Антипсихотические лекарственные средства. Риск развития экстрапирамидных нарушений и/или абстинентного синдрома у новорожденных, матери которых принимали вышеуказанные лекарственные средства в течение третьего триместра беременности

ЛЕКАРСТВАТРАНКВИЛИЗАТОРЫ БОЛЬШИ

BMP4 inhibits myogenic differentiation of bone marrow–derived mesenchymal stromal cells in mdx mice

AbstractBackground aimsBone marrow–derived mesenchymal stromal cells (BMSCs) are a promising therapeutic option for treating Duchenne muscular dystrophy (DMD). Myogenic differentiation occurs in the skeletal muscle of the mdx mouse (a mouse model of DMD) after BMSC transplantation. The transcription factor bone morphogenic protein 4 (BMP4) plays a crucial role in growth regulation, differentiation and survival of many cell types, including BMSCs. We treated BMSCs with BMP4 or the BMP antagonist noggin to examine the effects of BMP signaling on the myogenic potential of BMSCs in mdx mice.MethodsWe added BMP4 or noggin to cultured BMSCs under myogenic differentiation conditions. We then injected BMP4- or noggin-treated BMSCs into the muscles of mdx mice to determine their myogenic potential.ResultsWe found that the expression levels of desmin and myosin heavy chain decreased after treating BMSCs with BMP4, whereas the expression levels of phosphorylated Smad, a downstream target of BMP4, were higher in these BMSCs than in the controls. Mdx mouse muscles injected with BMSCs pretreated with BMP4 showed decreased dystrophin expression and increased phosphorylated Smad levels compared with muscles injected with non-treated BMSCs. The opposite effects were seen after pretreatment with noggin, as expected.ConclusionsOur results identified BMP/Smad signaling as an essential negative regulator of promyogenic BMSC activity; inhibition of this pathway improved the efficiency of BMSC myogenic differentiation, which suggests that this pathway might serve as a target to regulate BMSC function for better myogenic differentiation during treatment of DMD and degenerative skeletal muscle diseases

Molecular differences in brain regional vulnerability to aging between males and females

BackgroundAging-related cognitive decline is associated with brain structural changes and synaptic loss. However, the molecular mechanisms of cognitive decline during normal aging remain elusive.ResultsUsing the GTEx transcriptomic data from 13 brain regions, we identified aging-associated molecular alterations and cell-type compositions in males and females. We further constructed gene co-expression networks and identified aging-associated modules and key regulators shared by both sexes or specific to males or females. A few brain regions such as the hippocampus and the hypothalamus show specific vulnerability in males, while the cerebellar hemisphere and the anterior cingulate cortex regions manifest greater vulnerability in females than in males. Immune response genes are positively correlated with age, whereas those involved in neurogenesis are negatively correlated with age. Aging-associated genes identified in the hippocampus and the frontal cortex are significantly enriched for gene signatures implicated in Alzheimer’s disease (AD) pathogenesis. In the hippocampus, a male-specific co-expression module is driven by key synaptic signaling regulators including VSNL1, INA, CHN1 and KCNH1; while in the cortex, a female-specific module is associated with neuron projection morphogenesis, which is driven by key regulators including SRPK2, REPS2 and FXYD1. In the cerebellar hemisphere, a myelination-associated module shared by males and females is driven by key regulators such as MOG, ENPP2, MYRF, ANLN, MAG and PLP1, which have been implicated in the development of AD and other neurodegenerative diseases.ConclusionsThis integrative network biology study systematically identifies molecular signatures and networks underlying brain regional vulnerability to aging in males and females. The findings pave the way for understanding the molecular mechanisms of gender differences in developing neurodegenerative diseases such as AD

Storage Stability and Phase Separation Behaviour of Polymer-Modified Bitumen : Characterization and Modelling

