418 research outputs found
Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy
Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational āhotspotā in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD
Plasma Membrane Factor XIIIA Transglutaminase Activity Regulates Osteoblast Matrix Secretion and Deposition by Affecting Microtubule Dynamics
Transglutaminase activity, arising potentially from transglutaminase 2 (TG2) and
Factor XIIIA (FXIIIA), has been linked to osteoblast differentiation where it is
required for type I collagen and fibronectin matrix deposition. In this study we
have used an irreversible TG-inhibitor to āblock āand-trackā
enzyme(s) targeted during osteoblast differentiation. We show that the
irreversible TG-inhibitor is highly potent in inhibiting osteoblast
differentiation and mineralization and reduces secretion of both fibronectin and
type I collagen and their release from the cell surface. Tracking of the dansyl
probe by Western blotting and immunofluorescence microscopy demonstrated that
the inhibitor targets plasma membrane-associated FXIIIA. TG2 appears not to
contribute to crosslinking activity on the osteoblast surface. Inhibition of
FXIIIA with NC9 resulted in defective secretory vesicle delivery to the plasma
membrane which was attributable to a disorganized microtubule network and
decreased microtubule association with the plasma membrane. NC9 inhibition of
FXIIIA resulted in destabilization of microtubules as assessed by cellular
Glu-tubulin levels. Furthermore, NC9 blocked modification of Glu-tubulin into
150 kDa high-molecular weight Glu-tubulin form which was specifically localized
to the plasma membrane. FXIIIA enzyme and its crosslinking activity were
colocalized with plasma membrane-associated tubulin, and thus, it appears that
FXIIIA crosslinking activity is directed towards stabilizing the interaction of
microtubules with the plasma membrane. Our work provides the first mechanistic
cues as to how transglutaminase activity could affect protein secretion and
matrix deposition in osteoblasts and suggests a novel function for plasma
membrane FXIIIA in microtubule dynamics
Multiplex in situ hybridization within a single transcript: RNAscope reveals dystrophin mRNA dynamics
Dystrophin plays a vital role in maintaining muscle health, yet low mRNA expression, lengthy transcription time and the limitations of traditional in-situ hybridization (ISH) methodologies mean that the dynamics of dystrophin transcription remain poorly understood. RNAscope is highly sensitive ISH method that can be multiplexed, allowing detection of individual transcript molecules at sub-cellular resolution, with different target mRNAs assigned to distinct fluorophores. We instead multiplex within a single transcript, using probes targeted to the 5ā and 3ā regions of muscle dystrophin mRNA. Our approach shows this method can reveal transcriptional dynamics in health and disease, resolving both nascent myonuclear transcripts and exported mature mRNAs in quantitative fashion (with the latter absent in dystrophic muscle, yet restored following therapeutic intervention). We show that even in healthy muscle, immature dystrophin mRNA predominates (60ā80% of total), with the surprising implication that the half-life of a mature transcript is markedly shorter than the time invested in transcription: at the transcript level, supply may exceed demand. Our findings provide unique spatiotemporal insight into the behaviour of this long transcript (with implications for therapeutic approaches), and further suggest this modified multiplex ISH approach is well-suited to long genes, offering a highly tractable means to reveal complex transcriptional dynamics
Characterization of Electronic Transport through Amorphous TiO_2 Produced by Atomic-Layer Deposition
Electrical transport in amorphous titanium dioxide (a-TiO_2) thin films, deposited by atomic layer deposition (ALD), and across heterojunctions of p+-Si|a-TiO_2|metal substrates that had various top metal contacts has been characterized by ac conductivity, temperature-dependent dc conductivity, space-charge-limited current spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, X-ray photoelectron spectroscopy, and current density versus voltage (JāV) characteristics. Amorphous TiO_2 films were fabricated using either tetrakis(dimethylamido)-titanium with a substrate temperature of 150 Ā°C or TiCl_4 with a substrate temperature of 50, 100, or 150 Ā°C. EPR spectroscopy of the films showed that the Ti^(3+) concentration varied with the deposition conditions and increases in the concentration of Ti^(3+) in the films correlated with increases in film conductivity. Valence band spectra for the a-TiO_2 films exhibited a defect-state peak below the conduction band minimum (CBM) and increases in the intensity of this peak correlated with increases in the Ti^(3+) concentration measured by EPR as well as with increases in film conductivity. The