A high-density immunoblotting methodology for quantification of total protein levels and phosphorylation modifications

The components of many signaling pathways have been identified and there is now a need to conduct quantitative data-rich temporal experiments for systems biology and modeling approaches to better understand pathway dynamics and regulation. Here we present a modified Western blotting method that allows the rapid and reproducible quantification and analysis of hundreds of data points per day on proteins and their phosphorylation state at individual sites. The approach is of particular use where samples show a high degree of sample-to-sample variability such as primary cells from multiple donors. We present a case study on the analysis of >800 phosphorylation data points from three phosphorylation sites in three signaling proteins over multiple time points from platelets isolated from ten donors, demonstrating the technique's potential to determine kinetic and regulatory information from limited cell numbers and to investigate signaling variation within a population. We envisage the approach being of use in the analysis of many cellular processes such as signaling pathway dynamics to identify regulatory feedback loops and the investigation of potential drug/inhibitor responses, using primary cells and tissues, to generate information about how a cell's physiological state changes over time

Development of Superconducting Tuning Quadrupole Corrector (MQT) Prototypes for the LHC

The main quadrupoles of the Large Hadron Collider (LHC) are connected in families of focusing and defocusing magnets. In order to make tuning corrections in the machine a number of quadrupole corrector magnets (designated MQT) are necessary. These 56 mm diameter aperture magnets have to be compact, with a maximum length of 395 mm and a coil radial thickness of 5 to 7.5 mm, while generating a minimum field gradient of 110 T/m. Two design options have been explored, both using the "counter-winding" system developed at CERN for the fabrication of low cost corrector coils. The first design, with the poles composed of two double-pancake coils, each counter-wound using a single wire, superposed to create 4-layer coils, was developed and built by ACCEL Instruments GmbH. A second design where single coils were counter-wound using a 3-wire ribbon to obtain 6-layer coils was developed at CERN. This paper describes the two designs and reports on the performance of the prototypes during testing

Using dense seismo-acoustic network to provide timely warning of the 2019 paroxysmal Stromboli eruptions

Stromboli Volcano is well known for its persistent explosive activity. On July 3rd and August 28th 2019, two paroxysmal explosions occurred, generating an eruptive column that quickly rose up to 5 km above sea level. Both events were detected by advanced local monitoring networks operated by Istituto Nazionale di Geofisica e Vulcanologia (INGV) and Laboratorio di Geofisica Sperimentale of the University of Firenze (LGS-UNIFI). Signals were also recorded by the Italian national seismic network at a range of hundreds of kilometres and by infrasonic arrays up to distances of 3700 km. Using state-of-the-art propagation modeling, we identify the various seismic and infrasound phases that are used for precise timing of the eruptions. We highlight the advantage of dense regional seismo-acoustic networks to enhance volcanic signal detection in poorly monitored regions, to provide timely warning of eruptions and reliable source amplitude estimate to Volcanic Ash Advisory Centres (VAAC)

Design, Performance and Series Production of Superconducting Trim Quadrupoles for the Large Hadron Collider

The Large Hadron Collider (LHC) will be equipped with several thousands of superconducting corrector magnets. Among the largest ones are the superconducting trim quadrupoles (MQTL). These twin-aperture magnets with a total mass of up to 1700 kg have a nominal gradient of 129 T/m at 1.9 K and a magnetic length of 1.3 m. Sixty MQTL are required for the LHC, 36 operating at 1.9 K in and 24 operating at 4.5 K. The paper describes the design features, and reports the measured quench performance and magnetic field quality of the production magnets. The MQTL magnet production is shared between CERN and industry. This sharing is simplified due to the modular construction, common to all twin-aperture correctors

Adaptive refinement and selection process through defect localization for reconstructing an inhomogeneous refraction index

We consider the iterative reconstruction of both the internal geometry and the values of an inhomogeneous acoustic refraction index through a piecewise constant approximation. In this context, we propose two enhancements intended to reduce the number of parameters to reconstruct, while preserving accuracy. This is achieved through the use of geometrical informations obtained from a previously developed defect localization method. The first enhancement consists in a preliminary selection of relevant parameters, while the second one is an adaptive refinement to enhance precision with a low number of parameters. Each of them is numerically illustrated

Using Mathematical Models In A Unified Approach To Predicting The Next Emerging Infectious Disease

Emerging infectious diseases (EIDs) pose a significant threat to human health, global economies, and conservation (Smolinski et al. 2003). They are defined as diseases that have recently increased in incidence (rate of the development of new cases during a given time period), are caused by pathogens that recently moved from one host population to another, have recently evolved, or have recently exhibited a change in pathogenesis (Morse 1993; Krause 1994). Some EIDs threaten global public health through pandemics with large-scale mortality (e.g., HN/AIDS). Others cause smaller outbreaks but have high case fatality ratios or lack effective therapies or vaccines (e.g. Ebola virus or methicillin-resistant Staphylococcus aureus). As a group, EIDs cause hundreds of thousands of deaths each year, and some outbreaks (e.g., SARS, H5N1) have cost the global economy tens of billions of dollars. Emerging diseases also affect plants, livestock, and wildlife and are recognized as a Significant threat to the conservation of biodiversity (Daszak et al. 2000). Approximately 60% of emerging human disease events are zoonotic, and over 75% of these diseases originate in wildlife (Jones et al. 2008). The global response to such epidemics is frequently reactive, and the effectiveness of conventional disease control operations is often too little, too late\u27: With rising globalization, the ease with which diseases spread globally has increased dramatically in recent times. Also, interactions between humans and wildlife have intensified through trade markets, agricultural intensification, logging and mining, and other forms of development that encroach into wild areas. Rapid human population growth, land use change, and change in global trade and travel require a shift toward a proactive, predictive, and preventive approaches for the next zoonotic pandemic

