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1.  Tau plasma levels in subjective cognitive decline: Results from the DELCODE study 
Scientific Reports  2017;7:9529.
Previous studies have demonstrated increased tau plasma levels in patients with Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD. Much less is known whether increased tau plasma levels can already be detected in the pre-MCI stage of subjective cognitive decline (SCD). In the present study we measured tau plasma levels in 111 SCD patients and 134 age- and gender-matched cognitively healthy controls participating in the DZNE (German Center for Neurodegenerative Diseases) longitudinal study on cognition and dementia (DELCODE). Tau plasma levels were measured using ultra-sensitive, single-molecule array (Simoa) technology. We found no significant different tau plasma levels in SCD (3.4 pg/ml) compared with healthy controls (3.6 pg/ml) after controlling for age, gender, and education (p = 0.137). In addition, tau plasma levels did not correlate with Aβ42 (r = 0.073; p = 0.634), tau (r = −0.179; p = 0.240), and p-tau181 (r = −0.208; p = 0.171) cerebrospinal fluid (CSF) levels in a subgroup of 45 SCD patients with available CSF. In conclusion, plasma tau is not increased in SCD patients. In addition, the lack of correlation between tau in plasma and CSF in the examined cohort suggests that tau levels are affected by different factors in both biofluids.
doi:10.1038/s41598-017-08779-0
PMCID: PMC5573353  PMID: 28842559
2.  Neuroligins Nlg2 and Nlg4 Affect Social Behavior in Drosophila melanogaster 
The genome of Drosophila melanogaster includes homologs to approximately one-third of the currently known human disease genes. Flies and humans share many biological processes, including the principles of information processing by excitable neurons, synaptic transmission, and the chemical signals involved in intercellular communication. Studies on the molecular and behavioral impact of genetic risk factors of human neuro-developmental disorders [autism spectrum disorders (ASDs), schizophrenia, attention deficit hyperactivity disorders, and Tourette syndrome] increasingly use the well-studied social behavior of D. melanogaster, an organism that is amenable to a large variety of genetic manipulations. Neuroligins (Nlgs) are a family of phylogenetically conserved postsynaptic adhesion molecules present (among others) in nematodes, insects, and mammals. Impaired function of Nlgs (particularly of Nlg 3 and 4) has been associated with ASDs in humans and impaired social and communication behavior in mice. Making use of a set of behavioral and social assays, we, here, analyzed the impact of two Drosophila Nlgs, Dnlg2 and Dnlg4, which are differentially expressed at excitatory and inhibitory central nervous synapses, respectively. Both Nlgs seem to be associated with diurnal activity and social behavior. Even though deficiencies in Dnlg2 and Dnlg4 appeared to have no effects on sensory or motor systems, they differentially impacted on social interactions, suggesting that social behavior is distinctly regulated by these Nlgs.
doi:10.3389/fpsyt.2017.00113
PMCID: PMC5502276
Drosophila melanogaster; social behavior; activity monitoring; interindividual distance; sensory–motor functions; mutations; human neuro-developmental diseases
3.  A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy 
Disease Models & Mechanisms  2017;10(2):105-118.
ABSTRACT
A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosis-like features and signs of sensory neuropathy. By applying a combined strategy of linkage analysis and whole-exome sequencing in the presented family, a homozygous nonsense mutation, c.4G>T (p.Glu2*), in FITM2 was identified. FITM2 and its paralog FITM1 constitute an evolutionary conserved protein family involved in partitioning of triglycerides into cellular lipid droplets. Despite the role of FITM2 in neutral lipid storage and metabolism, no indications for lipodystrophy were observed in the affected individuals. In order to obtain independent evidence for the involvement of FITM2 in the human pathology, downregulation of the single Fitm ortholog, CG10671, in Drosophila melanogaster was pursued using RNA interference. Characteristics of the syndrome, including progressive locomotor impairment, hearing loss and disturbed sensory functions, were recapitulated in Drosophila, which supports the causative nature of the FITM2 mutation. Mutation-based genetic counseling can now be provided to the family and insight is obtained into the potential impact of genetic variation in FITM2.
