Genetic diseases can be diagnosed early during pregnancy, but many monogenic disorders continue to cause considerable neonatal and pediatric morbidity and mortality. Early intervention through ...intrauterine gene editing, however, could correct the genetic defect, potentially allowing for normal organ development, functional disease improvement, or cure. Here we demonstrate safe intravenous and intra-amniotic administration of polymeric nanoparticles to fetal mouse tissues at selected gestational ages with no effect on survival or postnatal growth. In utero introduction of nanoparticles containing peptide nucleic acids (PNAs) and donor DNAs corrects a disease-causing mutation in the β-globin gene in a mouse model of human β-thalassemia, yielding sustained postnatal elevation of blood hemoglobin levels into the normal range, reduced reticulocyte counts, reversal of splenomegaly, and improved survival, with no detected off-target mutations in partially homologous loci. This work may provide the basis for a safe and versatile method of fetal gene editing for human monogenic disorders.
Unusual nucleic acid structures are salient triggers of endogenous repair and can occur in sequence-specific contexts. Peptide nucleic acids (PNAs) rely on these principles to achieve non-enzymatic ...gene editing. By forming high-affinity heterotriplex structures within the genome, PNAs have been used to correct multiple human disease-relevant mutations with low off-target effects. Advances in molecular design, chemical modification, and delivery have enabled systemic in vivo application of PNAs resulting in detectable editing in preclinical mouse models. In a model of β-thalassemia, treated animals demonstrated clinically relevant protein restoration and disease phenotype amelioration, suggesting a potential for curative therapeutic application of PNAs to monogenic disorders. This review discusses the rationale and advances of PNA technologies and their application to gene editing with an emphasis on structural biochemistry and repair.
Performance of the LHCb RICH detector at the LHC Adinolfi, M.; Aglieri Rinella, G.; Albrecht, E. ...
European physical journal. C, Particles and fields,
05/2013, Letnik:
73, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The LHCb experiment has been taking data at the Large Hadron Collider (LHC) at CERN since the end of 2009. One of its key detector components is the Ring-Imaging Cherenkov (RICH) system. This ...provides charged particle identification over a wide momentum range, from 2–100 GeV/
c
. The operation and control, software, and online monitoring of the RICH system are described. The particle identification performance is presented, as measured using data from the LHC. Excellent separation of hadronic particle types (
π
, K, p) is achieved.
Advances in Molecular Therapy have made gene editing through systemic or topical administration of reagents a feasible strategy to treat genetic diseases in a rational manner. Encapsulation of ...therapeutic agents in nanoparticles can improve intracellular delivery of therapeutic agents, provided that the nanoparticles are efficiently taken up within the target cells. In prior work we had established proof-of-principle that nanoparticles carrying gene editing reagents can mediate site-specific gene editing in fetal and adult animals in vivo that results in functional disease improvement in rodent models of β-thalassemia and cystic fibrosis. Modification of the surface of nanoparticles to include targeting molecules (e.g. antibodies) holds the promise of improving cellular uptake and specific cellular binding.
To improve particle uptake for diseases of the airway, like cystic fibrosis, our group tested the impact of nanoparticle surface modification with cell surface marker antibodies on uptake in human bronchial epithelial cells in vitro. Binding kinetics of antibodies (Podoplanin, Muc 1, Surfactant Protein C, and Intracellular Adhesion Molecule-1 (ICAM)) were determined to select appropriate antibodies for cellular targeting. The best target-specific antibody among those screened was ICAM antibody. Surface conjugation of nanoparticles with antibodies against ICAM improved cellular uptake in bronchial epithelial cells up to 24-fold.
This is a first demonstration of improved nanoparticle uptake in epithelial cells using conjugation of target specific antibodies. Improved binding, uptake or specificity of particles delivered systemically or to the luminal surface of the airway would potentially improve efficacy, reduce the necessary dose and thus safety of administered therapeutic agents. Incremental improvement in the efficacy and safety of particle-based therapeutic strategies may allow genetic diseases such as cystic fibrosis to be cured on a fundamental genetic level before birth or shortly after birth.
Introduction
Recurrent joint bleeds in haemophilia patients often cause musculoskeletal changes leading to functional capacity impairment.
Aim
In this study, we assessed the effects of aquatic ...activities performed to improve functional capacity in these patients.
Methods
The interventional protocol consisted of 24 hydrotherapy sessions during three months, in comparison with 24 swimming sessions. The pre‐ and post‐intervention assessment consisted of Functional Independence Score, haemophilia joint health score (HJHS), Pediatric Haemophilia Activities List (PedHAL), surface electromyography (SEMG) of thigh muscles to assess muscle electric activity, and load cell on extensor and flexor thigh muscles to evaluate muscular strength.
Results
Forty‐seven haemophilia patients were enrolled in this study, and 32 (23 severe haemophilia A, one moderate haemophilia A and 8 severe haemophilia B), median age 12y (6 to 40y), concluded the aquatic intervention. We observed a statistically significant increase with substantial improvement in functional capacity in the pre‐ and post‐intervention evaluation of hydrotherapy in comparison with the swimming protocol, with HJHS (p = .006 and p = .001 respectively), PedHAL (Sum score) (p = .022 and p = .001) and score FISH (p = .021). The swimming group revealed significant improvements in muscular strength, in all muscles tested (p = .005 and p = .001). SEMG signal amplitude reached significantly higher levels in all muscles evaluated after both interventions except for the vastus medialis (right) in the hydrotherapy group.