Exploring local knowledge and perceptions on zoonoses among pastoralists in northern and eastern Tanzania

Background: Zoonoses account for the most commonly reported emerging and re-emerging infectious diseases in Sub-Saharan Africa. However, there is limited knowledge on how pastoral communities perceive zoonoses in relation to their livelihoods, culture and their wider ecology. This study was carried out to explore local knowledge and perceptions on zoonoses among pastoralists in Tanzania. Methodology and principal findings: This study involved pastoralists in Ngorongoro district in northern Tanzania and Kibaha and Bagamoyo districts in eastern Tanzania. Qualitative methods of focus group discussions, participatory epidemiology and interviews were used. A total of 223 people were involved in the study. Among the pastoralists, there was no specific term in their local language that describes zoonosis. Pastoralists from northern Tanzania possessed a higher understanding on the existence of a number of zoonoses than their eastern districts' counterparts. Understanding of zoonoses could be categorized into two broad groups: a local syndromic framework, whereby specific symptoms of a particular illness in humans concurred with symptoms in animals, and the biomedical framework, where a case definition is supported by diagnostic tests. Some pastoralists understand the possibility of some infections that could cross over to humans from animals but harm from these are generally tolerated and are not considered as threats. A number of social and cultural practices aimed at maintaining specific cultural functions including social cohesion and rites of passage involve animal products, which present zoonotic risk. Conclusions: These findings show how zoonoses are locally understood, and how epidemiology and biomedicine are shaping pastoralists perceptions to zoonoses. Evidence is needed to understand better the true burden and impact of zoonoses in these communities. More studies are needed that seek to clarify the common understanding of zoonoses that could be used to guide effective and locally relevant interventions. Such studies should consider in their approaches the pastoralists' wider social, cultural and economic set up

Determining the shape of defects in non-absorbing inhomogeneous media from far-field measurements

International audienceWe consider non-absorbing inhomogeneous media represented by some refraction index. We have developed a method to reconstruct, from far-field measurements, the shape of the areas where the actual index differs from a reference index. Following the principle of the Factorization Method, we present a fast reconstruction algorithm relying on far field measurements and near field values, easily computed from the reference index. Our reconstruction result is illustrated by several numerical test cases

Self-assembled biotransesterified cyclodextrins as potential Artemisinin nanocarriers. II: In vitro behavior toward the immune system and in vivo biodistribution assessment of unloaded nanoparticles.

In a previous study, we reported on the formulation of Artemisinin-loaded surface-decorated nanoparticles (nanospheres and nanoreservoirs) by co-nanoprecipitation of PEG derivatives (PEG1500 and PEG4000-stearate, polysorbate 80) and biosynthesized γ-CD fatty esters. In the present study, the co-nanoprecipitation was extended to the use of a PEGylated phospholipid, namely DMPE-PEG2000. As our goal was to prepare long-circulating nanocarriers for further systemic delivery of Artemisinin (ART), here, we have investigated, on the one hand, the in vitro behavior of these surface-modified γ-CD-C10 particles toward the immune system (complement activation and macrophage uptake assays) and, on the other hand, their biodistribution features in mice. These experiments showed that the in vitro plasma protein adsorption and phagocytosis by macrophage cells triggered by γ-CD-C10 nanoparticles were significantly reduced when their surface was decorated with amphiphilic PEGylated molecules, in particular PEG1500-stearate, DMPE-mPEG2000 or polysorbate 80. The prolonged blood circulation time assessed by fluorescence imaging was demonstrated for unloaded γ-CD-C10-based nanospheres and nanoreservoir particles containing DMPE-PEG2000 and polysorbate80, respectively. These nanoparticles also proved to be non-hemolytic at the concentration range used in vivo. Within the limits of the conducted experiments, the co-nanoprecipitation technique may be considered as an alternative for surface modification of amphiphilic CD-based drug delivery systems and may be applied to the systemic delivery of ART

Negotiating Value: Comparing Human and Animal Fracture Care in Industrial Societies

At the beginning of the twentieth-century, human and veterinary surgeons faced the challenge of a medical marketplace transformed by technology. The socio-economic value ascribed to their patients – people and domestic animals – was changing, reflecting the increasing mechanisation of industry and the decreasing dependence of society upon non-human animals for labour. In human medicine, concern for the economic consequences of fractures “pathologised” any significant level of post-therapeutic disability, a productivist perspective contrary to the traditional corpus of medical values. In contrast, veterinarians adapted to the mechanisation of horse-power by shifting their primary professional interest to companion animals; a type of veterinary patient generally valued for the unique emotional attachment of the owner, and not the productive capacity of the animal. The economic rationalisation of human fracture care and the “sentimental” transformation of veterinary orthopaedic expertise indicates how these specialists utilised increasingly convergent rhetorical arguments to justify the application of innovative fracture care technologies to their humans and animal patients. Keywords: Fracture care, Industrialisation, Veterinary History, Human/animal relation