Editors' choice: Loss of FITM2 function in humans causes syndromic hearing loss without any signs of a lipodystrophy, although FITM2 is known to function in lipid droplet synthesis and metabolism.
doi:10.1242/dmm.026476
PMCID: PMC5312003  PMID: 28067622
FITM2; Lipid droplets; Drosophila; Hearing impairment; Motor development; Dystonia
4.  Elevated levels of circulating CDH5 and FABP1 in association with human drug‐induced liver injury 
Liver International  2016;37(1):132-140.
Abstract
Background & Aims
The occurrence of drug‐induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls.
Methods
An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins.
Results
We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid‐binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated.
Conclusions
These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.
doi:10.1111/liv.13174
PMCID: PMC5215406  PMID: 27224670
drug‐induced liver injury; biomarker discovery; affinity proteomics; plasma profiling; suspension bead arrays
5.  Ankyrin Repeats Convey Force to Gate the NOMPC Mechanotransduction Channel 
Cell  2015;162(6):1391-1403.
Summary
How metazoan mechanotransduction channels sense mechanical stimuli is not well understood. NOMPC channel in the transient receptor potential (TRP) family, a mechanotransduction channel for Drosophila touch sensation and hearing, contains 29 Ankyrin repeats (ARs) that associate with microtubules. These ARs have been postulated to act as a tether that conveys force to the channel. Here, we report that these N-terminal ARs form a cytoplasmic domain essential for NOMPC mechanogating in vitro, mechanosensitivity of touch receptor neurons in vivo, and touch-induced behaviors of Drosophila larvae. Duplicating the ARs elongates the filaments that tether NOMPC to microtubules in mechanosensory neurons. Moreover, microtubule association is required for NOMPC mechanogating. Importantly, transferring the NOMPC ARs to mechano-insensitive voltage-gated potassium channels confers mechanosensitivity to the chimeric channels. These experiments strongly support a tether mechanism of mechanogating for the NOMPC channel, providing insights regarding the basis of mechanosensitivity of mechanotransduction channels.
Graphical Abstract
doi:10.1016/j.cell.2015.08.024
PMCID: PMC4568062  PMID: 26359990
6.  Regulation of neuronal survival and morphology by the E3 ubiquitin ligase RNF157 
Cell Death and Differentiation  2014;22(4):626-642.
Neuronal health is essential for the long-term integrity of the brain. In this study, we characterized the novel E3 ubiquitin ligase ring finger protein 157 (RNF157), which displays a brain-dominant expression in mouse. RNF157 is a homolog of the E3 ligase mahogunin ring finger-1, which has been previously implicated in spongiform neurodegeneration. We identified RNF157 as a regulator of survival in cultured neurons and established that the ligase activity of RNF157 is crucial for this process. We also uncovered that independently of its ligase activity, RNF157 regulates dendrite growth and maintenance. We further identified the adaptor protein APBB1 (amyloid beta precursor protein-binding, family B, member 1 or Fe65) as an interactor and proteolytic substrate of RNF157 in the control of neuronal survival. Here, the nuclear localization of Fe65 together with its interaction partner RNA-binding protein SART3 (squamous cell carcinoma antigen recognized by T cells 3 or Tip110) is crucial to trigger apoptosis. In summary, we described that the E3 ligase RNF157 regulates important aspects of neuronal development.
doi:10.1038/cdd.2014.163
PMCID: PMC4356340  PMID: 25342469
7.  Diverse Roles of Axonemal Dyneins in Drosophila Auditory Neuron Function and Mechanical Amplification in Hearing 
Scientific Reports  2015;5:17085.