Polymer-modified bitumen (PMB) is a high-performance material for road construction and maintenance. But its storage stability and phase separation behaviour are still not sufficiently understood and need to be studied toward a more successful and sustainable application of PMB. In this thesis, the equilibrium thermodynamics and phase separation dynamics of PMB are investigated with the aim at a fundamental understanding on PMB storage stability and phase separation behaviour. The development of polymer modifiers for paving bitumen is reviewed. The phase separation process in unstable PMBs is captured by fluorescence microscopy at the storage temperature (180 °C). A coupled phase-field model of diffusion and flow is developed to simulate and predict the PMB storage stability and phase separation behaviour. The temperature dependency of PMB phase separation behaviour is modelled by introducing temperature-dependent model parameters between 140 °C and 180 °C. This model is implemented in a finite element software package and calibrated with the experimental observations of real PMBs. The results indicate that storage stability and phase separation behaviour of PMB are strongly dependent on the specific combination of the base bitumen and polymer. An unstable PMB starts to separate into two phases by diffusion, because of the poor polymer-bitumen compatibility. Once the density difference between the two phases becomes sufficiently significant, gravity starts to drive the flow of the two phases and accelerates the separation in the vertical direction. The proposed model, based on the Cahn-Hilliard equation, Flory-Huggins theory and Navier-Stokes equations, is capable of capturing the stability differences among the investigated PMBs and their distinct microstructures at different temperatures. The various material parameters of the PMBs determine the differences in the phase separation behaviour in terms of stability and temperature dependency. The developed model is able to simulate and explain the resulting differences due to the material parameters. The outcome of this study may thus assist in future efforts of ensuring storage stability and sustainable application of PMB.Polymermodifierade bitumen (PMB) är ett högpresterande material för väganläggning och underhåll. Men PMB:s lagringsstabilitet och fassepareringsegenskaper är inte tillräckligt förstådda än och behöver studeras för en mer framgångsrik och hållbar användning av PMB. I denna avhandling studeras termodynamisk jämvikt och fasseparation av PMB med målsättning att uppnå en grundläggande förståelse av PMB:s lagringsstabilitet och fassepareringsegenskaper. Utvecklingen av polymermodifierade bitumen sammanfattas. Fasseparationsprocessen av instabil PMB:s studeras med hjälp av fluorescens mikroskopi vid lagringstemperatur (180 °C). En kopplad fas-fälts modell som beskriver diffusion och flöde har utvecklats för att simulera och förutsäga PMB:s lagringsstabilitet och fassepareringsegenskaper. Temperaturberoendet hos PMB:s fasseparation har beskrivits genom att införa temperaturberoende modellparametrar mellan 140 °C och 180 °C. Denna modell är införd i ett finit element program och kalibrerad med experimentella observationer på verkliga PMB. Resultaten indikerar att lagringsstabiliteten och fasseparationen hos PMB är starkt beroende av den specifika kombinationen av basbitumen och polymer. En instabil PMB börjar separera i två faser genom diffusion, beroende på dålig bitumen-polymer kompatibilitet. När skillnaden i densitet mellan de två faserna blir tillräckligt stor kommer gravitationen att driva flödet av de två faserna och accelerera separationen i vertikalled. Den föreslagna modellen, baserad på Cahn-Hilliards ekvation, Flory-Huggins teori och Navier-Stokes ekvation, kan beskriva stabilitetsskillnaderna mellan de undersökta PMB:erna och deras distinkta mikrostruktur vid olika temperaturer. De olika materialparametrarna hos PMB bestämmer skillnaden i fassepareringsegenskaper i termer av stabilitet och temperaturberoende. Den utvecklade modellen kan simulera och förklara de resulterande skillnaderna på grund av materialparametrarna. Resultatet av denna studie kan bidra till att säkerställa lagringsstabilitet och hållbara applikationer för PMB.QC 20161102</p

Towards a Viscoelastic Model for Phase Separation in Polymer Modified Bitumen

In this thesis, a review is given on the most popular polymers used today for polymer modification of bitumen. Furthermore, the development of a model for phase separation in polymer modified bitumen (PMB) is proposed, that will enable a better control and understanding of PMB phase behaviour, allowing thus to enhanced long-term performance. PMB is hereby considered as a blend and focus is placed on its structure, its equilibrium thermodynamics and its phase separation dynamics. The effects of dynamic asymmetry on phase separation in PMB are analysed with related theories and some image data. Based on the discussion in this thesis, it is concluded that the effects of dynamic asymmetry between bitumen and polymer should be taken into consideration when studying phase separation in PMB. By analysing related literature and image data, it is found that some features of viscoelastic phase separation are shown during the phase separation process in some PMBs. It is therefore possible and useful to develop a viscoelastic model for PMB to describe its phase separation behaviour. In this, the stress-diffusion coupling is expected to play a key role in the model. Finally, recommendations are made towards the future research which is needed to realize the proposed model.QC 20150409</p

Bitumenegenskaper och skjuvmotstånd hos asfaltbeläggningar : framtagning av en urvalsmodell för bitumen

