895 research outputs found
Efectos del diseño y la construcción sobre la huella de carbono en columnas de hormigón armado para edificios residenciales
Constructing structural elements requires high performance materials. Important decisions about geometry and materials are made during the design and execution phases. This study analyzes and evaluates the relevant factors for reinforced concrete columns made in situ for residential buildings. This article identifies and highlights the most sensitive aspects in column design: geometry, type of cement, and concrete strength performance. Using C-40 concrete mixed with CEM-II proved to cut costs (up to 17.83%) and emissions (up to 13.59%). The ideal combination of rebar and concrete is between 1.47 and 1.73: this is the percentage of the ratio between the area of rebar and the area of the concrete section. The means used during the execution phase affect resource optimization. The location of a building has only a minor impact, wherein the wind zone exercises more influence than topographic altitude.La construcción de elementos estructurales requiere materiales de alto rendimiento. Las decisiones sobre la geometría y materiales se toman durante las fases de diseño y ejecución. Este estudio analiza y evalúa factores relevantes para columnas de hormigón armado en edificios residenciales. El trabajo identifica y resalta los aspectos más sensibles en el diseño de columnas: geometría, tipo de cemento y rendimiento de resistencia del concreto. El uso de hormigón C-40 mezclado con CEM-II demostró reducir costes (hasta 17.83%) y emisiones (hasta 13.59%). La combinación ideal de barras de refuerzo y concreto está entre 1.47 y 1.73: este es el porcentaje de la relación entre área de barras de refuerzo y área de la sección de hormigón. Los medios utilizados durante la fase de ejecución afectan la viabilidad de optimizar los recursos. La ubicación del edificio tiene un impacto menor, la zona eólica ejerce más influencia que la altitud topográfica
A systematic review and meta-analyses of pregnancy and fetal outcomes in women with multiple sclerosis: a contribution from the IMI2 ConcePTION project.
Neurologists managing women with Multiple Sclerosis (MS) need information about the safety of disease modifying drugs (DMDs) during pregnancy. However, this knowledge is limited. The present study aims to summarize previous studies by performing a systematic review and meta-analyses. The terms "multiple sclerosis" combined with DMDs of interest and a broad profile for pregnancy terms were used to search Embase and Medline databases to identify relevant studies published from January 2000 to July 2019.1260 studies were identified and ten studies met our inclusion criteria. Pooled risk ratios (RR) of pregnancy and birth outcomes in pregnancies exposed to DMDs compared to those not exposed were calculated using a random effects model. For spontaneous abortion RR = 1.14, 95% CI 0.99-1.32, for preterm births RR = 0.93, 95% CI 0.72-1.21 and for major congenital malformations RR = 0.86, 95% CI 0.47-1.56. The most common major congenital malformations reported in MS patients exposed to MS drugs were atrial septal defect (ASD) (N = 4), polydactyly (N = 4) and club foot (N = 3), which are among the most prevalent birth defects observed in the general population. In conclusion, interferons, glatiramer acetate or natalizumab, do not appear to increase the risk for spontaneous abortions, pre-term birth or major congenital malformations. There were very few patients included that were exposed to fingolimod, azathioprine and rituximab; therefore, these results cannot be generalized across drugs. Future studies including internal comparators are needed to enable treating physicians and their patients to decide on the best treatment options
Unraveling the role of protein dynamics in dihydrofolate reductase catalysis