Much like vertebrate hair cells, the chordotonal sensory neurons that mediate hearing in Drosophila are motile and amplify the mechanical input of the ear. Because the neurons bear mechanosensory primary cilia whose microtubule axonemes display dynein arms, we hypothesized that their motility is powered by dyneins. Here, we describe two axonemal dynein proteins that are required for Drosophila auditory neuron function, localize to their primary cilia, and differently contribute to mechanical amplification in hearing. Promoter fusions revealed that the two axonemal dynein genes Dmdnah3 (=CG17150) and Dmdnai2 (=CG6053) are expressed in chordotonal neurons, including the auditory ones in the fly’s ear. Null alleles of both dyneins equally abolished electrical auditory neuron responses, yet whereas mutations in Dmdnah3 facilitated mechanical amplification, amplification was abolished by mutations in Dmdnai2. Epistasis analysis revealed that Dmdnah3 acts downstream of Nan-Iav channels in controlling the amplificatory gain. Dmdnai2, in addition to being required for amplification, was essential for outer dynein arms in auditory neuron cilia. This establishes diverse roles of axonemal dyneins in Drosophila auditory neuron function and links auditory neuron motility to primary cilia and axonemal dyneins. Mutant defects in sperm competition suggest that both dyneins also function in sperm motility.
doi:10.1038/srep17085
PMCID: PMC4660584  PMID: 26608786
8.  CMV promoter mutants with a reduced propensity to productivity loss in CHO cells 
Scientific Reports  2015;5:16952.
The major immediate-early promoter and enhancer of the human cytomegalovirus (hCMV-MIE) is one of the most potent DNA elements driving recombinant gene expression in mammalian cells. Therefore, it is widely employed not only in research but also in large-scale industrial applications, e.g. for the production of therapeutic antibodies in Chinese hamster ovary cells (CHO). As we have reported previously, multi-site methylation of hCMV-MIE is linked to productivity loss in permanently transfected CHO cells lines. In particular, the cytosine located 179 bp upstream of the transcription start site (C-179) is frequently methylated. Therefore, our objective was to study whether mutation of C-179 and other cytosines within hCMV-MIE might lessen the instability of transgene expression. We discovered that the single mutation of C-179 to G can significantly stabilise the production of recombinant protein under control of hCMV-MIE in permanently transfected CHO cells.
doi:10.1038/srep16952
PMCID: PMC4652263  PMID: 26581326
9.  TAK1 and IKK2, novel mediators of SCF-induced signaling and potential targets for c-Kit-driven diseases 
Oncotarget  2015;6(30):28833-28850.
NF-κB activation depends on the IKK complex consisting of the catalytically active IKK1 and 2 subunits and the scaffold protein NEMO. Hitherto, IKK2 activation has always been associated with IκBα degradation, NF-κB activation, and cytokine production. In contrast, we found that in SCF-stimulated primary bone marrow-derived mast cells (BMMCs), IKK2 is alternatively activated. Mechanistically, activated TAK1 mediates the association between c-Kit and IKK2 and therefore facilitates the Lyn-dependent IKK2 activation which suffices to mediate mitogenic signaling but, surprisingly, does not result in NF-κB activation. Moreover, the c-Kit-mediated and Lyn-dependent IKK2 activation is targeted by MyD88-dependent pathways leading to enhanced IKK2 activation and therefore to potentiated effector functions. In neoplastic cells, expressing constitutively active c-Kit mutants, activated TAK1 and IKKs do also not induce NF-κB activation but mediate uncontrolled proliferation, resistance to apoptosis and enables IL-33 to mediate c-Kit-dependent signaling. Together, we identified the formation of the c-Kit-Lyn-TAK1 signalosome which mediates IKK2 activation. Unexpectedly, this IKK activation is uncoupled from the NF-κB-machinery but is critical to modulate functional cell responses in primary-, and mediates uncontrolled proliferation and survival of tumor-mast cells. Therefore, targeting TAK1 and IKKs might be a novel approach to treat c-Kit-driven diseases.
PMCID: PMC4745695  PMID: 26353931
mast cells; TAK1-IKK2 activation; c-Kit-Lyn-TAK1-IKK2 complex; mitogenic signaling; NF-κB-activation
10.  Hearing in Drosophila 
Graphical abstract
Highlights
•Dissecting sound transduction and auditory signal processing.•Defining transcription factors that organize auditory cilia and auditory neuron wiring.•Elucidating environmental and genetic causes of hearing impairments.•Delineating the genetic repertoire of auditory sensory cells.