The shear resistance of asphalt mixtures is a crucial material property to ensure the pavement quality and minimize shear-related distresses. For a high shear resistance, proper protocols to select suitable raw materials for asphalt mixtures, mainly bitumen and mineral aggregates, are of great importance. The study presented in this report focuses on the selection of bitumen for asphalt mixtures.  Towards a tool for bitumen selection, this study aims to understand the relationship between asphalt mixture shear properties and bitumen. The research objective is to identify the correlation between them. Following this direction, this report presents an experimental investigation on the dynamic shear properties of asphalt mixtures and their relationships with the bitumen properties. The influence of binder content is also considered. Six bituminous binders, two of which were polymer-modified, were used to prepare asphalt mixtures in laboratory. The binders were tested with various methods, while their asphalt mixtures were characterized by the dynamic shear test. With the test results, the correlation between them was analysed. It is indicated that the iso-modulus temperatures of bitumen after short-term ageing by dynamic shear rheometer testing at 10 rad/s have very strong correlations with the asphalt mixture viscosity at the maximum phase angle. This was valid for both the studied neat (unmodified) bitumen and polymer-modified bitumen (PMB), although the number of studied PMB samples was limited in this study.Skjuvmotståndet hos asfaltmassor är en viktig materialegenskap för att säkerställa god kvalitet på asfaltbeläggningar och minimera skjuvrelaterade skador såsom deformationer orsakade av tung trafik. För att få ett högt skjuvmotstånd är modeller viktiga verktyg för att välja lämpliga råmaterial för asfaltmassor, främst bitumen och ballast. Studien som presenteras i denna rapport fokuserar på val av bitumen för asfaltmassor.  Denna studie syftar till att förstå förhållandet mellan asfaltmassans skjuvegenskaper och bindemedlets egenskaper för att skapa en urvalsmodell. I rapporten redovisas en experimentell undersökning av hur de dynamiska skjuvegenskaperna hos asfaltmassor korrelerar med bitumenegenskaper. Bindemedels-haltens inverkan beaktas också i studien. Sex bituminösa bindemedel, varav två var polymermodi-fierade, användes för att tillverka asfaltmassor i laboratorium. Bindemedlen testades med olika provningsmetoder, medan deras asfaltmassor karaktäriserades av dynamisk skjuvprovning varefter korrelationen mellan resultaten analyserades. Resultaten indikerar att bindemedlens iso-modul-temperaturer efter korttidsåldring har mycket stark korrelation med asfaltmassans viskositet vid maximal fasvinkel. Iso-modultemperaturer mättes med dynamisk skjuvreometer (DSR, dynamic shear rheometer) vid 10 rad/s. Sambandet gällde både omodifierade och polymermodifierade bitumen även om antalet testade modifierade bindemedel var lågt i studien

Karaktärisering av asfaltmassor och bitumen för att minimera skjuvrelaterade skador i asfaltbeläggning : en litteraturstudie

The shear stress and strain induced by traffic loading play a critical role in the development of major distresses in asphalt pavements. Aiming to facilitate further experimental studies on bitumen selection for asphalt pavements to minimize the shear-related distresses, this report presents a state-of-the-art literature study on the shear characterization of asphalt mixtures and bitumen. The significance of shear-related distresses in asphalt pavement is analysed. The advance in shear tests of asphalt mixtures and rheological characterization methods of bituminous binders is reviewed. The potential correlation existing between bitumen properties and the shear resistance of asphalt mixtures is discussed. Considering the shear-related pavement distresses, many previous studies have indicated the importance of asphalt mixture properties such as shear strength, shear modulus, shear phase angle, shear viscosity at maximum phase angle, shear creep compliance and recovery capacity after the loading. The related bitumen properties to these mixture properties are identified and reviewed in this report by looking into models and past experimental studies, including the adhesive and cohesive strength, viscosity, complex shear modulus, phase angle, shear creep compliance and recovery. With this review, a ground is established for future developments on related research topics towards a performance-related bitumen selection protocol.Skjuvspänningen och skjuvtöjningen som framkallas av trafikbelastning spelar en avgörande roll i utvecklingen av stora skador i asfaltbeläggningar. Denna rapport presenterar en litteraturstudie om skjuvkaraktärisering av asfaltmassor och bitumen. Syftet är att underlätta för experimentella studier om val av bitumen till asfaltbeläggningar för att minimera skjuvrelaterade skador. I rapporten analyseras betydelsen av skjuvrelaterad nedbrytning i asfaltbeläggning. Skjuvtester av asfaltmassor och reologiska karakteriseringsmetoder för bituminöst bindemedel presenteras och granskas. De möjliga korrelationerna som finns mellan bitumenegenskaper och asfaltmassans skjuvmotstånd diskuteras. Med tanke på de skjuvningsrelaterade beläggningsskadorna har många tidigare studier visat på vikten av egenskaper hos asfalten, såsom skjuvhållfasthet, skjuvmodul, fasvinkel, skjuvviskositet vid maximal fasvinkel, skjuvkrypning och återgång efter belastningen. De motsvarande bitumenegenskaperna till dessa egenskaper hos asfalten har identifierats genom att undersöka modeller och tidigare experimentella studier, inklusive vidhäftning mot ballasten, kohesion hos bitumen, viskositet, komplex skjuvmodul, fasvinkel, skjuvkrypning och återgång. Med denna granskning skapas en grund för utvecklingen mot en ny urvalsmodell för bitumen.BVFF Framtagning av urvalsmodell för bitumen kopplat till skjuvrelaterad nedbrytning av asfaltbeläggnin

