A 20 kA Test Bench for High-Precision Current Measurements

The d.c. currents in the LHC dipole and quadrupole chains will require settings and adjustments with a precision of a few ppm. For an ultimate current level of 13 kA this represents an unprecedented accuracy. Compared to the requirements of previous accelerators at CERN, such as the LEP, this is a factor of ten better in accuracy at more than twice the current. State-of-the-art, zero-flux current transducers from Industry will be used for the precision measurements. As no existing laboratory would be capable of performing the calibrations of these transducers to the required precision, a major upgrading of the current Standards laboratory at CERN was decided. The paper describes the various phases of the project, from field calculations and design to construction and final commissioning of this unique test bench. The highly automated facility allows determination of off-sets, linearity and drift of transducers up to 20 kA but provides equally the means to study the sensitivity of the transducers to external stray fields as generated by currents in adjacent busbars

An approach to produce a stack of photo definable polyimide based flat UTCPs

Getting output of multiple chips within the volume of a single chip is the driving force behind development of this novel 3D integration technology which has a broad range of industrial and medical electronic applications. This can be achieved by laminating multiple layers of spin-on polyimide based ultrathin chip packages (UTCPs) with fine pitch through hole interconnects

The MMN as a viable and objective marker of auditory development in CI users

In the present article, we review the studies on the use of the mismatch negativity (MMN) as a tool for an objective assessment of cochlear-implant (CI) functioning after its implantation and as a function of time of CI use. The MMN indexes discrimination of different sound stimuli with a precision matching with that of behavioral discrimination and can therefore be used as its objective index. Importantly, these measurements can be reliably carried out even in the absence of attention and behavioral responses and therefore they can be extended to populations that are not capable of behaviorally reporting their perception such as infants and different clinical patient groups. In infants and small children with CI, the MMN provides the only means for assessing the adequacy of the CI functioning, its improvement as a function of time of CI use, and the efficiency of different rehabilitation procedures. Therefore, the MMN can also be used as a tool in developing and testing different novel rehabilitation procedures. Importantly, the recently developed multi-feature MMN paradigms permit the objective assessment of discrimination accuracy for all the different auditory dimensions (such as frequency, intensity, and duration) in a short recording time of about 30 min. Most recently, such stimulus paradigms have been successfully developed for an objective assessment of music perception, too. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Helical mutations in type I collagen that affect the processing of the amino-propeptide result in an Osteogenesis Imperfecta/Ehlers-Danlos Syndrome overlap syndrome

Background: Whereas mutations affecting the helical domain of type I procollagen classically cause Osteogenesis Imperfecta (OI), helical mutations near the amino (N)-proteinase cleavage site have been suggested to result in a mixed OI/Ehlers-Danlos syndrome (EDS)-phenotype. Methods: We performed biochemical and molecular analysis of type I (pro-) collagen in a cohort of seven patients referred with a clinical diagnosis of EDS and showing only subtle signs of OI. Transmission electron microscopy of the dermis was available for one patient. Results: All of these patients harboured a COL1A1 / COL1A2 mutation residing within the most N-terminal part of the type I collagen helix. These mutations affect the rate of type I collagen N-propeptide cleavage and disturb normal collagen fibrillogenesis. Importantly, patients with this type of mutation do not show a typical OI phenotype but mainly present as EDS patients displaying severe joint hyperlaxity, soft and hyperextensible skin, abnormal wound healing, easy bruising, and sometimes signs of arterial fragility. In addition, they show subtle signs of OI including blue sclerae, relatively short stature and osteopenia or fractures. Conclusion: Recognition of this distinct phenotype is important for accurate genetic counselling, clinical management and surveillance, particularly in relation to the potential risk for vascular rupture associated with these mutations. Because these patients present clinical overlap with other EDS subtypes, biochemical collagen analysis is necessary to establish the correct diagnosis

Head-to-head comparison of aggressive conventional therapy and three biological treatments and comparison of two de-escalation strategies in patients who respond to treatment : study protocol for a multicenter, randomized, open-label, blinded-assessor, phase 4 study