The dissection of the Drosophila auditory system has revealed multiple parallels between fly and vertebrate hearing. Recent studies have analyzed the operation of auditory sensory cells and the processing of sound in the fly's brain. Neuronal responses to sound have been characterized, and novel classes of auditory neurons have been defined; transient receptor potential (TRP) channels were implicated in auditory transduction, and genetic and environmental causes of auditory dysfunctions have been identified. This review discusses the implications of these recent advances on our understanding of how hearing happens in the fly.
doi:10.1016/j.conb.2015.02.001
PMCID: PMC4582067  PMID: 25710304
11.  Generation of a variety of stable Influenza A reporter viruses by genetic engineering of the NS gene segment 
Scientific Reports  2015;5:11346.
Influenza A viruses (IAV) pose a constant threat to the human population and therefore a better understanding of their fundamental biology and identification of novel therapeutics is of upmost importance. Various reporter-encoding IAV were generated to achieve these goals, however, one recurring difficulty was the genetic instability especially of larger reporter genes. We employed the viral NS segment coding for the non-structural protein 1 (NS1) and nuclear export protein (NEP) for stable expression of diverse reporter proteins. This was achieved by converting the NS segment into a single open reading frame (ORF) coding for NS1, the respective reporter and NEP. To allow expression of individual proteins, the reporter genes were flanked by two porcine Teschovirus-1 2A peptide (PTV-1 2A)-coding sequences. The resulting viruses encoding luciferases, fluorescent proteins or a Cre recombinase are characterized by a high genetic stability in vitro and in mice and can be readily employed for antiviral compound screenings, visualization of infected cells or cells that survived acute infection.
doi:10.1038/srep11346
PMCID: PMC4464305  PMID: 26068081
12.  The clock gene Period1 regulates innate routine behaviour in mice 
Laboratory mice are well capable of performing innate routine behaviour programmes necessary for courtship, nest-building and exploratory activities although housed for decades in animal facilities. We found that in mice inactivation of the clock gene Period1 profoundly changes innate routine behaviour programmes like those necessary for courtship, nest building, exploration and learning. These results in wild-type and Period1 mutant mice, together with earlier findings on courtship behaviour in wild-type and period-mutant Drosophila melanogaster, suggest a conserved role of Period-genes on innate routine behaviour. Additionally, both per-mutant flies and Period1-mutant mice display spatial learning and memory deficits. The profound influence of Period1 on routine behaviour programmes in mice, including female partner choice, may be independent of its function as a circadian clock gene, since Period1-deficient mice display normal circadian behaviour.
doi:10.1098/rspb.2014.0034
PMCID: PMC3953852  PMID: 24598427
ultrasonic vocalization; courtship; nest building; rearing; novelty
13.  Isothermal microcalorimetry accurately detects bacteria, tumorous microtissues, and parasitic worms in a label-free well-plate assay 
Biotechnology Journal  2015;10(3):460-468.
Isothermal microcalorimetry is a label-free assay that allows monitoring of enzymatic and metabolic activities. The technique has strengths, but most instruments have a low throughput, which has limited their use for bioassays. Here, an isothermal microcalorimeter, equipped with a vessel holder similar to a 48-well plate, was used. The increased throughput of this microcalorimeter makes it valuable for biomedical and pharmaceutical applications. Our results show that the sensitivity of the instrument allows the detection of 3 × 104 bacteria per vial. Growth of P. mirabilis in Luria Broth medium was detected between 2 and 9 h with decreasing inoculum. The culture released 2.1J with a maximum thermal power of 76 μW. The growth rate calculated using calorimetric and spectrophotometric data were 0.60 and 0.57 h–1, respectively. Additional insight on protease activities of P. mirabilis matching the last peak in heat production could be gathered as well. Growth of tumor microtissues releasing a maximum thermal power of 2.1 μW was also monitored and corresponds to a diameter increase of the microtissues from ca. 100 to 428 μm. This opens new research avenues in cancer research, diagnostics, and development of new antitumor drugs. For parasitic worms, the technique allows assessment of parasite survival using motor and metabolic activities even with a single worm.
doi:10.1002/biot.201400494
PMCID: PMC4406140  PMID: 25511812
Analytical biotechnology; Cell biology; Diseases; Isothermal microcalorimetry; Metabolic flux analysis
14.  Subthreshold IKK activation modulates the effector functions of primary mast cells and allows specific targeting of transformed mast cells 
Oncotarget  2015;6(7):5354-5368.