Karaktärisering av asfaltmassor och bitumen för att minimera skjuvrelaterade skador i asfaltbeläggning : en litteraturstudie

The shear stress and strain induced by traffic loading play a critical role in the development of major distresses in asphalt pavements. Aiming to facilitate further experimental studies on bitumen selection for asphalt pavements to minimize the shear-related distresses, this report presents a state-of-the-art literature study on the shear characterization of asphalt mixtures and bitumen. The significance of shear-related distresses in asphalt pavement is analysed. The advance in shear tests of asphalt mixtures and rheological characterization methods of bituminous binders is reviewed. The potential correlation existing between bitumen properties and the shear resistance of asphalt mixtures is discussed. Considering the shear-related pavement distresses, many previous studies have indicated the importance of asphalt mixture properties such as shear strength, shear modulus, shear phase angle, shear viscosity at maximum phase angle, shear creep compliance and recovery capacity after the loading. The related bitumen properties to these mixture properties are identified and reviewed in this report by looking into models and past experimental studies, including the adhesive and cohesive strength, viscosity, complex shear modulus, phase angle, shear creep compliance and recovery. With this review, a ground is established for future developments on related research topics towards a performance-related bitumen selection protocol.Skjuvspänningen och skjuvtöjningen som framkallas av trafikbelastning spelar en avgörande roll i utvecklingen av stora skador i asfaltbeläggningar. Denna rapport presenterar en litteraturstudie om skjuvkaraktärisering av asfaltmassor och bitumen. Syftet är att underlätta för experimentella studier om val av bitumen till asfaltbeläggningar för att minimera skjuvrelaterade skador. I rapporten analyseras betydelsen av skjuvrelaterad nedbrytning i asfaltbeläggning. Skjuvtester av asfaltmassor och reologiska karakteriseringsmetoder för bituminöst bindemedel presenteras och granskas. De möjliga korrelationerna som finns mellan bitumenegenskaper och asfaltmassans skjuvmotstånd diskuteras. Med tanke på de skjuvningsrelaterade beläggningsskadorna har många tidigare studier visat på vikten av egenskaper hos asfalten, såsom skjuvhållfasthet, skjuvmodul, fasvinkel, skjuvviskositet vid maximal fasvinkel, skjuvkrypning och återgång efter belastningen. De motsvarande bitumenegenskaperna till dessa egenskaper hos asfalten har identifierats genom att undersöka modeller och tidigare experimentella studier, inklusive vidhäftning mot ballasten, kohesion hos bitumen, viskositet, komplex skjuvmodul, fasvinkel, skjuvkrypning och återgång. Med denna granskning skapas en grund för utvecklingen mot en ny urvalsmodell för bitumen

Polymer modification of bitumen : Advances and challenges

Advances and challenges in the field of bitumen polymer modification for road construction during the last 40 years are reviewed in this paper. The history of bitumen polymer modification is described chronologically. Some popular plastomers and thermoplastic elastomers in bitumen modification are discussed regarding their advantages and disadvantages, including polyethylene (PE), polypropylene (PP), ethylene-vinyl acetate (EVA), ethylene-butyl acrylate (EBA), styrene-butadiene-styrene (SBS), styrene-isoprene-styrene (SIS) and styrene-ethylene/butylene-styrene (SEBS). Although these polymers all improve bitumen properties to some extent, there are still some drawbacks limiting the future development of bitumen polymer modification, such as high cost, low ageing resistance and poor storage stability of polymer modified bitumen (PMB). Researchers attempted various ways to remove these drawbacks. Some technical developments for removing drawbacks are reviewed in this paper, including saturation, sulfur vulcanization, adding antioxidants, using hydrophobic clay minerals, functionalization and application of reactive polymers. The future development of polymers for bitumen modification is analyzed as well. Since it is currently challenging to perfectly achieve all expected PMB properties at the same time, some compromised recommendations are given in this paper, among which greatly enhancing the properties with an acceptably high cost, significantly reducing the cost with relatively poor properties and their combinations. Functionalization is emphasized as a promising way to enhance the properties of currently used polymers and develop new-type polymer modifiers with much greater success in the future. It is also recommended that future research on bitumen polymer modification focuses more on function development towards enhancing: adhesion with aggregates, long-term performance and recyclability.QC 20140612</p