temperature-dependent conduction data showed Arrhenius behavior at room temperature with an activation energy that decreased with decreasing temperature, suggesting that conduction did not occur primarily through either the valence or conduction bands. The data from all of the measurements are consistent with a Ti^(3+) defect-mediated transport mode involving a hopping mechanism with a defect density of 10^(19) cm^(ā3), a 0.83 wide defect band centered 1.47 eV below the CBM, and a free-electron concentration of 10^(16) cm^(ā3). The data are consistent with substantial room-temperature anodic conductivity resulting from the introduction of defect states during the ALD fabrication process as opposed to charge transport intrinsically associated with the conduction band of TiO_2
Publicising lattice field theory through visualisation
The gluon field configurations that form the foundation of every lattice QCD calculation contain a rich diversity of emergent nonperturbative structure. Visualisations of these phenomena not only serve to explain the concept of a nontrivial vacuum but also entertain a diverse audience from research funding panels to the next generation of science enthusiasts. In this brief review, a collection of QCD-vacuum visualisations is presented including the structure of chromo-electromagnetic fields, centre-cluster evolution at finite temperature, the structure of projected centre vortices, and novel correlations between the electromagnetic fields of QED and the chromo-electromagnetic fields of QCD in QED+QCD dynamical-fermion simulations from the QCDSF collaboration.James Biddle, Josh Charvetto, Waseem Kamleh, Derek Leinweber, Helen Piercy, Ethan Puckridge, Finn Stokes, Ross D. Young, James Zanott
Pregnant women with bronchial asthma benefit from progressive muscle relaxation: A randomized, prospective, controlled trial
Background: Asthma is a serious medical problem in pregnancy and is often associated with stress, anger and poor quality of life. The aim of this study was to determine the efficacy of progressive muscle relaxation (PMR) on change in blood pressure, lung parameters, heart rate, anger and health-related quality of life in pregnant women with bronchial asthma. Methods: We treated a sample of 64 pregnant women with bronchial asthma from the local population in an 8-week randomized, prospective, controlled trial. Thirty-two were selected for PMR, and 32 received a placebo intervention. The systolic blood pressure, forced expiratory volume in the first second, peak expiratory flow and heart rate were tested, and the State-Trait Anger Expression Inventory and Health Survey (SF-36) were employed. Results: According to the intend-to-treat principle, a significant reduction in systolic blood pressure and a significant increase in both forced expiratory volume in the first second and peak expiratory flow were observed after PMR. The heart rate showed a significant increase in the coefficient of variation, root mean square of successive differences and high frequency ranges, in addition to a significant reduction in low and middle frequency ranges. A significant reduction on three of five State-Trait Anger Expression Inventory scales, and a significant increase on seven of eight SF-36 scales were observed. Conclusions: PMR appears to be an effective method to improve blood pressure, lung parameters and heart rate, and to decrease anger levels, thus enhancing health-related quality of life in pregnant women with bronchial asthma. Copyright (c) 2006 S. Karger AG, Basel
Ab initio atomistic thermodynamics and statistical mechanics of surface properties and functions
Previous and present "academic" research aiming at atomic scale understanding
is mainly concerned with the study of individual molecular processes possibly
underlying materials science applications. Appealing properties of an
individual process are then frequently discussed in terms of their direct
importance for the envisioned material function, or reciprocally, the function
of materials is somehow believed to be understandable by essentially one
prominent elementary process only. What is often overlooked in this approach is
that in macroscopic systems of technological relevance typically a large number
of distinct atomic scale processes take place. Which of them are decisive for
observable system properties and functions is then not only determined by the
detailed individual properties of each process alone, but in many, if not most
cases also the interplay of all processes, i.e. how they act together, plays a
crucial role. For a "predictive materials science modeling with microscopic
understanding", a description that treats the statistical interplay of a large
number of microscopically well-described elementary processes must therefore be
applied. Modern electronic structure theory methods such as DFT have become a
standard tool for the accurate description of individual molecular processes.
