleja. Lopuksi tutkimuksessa verrattiin mikro- ja makrotasoa keskenään. Tulosten perusteella Suomen Lääkäriliitto on selvästi radikaalimpi näkemyksissään markkinoistumisesta kuin lääkärit keskimäärin.