Mast cell differentiation and proliferation depends on IL-3. IL-3 induces the activation of MAP-kinases and STATs and consequently induces proliferation and survival. Dysregulation of IL-3 signaling pathways also contribute to inflammation and tumorigenesis. We show here that IL-3 induces a SFK- and Ca2+-dependent activation of the inhibitor of κB kinases 2 (IKK2) which results in mast cell proliferation and survival but does not induce IκBα-degradation and NFκB activation. Therefore we propose the term “subthreshold IKK activation”.
This subthreshold IKK activation also primes mast cells for enhanced responsiveness to IL-33R signaling. Consequently, co-stimulation with IL-3 and IL-33 increases IKK activation and massively enhances cytokine production induced by IL-33.
We further reveal that in neoplastic mast cells expressing constitutively active Ras, subthreshold IKK activation is associated with uncontrolled proliferation. Consequently, pharmacological IKK inhibition reduces tumor growth selectively by inducing apoptosis in vivo.
Together, subthreshold IKK activation is crucial to mediate the full IL-33-induced effector functions in primary mast cells and to mediate uncontrolled proliferation of neoplastic mast cells. Thus, IKK2 is a new molecularly defined target structure.
PMCID: PMC4467154  PMID: 25749030
Mast cells; subthreshold IKK activation; mitogenic signaling; NFκB-activation
16.  Prestin is an anion transporter dispensable for mechanical feedback amplification in Drosophila hearing 
In mammals, the membrane-based protein Prestin confers unique electromotile properties to cochlear outer hair cells, which contribute to the cochlear amplifier. Like mammals, the ears of insects, such as those of Drosophila melanogaster, mechanically amplify sound stimuli and have also been reported to express Prestin homologs. To determine whether the D. melanogaster Prestin homolog (dpres) is required for auditory amplification, we generated and analyzed dpres mutant flies. We found that dpres is robustly expressed in the fly’s antennal ear. However, dpres mutant flies show normal auditory nerve responses, and intact non-linear amplification. Thus we conclude that, in D. melanogaster, auditory amplification is independent of Prestin. This finding resonates with prior phylogenetic analyses, which suggest that the derived motor function of mammalian Prestin replaced, or amended, an ancestral transport function. Indeed, we show that dpres encodes a functional anion transporter. Interestingly, the acquired new motor function in the phylogenetic lineage leading to birds and mammals coincides with loss of the mechanotransducer channel NompC (=TRPN1), which has been shown to be required for auditory amplification in flies. The advent of Prestin (or loss of NompC, respectively) may thus mark an evolutionary transition from a transducer-based to a Prestin-based mechanism of auditory amplification.