Protein dynamics have controversially been proposed to be at the heart of enzyme catalysis, but identification and analysis of dynamical effects in enzyme-catalyzed reactions have proved very challenging. Here, we tackle this question by comparing an enzyme with its heavy (15N, 13C, 2H substituted) counterpart, providing a subtle probe of dynamics. The crucial hydride transfer step of the reaction (the chemical step) occurs more slowly in the heavy enzyme. A combination of experimental results, quantum mechanics/molecular mechanics simulations, and theoretical analyses identify the origins of the observed differences in reactivity. The generally slightly slower reaction in the heavy enzyme reflects differences in environmental coupling to the hydride transfer step. Importantly, the barrier and contribution of quantum tunneling are not affected, indicating no significant role for “promoting motions” in driving tunneling or modulating the barrier. The chemical step is slower in the heavy enzyme because protein motions coupled to the reaction coordinate are slower. The fact that the heavy enzyme is only slightly less active than its light counterpart shows that protein dynamics have a small, but measurable, effect on the chemical reaction rate
Computational mutagenesis reveals the role of active-site tyrosine in stabilising a boat conformation for the substrate:QM/MM molecular dynamics studies of wild-type and mutant xylanases
Molecular dynamics simulations have been performed for non-covalent complexes of phenyl
b-xylobioside with the retaining endo-b-1,4-xylanase from B. circulans (BCX) and its Tyr69Phe mutant
using a hybrid QM/MM methodology. A trajectory initiated for the wild-type enzyme–substrate
complex with the proximal xylose ring bound at the –1 subsite (adjacent to the scissile glycosidic bond)
in the 4C1 chair conformation shows spontaneous transformation to the 2,5B boat conformation, and
potential of mean force calculations indicate that the boat is ~30 kJ mol-1 lower in free energy than the
chair. Analogous simulations for the mutant lacking one oxygen atom confirm the key role of Tyr69 in
stabilizing the boat in preference to the 4C1 chair conformation, with a relative free energy difference of
about 20 kJ mol-1, by donating a hydrogen bond to the endocyclic oxygen of the proximal xylose ring.
QM/MM MD simulations for phenyl b-xyloside in water, with and without a propionate/propionic
acid pair to mimic the catalytic glutamate/glutamic acid pair of the enzyme, show the 4C1 chair to be
stable, although a hydrogen bond between the OH group at C2 of xylose and the propionate moiety
seems to provide some stabilization for the 2,5B conformatio
Loop Interactions during Catalysis by Dihydrofolate Reductase fromMoritella profunda
Dihydrofolate reductase (DHFR) is often used as a model system to
study the relation between protein dynamics and catalysis. We have studied a
number of variants of the cold-adapted DHFR from Moritella profunda
(MpDHFR), in which the catalytically important M20 and FG loops have been
altered, and present a comparison with the corresponding variants of the wellstudied
DHFR from Escherichia coli (EcDHFR). Mutations in the M20 loop do not
affect the actual chemical step of transfer of hydride from reduced nicotinamide
adenine dinucleotide phosphate to the substrate 7,8-dihydrofolate in the catalytic
cycle in either enzyme; they affect the steady state turnover rate in EcDHFR but
not in MpDHFR. Mutations in the FG loop also have different effects on catalysis
by the two DHFRs. Despite the two enzymes most likely sharing a common catalytic cycle at pH 7, motions of these loops,
known to be important for progression through the catalytic cycle in EcDHFR, appear not to play a significant role in MpDHFR
"Nanohybrids" based on pH-responsive hydrogels and inorganic nanoparticles for drug delivery and sensor applications.
