A system for online beam emittance measurements and proton beam characterization

A system for online measurement of the transverse beam emittance was developed. It is named $^{4}$PrOB$\varepsilon$aM (4-Profiler Online Beam Emittance Measurement) and was conceived to measure the emittance in a fast and efficient way using the multiple beam profiler method. The core of the system is constituted by four consecutive UniBEaM profilers, which are based on silica fibers passing across the beam. The $^{4}$PrOB$\varepsilon$aM system was deployed for characterization studies of the 18~MeV proton beam produced by the IBA Cyclone 18 MeV cyclotron at Bern University Hospital (Inselspital). The machine serves daily radioisotope production and multi-disciplinary research, which is carried out with a specifically conceived Beam Transport Line (BTL). The transverse RMS beam emittance of the cyclotron was measured as a function of several machine parameters, such as the magnetic field, RF peak voltage, and azimuthal angle of the stripper. The beam emittance was also measured using the method based on the quadrupole strength variation. The results obtained with both techniques were compared and a good agreement was found. In order to characterize the longitudinal dynamics, the proton energy distribution was measured. For this purpose, a method was developed based on aluminum absorbers of different thicknesses, a UniBEaM detector, and a Faraday cup. The results were an input for a simulation of the BTL developed in the MAD-X software. This tool allows machine parameters to be tuned online and the beam characteristics to be optimized for specific applications.Comment: published in Journal of Instrumentatio

Optimization of 68Ga production at an 18 MeV medical cyclotron with solid targets by means of cross-section measurement of 66Ga, 67Ga and 68Ga.

The future development of personalized nuclear medicine relies on the availability of novel medical radionuclides. In particular, radiometals are attracting considerable interest since they can be used to label both proteins and peptides. Among them, the β+-emitter 68Ga is widely used in nuclear medicine for positron emission tomography (PET). It is used in theranostics as the diagnostic partner of the therapeutic β--emitters 177Lu and 90Y for the treatment of a wide range of diseases, including prostate cancer. Currently, 68Ga is usually obtained via 68Ge/68Ga generators. However, their availability, high price and limited produced radioactivity per elution are a major barrier for a wider use of the 68Ga-based diagnostic radiotracers. A promising solution is the production of 68Ga by means of proton irradiation of enriched 68Zn liquid or solid targets. Along this line, a research program is ongoing at the Bern medical cyclotron, equipped with a solid target station. In this paper, we report on the measurements of 68Ga, 67Ga and 66Ga production cross-sections using natural Zn and enriched 68Zn material, which served as the basis to perform optimized 68Ga production tests with enriched 68Zn solid targets

Autogenous regulation of Escherichia coli polynucleotide phosphorylase expression revisited

The Escherichia coli polynucleotide phosphorylase (PNPase, encoded by pnp), a phosphorolytic exoribonuclease, post-transcriptionally regulates its own expression at the level of mRNA stability and translation. Its primary transcript is very efficiently processed by RNase III, an endonuclease that makes a staggered double strand cleavage about in the middle of a long stem-loop in the 5'-untranslated region. The processed pnp mRNA is then rapidly degraded in a PNPase-dependent manner. Two non-mutually exclusive models have been proposed to explain PNPase autogenous regulation. The earlier one suggested that PNPase impedes translation of the RNase III processed pnp mRNA thus exposing the transcript to degradative pathways. More recently this has been replaced by the current model, which maintains that PNPase would simply degrade the promoter proximal small RNA generated by the RNase III endonucleolytic cleavage thus destroying the double stranded structure at the 5'-end that otherwise stabilizes the pnp mRNA. In our opinion, however, the first model was not completely ruled out. Moreover, the RNA decay pathway acting upon the pnp mRNA after disruption of the 5' double stranded structure remained to be determined. Here we provide additional support to the current model and show that the RNase III-processed pnp mRNA devoid of the double stranded structure at its 5'-end is not translatable and is degraded by RNase E in a PNPase-independent manner. Thus the role of PNPase in autoregulation is simply to remove, in concert with RNase III, the 5'-fragment of the cleaved structure that both allows translation and prevents the RNase E-mediated PNPase-independent degradation of the pnp transcript

Intermittent C1-Inhibitor Deficiency Associated with Recessive Inheritance: Functional and Structural Insight

C1-inhibitor is a serine protease inhibitor (serpin) controlling complement and contact system activation. Gene mutations result in reduced C1-inhibitor functional plasma level causing hereditary angioedema, a life-threatening disorder. Despite a stable defect, the clinical expression of hereditary angioedema is unpredictable, and the molecular mechanism underlying this variability remains undisclosed. Here we report functional and structural studies on the Arg378Cys C1-inhibitor mutant found in a patient presenting reduced C1-inhibitor levels, episodically undergoing normalization. Expression studies resulted in a drop in mutant C1-innhibitor secretion compared to wild-type. Notwithstanding, the purified proteins had similar features. Thermal denaturation experiments showed a comparable denaturation profile, but the mutant thermal stability decays when tested in conditions reproducing intracellular crowding.Our findings suggest that once correctly folded, the Arg378Cys C1-inhibitor is secreted as an active, although quite unstable, monomer. However, it could bear a folding defect, occasionally promoting protein oligomerization and interfering with the secretion process, thus accounting for its plasma level variability. This defect is exacerbated by the nature of the mutation since the acquired cysteine leads to the formation of non-functional homodimers through inter-molecular disulphide bonding. All the proposed phenomena could be modulated by specific environmental conditions, rendering this mutant exceptionally vulnerable to mild stress