Here, we discuss the present status of emerging methodologies which attempt to
achieve a (hopefully seamless) match of DFT with concepts from statistical
mechanics or thermodynamics, in order to also address the interplay of the
various molecular processes. The new quality of, and the novel insights that
can be gained by, such techniques is illustrated by how they allow the
description of crystal surfaces in contact with realistic gas-phase
environments.Comment: 24 pages including 17 figures, related publications can be found at
http://www.fhi-berlin.mpg.de/th/paper.htm
The entrepreneurial marketing management and commercialization arrangements of born-global bio-enterprises: the case of UK companies
Born global bio-enterprises are a unique ābreedā of relatively small biotechnology enterprises operating in multiple countries. The companies are nimble and seemingly well-prepared for challenges that ephemeral markets such as the internationalised biotechnology sector brings. The international marketing management challenges they encounter appear to stimulate their entrepreneurial marketing and commercialisation instincts. Surprisingly, there is a dearth of studies that examine their entrepreneurial predispositions. As such, this study is an attempt to explain their entrepreneurial tendencies by investigating the marketing and commercialisation strategies adopted by born global bio-enterprises in the UKās biotechnology industry. The study assumes a multi-case approach examining five archetypical born global bio-enterprises currently active in the UK. It contributes to the international entrepreneurship and marketing management literature. Specifically, it provides international business managers with new knowledge about various marketing manoeuvres they can apply in international networks for their marketing mileage. In doing so, the study proposes a theoretical framework mapping out entrepreneurial marketing and commercialisation arrangements in internationalised biotechnology markets. Its findings are useful to various stakeholders including: policy makers, managers of technology-based companies and business management researchers
British Association of dermatologists guidelines for biologic therapy for psoriasis 2020 ā a rapid update
The overall aim of the guideline is to provide upātoādate, evidenceābased recommendations on the use of biologic therapies targeting TNF (adalimumab, etanercept, certolizumab pegol, infliximab), IL12/23p40 (ustekinumab), IL17A (ixekizumab, secukinumab), IL17RA (brodalumab) and IL23p19 (guselkumab, risankizumab, tildrakizumab) in adults, children and young people for the treatment of psoriasis; consideration is given to the specific needs of people with psoriasis and psoriatic arthritis
Characterization of Electronic Transport through Amorphous TiO_2 Produced by Atomic-Layer Deposition
Electrical transport in amorphous titanium dioxide (a-TiO_2) thin films, deposited by atomic layer deposition (ALD), and across heterojunctions of p+-Si|a-TiO_2|metal substrates that had various top metal contacts has been characterized by ac conductivity, temperature-dependent dc conductivity, space-charge-limited current spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, X-ray photoelectron spectroscopy, and current density versus voltage (JāV) characteristics. Amorphous TiO_2 films were fabricated using either tetrakis(dimethylamido)-titanium with a substrate temperature of 150 Ā°C or TiCl_4 with a substrate temperature of 50, 100, or 150 Ā°C. EPR spectroscopy of the films showed that the Ti^(3+) concentration varied with the deposition conditions and increases in the concentration of Ti^(3+) in the films correlated with increases in film conductivity. Valence band spectra for the a-TiO_2 films exhibited a defect-state peak below the conduction band minimum (CBM) and increases in the intensity of this peak correlated with increases in the Ti^(3+) concentration measured by EPR as well as with increases in film conductivity. The temperature-dependent conduction data showed Arrhenius behavior at room temperature with an activation energy that decreased with decreasing temperature, suggesting that conduction did not occur primarily through either the valence or conduction bands. The data from all of the measurements are consistent with a Ti^(3+) defect-mediated transport mode involving a hopping mechanism with a defect density of 10^(19) cm^(ā3), a 0.83 wide defect band centered 1.47 eV below the CBM, and a free-electron concentration of 10^(16) cm^(ā3). The data are consistent with substantial room-temperature anodic conductivity resulting from the introduction of defect states during the ALD fabrication process as opposed to charge transport intrinsically associated with the conduction band of TiO_2
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