Background: New targeted therapies and improved treatment strategies have dramatically improved the outcomes of patients with rheumatoid arthritis (RA). However, it is unknown whether different early aggressive interventions can induce stable remission or a low-active disease state that can be maintained with conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy, and whether they differ in efficacy and safety. The Nordic Rheumatic Diseases Strategy Trials And Registries (NORD-STAR) study will assess and compare (1) the proportion of patients who achieve remission in a head-to-head comparison between csDMARD plus glucocorticoid therapy and three different biological DMARD (bDMARD) therapies with different modes of action and (2) two de-escalation strategies in patients who respond to first-line therapy. Methods/design: In a pragmatic, 80-160-week, multicenter, randomized, open-label, assessor-blinded, phase 4 study, 800 patients with early RA (symptom duration less than 24 months) are randomized 1: 1: 1: 1 to one of four different treatment arms: (1) aggressive csDMARD therapy with methotrexate + sulphasalazine + hydroxychloroquine + i. a. glucocorticoids (arm 1A) or methotrexate + prednisolone p.o. (arm 1B), (2) methotrexate + certolizumab-pegol, (3) methotrexate + abatacept, or (4) methotrexate + tocilizumab. The primary clinical endpoint is the proportion of patients reaching Clinical Disease Activity Index (CDAI) remission at week 24. Patients in stable remission over 24 consecutive weeks enter part 2 of the study earliest after 48 weeks. Patients not achieving sustained CDAI remission over 24 consecutive weeks, exit the study after 80 weeks. In part 2, patients are re-randomized to two different de-escalation strategies, either immediate or delayed (after 24 weeks) tapering, followed by cessation of study medication. All patients remain on stable doses of methotrexate. The primary clinical endpoint in part 2 is the proportion of patients in remission (CDAI Discussion: NORD-STAR is the first investigator-initiated, randomized, early RA trial to compare (1) csDMARD and three different bDMARD therapies head to head and (2) two different de-escalation strategies. The trial has the potential to identify which treatment strategy to apply in early RA to achieve the best possible outcomes for both patients and society.Peer reviewe

Brain responses to musical feature changes in adolescent cochlear implant users

Cochlear implants (CIs) are primarily designed to assist deaf individuals in perception of speech, although possibilities for music fruition have also been documented. Previous studies have indicated the existence of neural correlates of residual music skills in postlingually deaf adults and children. However, little is known about the behavioral and neural correlates of music perception in the new generation of prelingually deaf adolescents who grew up with CIs. With electroencephalography (EEG), we recorded the mismatch negativity (MMN) of the auditory event-related potential to changes in musical features in adolescent CI users and in normal-hearing (NH) age mates. EEG recordings and behavioral testing were carried out before (T1) and after (T2) a 2-week music training program for the CI users and in two sessions equally separated in time for NH controls. We found significant MMNs in adolescent CI users for deviations in timbre, intensity, and rhythm, indicating residual neural prerequisites for musical feature processing. By contrast, only one of the two pitch deviants elicited an MMN in CI users. This pitch discrimination deficit was supported by behavioral measures, in which CI users scored significantly below the NH level. Overall, MMN amplitudes were significantly smaller in CI users than in NH controls, suggesting poorer music discrimination ability. Despite compliance from the CI participants, we found no effect of the music training, likely resulting from the brevity of the program. This is the first study showing significant brain responses to musical feature changes in prelingually deaf adolescent CI users and their associations with behavioral measures, implying neural predispositions for at least some aspects of music processing. Future studies should test any beneficial effects of a longer lasting music intervention in adolescent CI users.Peer reviewe

Elimination of the Warburg effect in Chinese hamster ovary (CHO) cells improves cell phenotype as a protein production platform

Lactate is a common metabolite and is central to many important processes. One of its more prominent roles is in the Warburg effect, in which cancer cells exhibit high rates of glycolytic flux followed by secretion of lactate, even in the presence of oxygen. This fermentation of pyruvate to lactate via lactate dehydrogenase (Ldh) accompanies increased proliferation of cancer cells and several other types of rapidly proliferating cell types in immune cell activation and embryonic development. Aerobic glycolysis is also prominent in biotherapeutic protein production, where mammalian production cells often secrete high levels of lactate. The accumulation of lactate is deleterious for cell growth, viability, product formation, and quality, both directly via acidification of the media and indirectly through base addition to control culture pH. Despite a clear genetic target, efforts to eliminate lactate secretion via knockout of Ldh(s) in mammalian cells have been unsuccessful, pointing to the essentiality of Ldh mediated NAD regeneration. A wide variety of approaches have been utilized to limit lactate accumulation in culture, including knockdown or inhibition of Ldh, replacement of glucose with alternate sugars, controlled feeding strategies, and many others, however none have proven successful in eliminating the Warburg effect. We report the elimination of the Warburg effect in a CHO cell line by using CRISPR/Cas9-based engineering to simultaneously knockout enzymes responsible for lactate production and ancillary regulators. The resulting cell lines remain proliferative while consuming significantly less glucose and can be used to generate protein producing lines using standard industrial processes. In a pH-controlled fedbatch process, the Warburg null cells require minimal base addition to maintain a stable pH, allowing an extended growth phase. The knockout strategy was also successfully applied to a CHO cell line producing Rituximab, again resulting in a prolonged growth phase. Additionally, protein production was maintained, while product quality was improved with increased glycan galactosylation. Thus, CHO cells without the capacity of Warburg metabolism may be useful for engineering production cell lines with enhanced bioproduction traits