VID22 counteracts G-quadruplex-induced genome instability

Genome instability is a condition characterized by the accumulation of genetic alterations and is a hallmark of cancer cells. To uncover new genes and cellular pathways affecting endogenous DNA damage and genome integrity, we exploited a Synthetic Genetic Array (SGA)-based screen in yeast. Among the positive genes, we identified VID22, reported to be involved in DNA double-strand break repair. vid22Δ cells exhibit increased levels of endogenous DNA damage, chronic DNA damage response activation and accumulate DNA aberrations in sequences displaying high probabilities of forming G-quadruplexes (G4-DNA). If not resolved, these DNA secondary structures can block the progression of both DNA and RNA polymerases and correlate with chromosome fragile sites. Vid22 binds to and protects DNA at G4-containing regions both in vitro and in vivo. Loss of VID22 causes an increase in gross chromosomal rearrangement (GCR) events dependent on G-quadruplex forming sequences. Moreover, the absence of Vid22 causes defects in the correct maintenance of G4-DNA rich elements, such as telomeres and mtDNA, and hypersensitivity to the G4-stabilizing ligand TMPyP4. We thus propose that Vid22 is directly involved in genome integrity maintenance as a novel regulator of G4 metabolism

Static analysis-based approaches for secure software development

Software security is a matter of major concern for software development enterprises that wish to deliver highly secure software products to their customers. Static analysis is considered one of the most effective mechanisms for adding security to software products. The multitude of static analysis tools that are available provide a large number of raw results that may contain security-relevant information, which may be useful for the production of secure software. Several mechanisms that can facilitate the production of both secure and reliable software applications have been proposed over the years. In this paper, two such mechanisms, particularly the vulnerability prediction models (VPMs) and the optimum checkpoint recommendation (OCR) mechanisms, are theoretically examined, while their potential improvement by using static analysis is also investigated. In particular, we review the most significant contributions regarding these mechanisms, identify their most important open issues, and propose directions for future research, emphasizing on the potential adoption of static analysis for addressing the identified open issues. Hence, this paper can act as a reference for researchers that wish to contribute in these subfields, in order to gain solid understanding of the existing solutions and their open issues that require further research

Software engineering processes for self-adaptive systems

In this paper, we discuss how for self-adaptive systems some activities that traditionally occur at development-time are moved to run-time. Responsibilities for these activities shift from software engineers to the system itself, causing the traditional boundary between development-time and run-time to blur. As a consequence, we argue how the traditional software engineering process needs to be reconceptualized to distinguish both development-time and run-time activities, and to support designers in taking decisions on how to properly engineer such systems. Furthermore, we identify a number of challenges related to this required reconceptualization, and we propose initial ideas based on process modeling. We use the Software and Systems Process Engineering Meta-Model (SPEM) to specify which activities are meant to be performed off-line and on-line, and also the dependencies between them. The proposed models should capture information about the costs and benefits of shifting activities to run-time, since such models should support software engineers in their decisions when they are engineering self-adaptive systems

Insulin Storage and Glucose Homeostasis in Mice Null for the Granule Zinc Transporter ZnT8 and Studies of the Type 2 Diabetes–Associated Variants

International audienceObjective. Zinc ions are essential for the formation of hexameric insulin and hormone crystallisation. Correspondingly, a non-synonymous single nucleotide polymorphism rs13266634 in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8, is associated with type 2 diabetes. Here, we describe the effects of deleting the ZnT8 gene in mice and explore the action of the at-risk allele. Research Design and Methods. Slc30a8 null mice were generated and backcrossed at least twice onto a C57BL/6J background. Glucose and insulin tolerance were measured by intraperitoneal injection, or euglycemic clamp, respectively. Insulin secretion, electrophysiology, imaging, and the generation of adenoviruses encoding the low- (W325) or elevated- (R325) risk ZnT8 alleles, were undertaken using standard protocols. Results. ZnT8(-/-) mice displayed age, sex and diet-dependent abnormalities in glucose tolerance, insulin secretion and body weight. Islets isolated from null mice had reduced granule zinc content, and showed age-dependent changes in granule morphology, with markedly fewer dense cores but more rod-like crystals. Glucose-stimulated insulin secretion, granule fusion and insulin crystal dissolution, as assessed by total internal reflection fluorescence microscopy, were unchanged or enhanced in ZnT8(-/-) islets. Insulin processing was normal. Molecular modelling revealed that residue-325 was located at the interface between ZnT8 monomers. Correspondingly, the R325 variant displayed lower apparent Zn(2+) transport activity than W325 ZnT8 by fluorescence-based assay. Discussion and conclusions. ZnT8 is required for normal insulin crystallisation and insulin release in vivo but not, remarkably, in vitro. Defects in the former processes in carriers of the R allele may increase type 2 diabetes risk

A 3D cellular context for the macromolecular world

We report the outcomes of the discussion initiated at the workshop entitled A 3D Cellular Context for the Macromolecular World and propose how data from emerging three-dimensional (3D) cellular imaging techniques—such as electron tomography, 3D scanning electron microscopy and soft X-ray tomography—should be archived, curated, validated and disseminated, to enable their interpretation and reuse by the biomedical community