Allyl-PEG capped inorganic NPs, including magnetic iron oxide (IONPs), fluorescent CdSe/ZnS quantum dots (QDs), and metallic gold (AuNPs of 5 and 10 nm) both individually and in combination, were covalently attached to pH-responsive poly(2-vinylpyridine-co-divinylbenzene) nanogels via a facile and robust one-step surfactant-free emulsion polymerization procedure. Control of the NPs associated to the nanogels was achieved by the late injection of the NPs to the polymerization solution at a stage when just polymeric radicals were present. Remarkably, by varying the total amount of NPs injected, the swelling behavior could be affected. Furthermore, the magnetic response as well as the optical features of the nanogels containing either IONPs or QDs could be modified. In addition, a radical quenching in case of gold nanoparticles was observed, thus affecting the final nanogel geometry
Controlled Release of Doxorubicin Loaded within Magnetic Thermo-responsive Nanocarriers under Magnetic and Thermal Actuation in a Microfluidic Channel
We report a procedure to grow thermo-responsive polymer shells at the surface of magnetic nanocarriers made of multiple iron oxide superparamagnetic nanoparticles embedded in poly(maleic anhydride-alt-1-ocatadecene) polymer nanobeads. Depending on the comonomers and on their relative composition, tunable phase transition temperatures in the range between 26 and 47 °C under physiological conditions could be achieved. Using a suitable microfluidic platform combining magnetic nanostructures and channels mimicking capillaries of the circulatory system, we demonstrate that thermo-responsive nanobeads are suitable for localized drug delivery with combined thermal and magnetic activation. Below the critical temperature nanobeads are stable in suspension, retain their cargo, and cannot be easily trapped by magnetic fields. Increasing the temperature above the critical temperature causes the aggregation of nanobeads, forming clusters with a magnetic moment high enough to permit their capture by suitable magnetic g..
Genetic Evidence for Involvement of Neuronally Expressed S1P1 Receptor in Nociceptor Sensitization and Inflammatory Pain
Sphingosine-1-phosphate (S1P) is a key regulator of immune response. Immune cells, epithelia and blood cells generate high levels of S1P in inflamed tissue. However, it is not known if S1P acts on the endings of nociceptive neurons, thereby contributing to the generation of inflammatory pain. We found that the S1P1 receptor for S1P is expressed in subpopulations of sensory neurons including nociceptors. Both S1P and agonists at the S1P1 receptor induced hypersensitivity to noxious thermal stimulation in vitro and in vivo. S1P-induced hypersensitivity was strongly attenuated in mice lacking TRPV1 channels. S1P and inflammation-induced hypersensitivity was significantly reduced in mice with a conditional nociceptor-specific deletion of the S1P1 receptor. Our data show that neuronally expressed S1P1 receptors play a significant role in regulating nociceptor function and that S1P/S1P1 signaling may be a key player in the onset of thermal hypersensitivity and hyperalgesia associated with inflammation
Protein motions and dynamic effects in enzyme catalysis
The role of protein motions in promoting the chemical step of enzyme catalysed reactions remains a subject of considerable debate. Here, a unified view of the role of protein dynamics in dihydrofolate reductase catalysis is described. Recently the role of such motions has been investigated by characterising the biophysical properties of isotopically substituted enzymes through a combination of experimental and computational analyses. Together with previous work, these results suggest that dynamic coupling to the chemical coordinate is detrimental to catalysis and may have been selected against during DHFR evolution. The full catalytic power of Nature's catalysts appears to depend on finely tuning protein motions in each step of the catalytic cycle
Screen-printed back-to-back electroanalytical sensors
We introduce the concept of screen-printed back-to-back electroanalytical
sensors where in this facile and generic approach, screenprinted
electrodes are printed back-to-back with a common electrical
connection to the two working electrodes with the counter and
reference electrodes for each connected in the same manner as a
normal “traditional” screen-printed sensor would be. This approach
utilises the usually redundant back of the screen-printed sensor,
converting this “dead-space” into a further electrochemical sensor
which results in improvements in the analytical performance. In the
use of the back-to-back design, the electrode area is consequently
doubled with improvements in the analytical performance observed
with the analytical sensitivity (gradient of a plot of peak height/
analytical signal against concentration) doubling and the corresponding
limit-of-detection being reduced.We also demonstrate that
through intelligent electrode design, a quadruple in the observed
analytical sensitivity can also be realised when double microband
electrodes are used in the back-to-back configuration as long as they
are placed sufficiently apart such that no diffusional interaction
occurs. Such work is generic in nature and can be facilely applied to a
plethora of screen-printed (and related) sensors utilising the
commonly overlooked redundant back of the electrode providing
facile improvements in the electroanalytical performance
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