Origins of the Greenland shark (Somniosus microcephalus): Impacts of ice-olation and introgression

Herein, we use genetic data from 277 sleeper sharks to perform coalescent-based modeling to test the hypothesis of early Quaternary emergence of the Greenland shark (Somniosus microcephalus) from ancestral sleeper sharks in the Canadian Arctic-Subarctic region. Our results show that morphologically cryptic somniosids S. microcephalus and Somniosus pacificus can be genetically distinguished using combined mitochondrial and nuclear DNA markers. Our data confirm the presence of genetically admixed individuals in the Canadian Arctic and sub-Arctic, and temperate Eastern Atlantic regions, suggesting introgressive hybridization upon secondary contact following the initial species divergence. Conservative substitution rates fitted to an Isolation with Migration (IM) model indicate a likely species divergence time of 2.34 Ma, using the mitochondrial sequence DNA, which in conjunction with the geographic distribution of admixtures and Pacific signatures likely indicates speciation associated with processes other than the closing of the Isthmus of Panama. This time span coincides with further planetary cooling in the early Quaternary period followed by the onset of oscillating glacial-interglacial cycles. We propose that the initial S. microcephalus–S. pacificus split, and subsequent hybridization events, were likely associated with the onset of Pleistocene glacial oscillations, whereby fluctuating sea levels constrained connectivity among Arctic oceanic basins, Arctic marginal seas, and the North Atlantic Ocean. Our data demonstrates support for the evolutionary consequences of oscillatory vicariance via transient oceanic isolation with subsequent secondary contact associated with fluctuating sea levels throughout the Quaternary period—which may serve as a model for the origins of Arctic marine fauna on a broad taxonomic scale

Arabidopsis mitogen-activated protein kinase kinases MKK1 and MKK2 have overlapping functions in defense signaling mediated by MEKK1, MPK4, and MKS1

The Arabidopsis (Arabidopsis thaliana) MKK1 and MKK2 mitogen-activated protein kinase kinases have been implicated in biotic and abiotic stress responses as part of a signaling cascade including MEKK1 and MPK4. Here, the double loss-of-function mutant (mkk1/2) of MKK1 and MKK2 is shown to have marked phenotypes in development and disease resistance similar to those of the single mekk1 and mpk4 mutants. Because mkk1 or mkk2 single mutants appear wild type, basal levels of MPK4 activity are not impaired in them, and MKK1 and MKK2 are in part functionally redundant in unchallenged plants. These findings are confirmed and extended by biochemical and molecular analyses implicating the kinases in jasmonate- and salicylate-dependent defense responses, mediated in part via the MPK4 substrate MKS1. In addition, transcriptome analyses delineate overlapping and specific effects of the kinases on global gene expression patterns demonstrating both redundant and unique functions for MKK1 and MKK2

Using Polarized Spectroscopy to Investigate Order in Thin-Films of Ionic Self-Assembled Materials Based on Azo-Dyes

Three series of ionic self-assembled materials based on anionic azo-dyes and cationic benzalkonium surfactants were synthesized and thin films were prepared by spin-casting. These thin films appear isotropic when investigated with polarized optical microscopy, although they are highly anisotropic. Here, three series of homologous materials were studied to rationalize this observation. Investigating thin films of ordered molecular materials relies to a large extent on advanced experimental methods and large research infrastructure. A statement that in particular is true for thin films with nanoscopic order, where X-ray reflectometry, X-ray and neutron scattering, electron microscopy and atom force microscopy (AFM) has to be used to elucidate film morphology and the underlying molecular structure. Here, the thin films were investigated using AFM, optical microscopy and polarized absorption spectroscopy. It was shown that by using numerical method for treating the polarized absorption spectroscopy data, the molecular structure can be elucidated. Further, it was shown that polarized optical spectroscopy is a general tool that allows determination of the molecular order in thin films. Finally, it was found that full control of thermal history and rigorous control of the ionic self-assembly conditions are required to reproducibly make these materials of high nanoscopic order. Similarly, the conditions for spin-casting are shown to be determining for the overall thin film morphology, while molecular order is maintained