Conclusion
Our results concluded that both swimming and hydrotherapy were associated with physical improvement in haemophilia patients; however, only hydrotherapy lead to a more significant improvement in functional capacity.
Context.
The Atacama Large Millimeter/submillimeter Array (ALMA) has been in operation since 2011, but it has not yet been populated with the full suite of its planned frequency bands. In particular, ...ALMA Band 2 (67−90 GHz) is the final band in the original ALMA band definition to be approved for production.
Aims.
We aim to produce a wideband, tuneable, sideband-separating receiver with 28 GHz of instantaneous bandwidth per polarisation operating in the sky frequency range of 67−116 GHz. Our design anticipates new ALMA requirements following the recommendations of the 2030 ALMA Development Roadmap.
Methods.
The cryogenic cartridge is designed to be compatible with the ALMA Band 2 cartridge slot, where the coldest components – the feedhorns, orthomode transducers, and cryogenic low noise amplifiers – operate at a temperature of 15 K. We use multiple simulation methods and tools to optimise our designs for both the passive optics and the active components. The cryogenic cartridge is interfaced with a room-temperature (warm) cartridge hosting the local oscillator and the downconverter module. This warm cartridge is largely based on GaAs semiconductor technology and is optimised to match the cryogenic receiver bandwidth with the required instantaneous local oscillator frequency tuning range.
Results.
Our collaboration has resulted in the design, fabrication, and testing of multiple technical solutions for each of the receiver components, producing a state-of-the-art receiver covering the full ALMA Band 2 and 3 atmospheric window. The receiver is suitable for deployment on ALMA in the coming years and it is capable of dual-polarisation, sideband-separating observations in intermediate frequency bands spanning 4−18 GHz for a total of 28 GHz on-sky bandwidth per polarisation channel.
Conclusions.
We conclude that the 67−116 GHz wideband implementation for ALMA Band 2 is now feasible and that this receiver provides a compelling instrumental upgrade for ALMA that will enhance observational capabilities and scientific reach.
We investigate the detectability of the primordial cosmic microwave background (CMB) polarization B-mode power spectrum on large scales in the presence of instrumental noise and realistic foreground ...contamination. We have worked out a method to estimate the errors on component separation and to propagate them up to the power spectrum estimation. The performance of our method is illustrated by applying it to the instrumental specifications of the Planck satellite and to the proposed configuration for the next-generation CMB polarization experiment COrE. We demonstrate that a proper component separation step is required in order to achieve the detection of B-modes on large scales and that the final sensitivity to B-modes of a given experiment is determined by a delicate balance between the noise level and the residual foregrounds, which depend on the set of frequencies exploited in the CMB reconstruction, on the signal-to-noise ratio of each frequency map and on our ability to correctly model the spectral behaviour of the foreground components. We have produced a flexible software tool that allows a comparison of performances on B-mode detection of different instrumental specifications (choice of frequencies, noise level at each frequency, etc.) as well as of different proposed approaches to component separation.
We propose the exploitation of a holed-designed poly(dimethyl)siloxane (PDMS) membrane as an innovative microarray spotter. The membrane is fabricated by a simple technological approach and can be ...reused several times. A good level of reproducibility is found upon spotting fluorescent proteins at different concentrations over large areas.
A mixed reality environment, namely the space resulting from displaying virtual contents co-registered to the real space, represents an effective paradigm for applying the potential of virtual ...reality in the everyday life instead of having it confined within a computer screen. In this context, gesture-based interaction seems to be the most suited approach for human-machine interfacing. However, in order that interaction to be visually consistent, the tridimensional composition of the virtual objects onto the real background should be per-formed respecting the distance of each rendered pixel according to the user viewpoint. This paper describes a simple yet effective hand/finger-based interaction system and a virtual-to-real occlusion-handling approach, able to process in real time the stereoscopic video see-through stream to achieve pixel-wise z-order info, crucial to evaluating whether each rendered pixel should be displayed. The experiments confirm the efficacy of the proposed method in a simulation context.
End of Line tests have a crucial role in industrial processes to validate the products' quality. In automotive industry, engines at the end of assembling process are fully tested within hot test ...cells at different working conditions by mean specific test cycles. Vibration monitoring is widely used in order to identify potential faults in the assembly process. This contact technique leads to several disadvantages, mainly due to the accessibility and the characteristics of surfaces for accelerometers mounting (e.g. rotating parts, geometries complexes, high temperatures) and to the time-consuming setup procedures. These limitations can be overcome by using microphone sensors. This paper describes the development phases of an acoustic based fault diagnosis system, its integration on hot test cells and the results obtained over large number of engines tested. By mean some specific technical solutions the acoustics approach in the EOL fault diagnosis of combustion engines has showed itself to be compatible with the characteristics of the production industry environment, providing reliable and repeatable results. The latter has been demonstrated also by comparison with the traditional accelerometer technique.
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