Electronic supplementary material
The online version of this article (doi:10.1007/s00359-014-0960-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00359-014-0960-9
PMCID: PMC4282873  PMID: 25412730
Prestin; Mechanical amplification of sound; Auditory amplification; Drosophila hearing; NompC
17.  The differential production cross section of the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\phi $$\end{document}ϕ(1020) meson in \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sqrt{s}$$\end{document}s = 7 TeV \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$pp$$\end{document}pp collisions measured with the ATLAS detector 
Aad, G. | Abajyan, T. | Abbott, B. | Abdallah, J. | Abdel Khalek, S. | Abdelalim, A. A. | Abdinov, O. | Aben, R. | Abi, B. | Abolins, M. | AbouZeid, O. S. | Abramowicz, H. | Abreu, H. | Acharya, B. S. | Adamczyk, L. | Adams, D. L. | Addy, T. N. | Adelman, J. | Adomeit, S. | Adragna, P. | Adye, T. | Aefsky, S. | Aguilar-Saavedra, J. A. | Agustoni, M. | Aharrouche, M. | Ahlen, S. P. | Ahles, F. | Ahmad, A. | Ahsan, M. | Aielli, G. | Åkesson, T. P. A. | Akimoto, G. | Akimov, A. V. | Alam, M. S. | Alam, M. A. | Albert, J. | Albrand, S. | Aleksa, M. | Aleksandrov, I. N. | Alessandria, F. | Alexa, C. | Alexander, G. | Alexandre, G. | Alexopoulos, T. | Alhroob, M. | Aliev, M. | Alimonti, G. | Alison, J. | Allbrooke, B. M. M. | Allport, P. P. | Allwood-Spiers, S. E. | Almond, J. | Aloisio, A. | Alon, R. | Alonso, A. | Alonso, F. | Altheimer, A. | Alvarez Gonzalez, B. | Alviggi, M. G. | Amako, K. | Amelung, C. | Ammosov, V. V. | Amor Dos Santos, S. 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M. | Gray, J. A. | Graziani, E. | Grebenyuk, O. G. | Greenshaw, T. | Greenwood, Z. D. | Gregersen, K. | Gregor, I. M. | Grenier, P. | Griffiths, J. | Grigalashvili, N. | Grillo, A. A. | Grinstein, S. | Gris, Ph. | Grishkevich, Y. V. | Grivaz, J. -F. | Gross, E. | Grosse-Knetter, J. | Groth-Jensen, J. | Grybel, K. | Guest, D. | Guicheney, C. | Guido, E. | Guindon, S. | Gul, U. | Gunther, J. | Guo, B. | Guo, J. | Gutierrez, P. | Guttman, N. | Gutzwiller, O. | Guyot, C. | Gwenlan, C.
A measurement is presented of the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\phi \times \mathcal {BR}(\phi \rightarrow K^{+}K^{-})$$\end{document}ϕ×BR(ϕ→K+K-) production cross section at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sqrt{s}$$\end{document}s = 7 TeV using \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$pp$$\end{document}pp collision data corresponding to an integrated luminosity of 383 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm {\upmu b^{-1}}$$\end{document}μb-1, collected with the ATLAS experiment at the LHC. Selection of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\phi $$\end{document}ϕ(1020) mesons is based on the identification of charged kaons by their energy loss in the pixel detector. The differential cross section is measured as a function of the transverse momentum, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p_{\mathrm {T,\phi }}$$\end{document}pT,ϕ, and rapidity, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$y_{\phi }$$\end{document}yϕ, of the \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\phi $$\end{document}ϕ(1020) meson in the fiducial region 500 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$$$\end{document}pT,K> 230 MeV and kaon momentum \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$p_{K}<$$\end{document}pK< 800 MeV. The integrated \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\phi (1020)$$\end{document}ϕ(1020)-meson production cross section in this fiducial range is measured to be \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sigma _{\phi } \times \mathcal {BR}(\phi \rightarrow K^{+}K^{-}) $$\end{document}σϕ×BR(ϕ→K+K-) = 570 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\pm $$\end{document}± 8 (stat) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\pm $$\end{document}± 66 (syst) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\pm $$\end{document}± 20 (lumi) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\mathrm {\upmu b}$$\end{document}μb.
doi:10.1140/epjc/s10052-014-2895-2
PMCID: PMC4371126  PMID: 25814898
18.  hemingway is required for sperm flagella assembly and ciliary motility in Drosophila 
Molecular Biology of the Cell  2014;25(8):1276-1286.
Motile cilia play important functions in many organisms. In Drosophila, hemingway (hmw) encodes a novel protein conserved in species with motile cilia. hmw-mutant flies are hearing impaired and male sterile. HMW is required for acquisition of motile properties of cilia in the fly sound receiver and stability of the sperm axoneme.
Cilia play major functions in physiology and development, and ciliary dysfunctions are responsible for several diseases in humans called ciliopathies. Cilia motility is required for cell and fluid propulsion in organisms. In humans, cilia motility deficiencies lead to primary ciliary dyskinesia, with upper-airways recurrent infections, left–right asymmetry perturbations, and fertility defects. In Drosophila, we identified hemingway (hmw) as a novel component required for motile cilia function. hmw encodes a 604–amino acid protein characterized by a highly conserved coiled-coil domain also found in the human orthologue, KIAA1430. We show that HMW is conserved in species with motile cilia and that, in Drosophila, hmw is expressed in ciliated sensory neurons and spermatozoa. We created hmw-knockout flies and found that they are hearing impaired and male sterile. hmw is implicated in the motility of ciliated auditory sensory neurons and, in the testis, is required for elongation and maintenance of sperm flagella. Because HMW is absent from mature flagella, we propose that HMW is not a structural component of the motile axoneme but is required for proper acquisition of motile properties. This identifies HMW as a novel, evolutionarily conserved component necessary for motile cilium function and flagella assembly.
doi:10.1091/mbc.E13-10-0616
PMCID: PMC3982993  PMID: 24554765
19.  Reception and learning of electric fields in bees 
Honeybees, like other insects, accumulate electric charge in flight, and when their body parts are moved or rubbed together. We report that bees emit constant and modulated electric fields when flying, landing, walking and during the waggle dance. The electric fields emitted by dancing bees consist of low- and high-frequency components. Both components induce passive antennal movements in stationary bees according to Coulomb's law. Bees learn both the constant and the modulated electric field components in the context of appetitive proboscis extension response conditioning. Using this paradigm, we identify mechanoreceptors in both joints of the antennae as sensors. Other mechanoreceptors on the bee body are potentially involved but are less sensitive. Using laser vibrometry, we show that the electrically charged flagellum is moved by constant and modulated electric fields and more strongly so if sound and electric fields interact. Recordings from axons of the Johnston organ document its sensitivity to electric field stimuli. Our analyses identify electric fields emanating from the surface charge of bees as stimuli for mechanoreceptors, and as biologically relevant stimuli, which may play a role in social communication.
doi:10.1098/rspb.2013.0528
PMCID: PMC3619523  PMID: 23536603
electric surface charge; mechanoreceptors as sensors for electric fields; Johnston organ; learning of electric field stimuli
20.  Do medical students want to learn about global health? 
Global Health Action  2014;7:10.3402/gha.v7.23943.
Background
One objective of the United Nations Global Strategy for Women's and Children's Health relates to ensuring a sufficiently skilled workforce. To prepare future healthcare professionals for their role in the 21st century as members of this workforce, awareness of global health is essential, but few studies have explored student perspectives on such education. The main objectives of this study were to establish the views of medical students on learning about women's and children's health in low-income countries, to identify the nature and extent of learning already experienced, and to assess the demand for such learning.
Design
A questionnaire survey was conducted at three meetings of the International Federation of Medical Students Associations (IFMSA). Questionnaires were distributed to 500 participants from 75 countries and 336 medical schools, and 492 usable questionnaires were returned. Data were analysed using SPSS Version 20 and statistical analysis was undertaken using Fisher's exact test.
Results
There were 492 questionnaires included in the analysis. Forty-eight per cent of participants were from low–middle income countries and 52% were from high-income countries. Less than half (43%) of the respondents had received some teaching on women's and children's health in low-income countries. Teaching received was primarily (96%) through lectures in the second year of study. Ninety-one per cent of respondents thought such teaching would be important and stated that group work (66%) would be the preferred method. In total, only 14% thought they had received sufficient teaching on global health and on women's and children's health in low-income countries.
Conclusions
This study has revealed a high demand among medical students for global health teaching, particularly on women's and children's health in low-income countries. The timing and methods of existing teaching on these topics does not match that desired by medical students. To help address this gap, a collaborative approach is proposed which includes students’ views in the processes for revitalising medical curricula to meet the needs of the 21st century.
doi:10.3402/gha.v7.23943
PMCID: PMC4028928  PMID: 24848658
global; maternal; child; health; student; curriculum; medical education
21.  Forearm pressure distribution during ambulation with elbow crutches: a cross-sectional study 
Background
Increasing numbers of patients require permanent walking aids to maintain mobility. Current elbow crutches are not designed for long-term use, and overuse is often associated with hematoma formation and pain along the forearm. We therefore hypothesized that the highest pressures between the forearm and crutch cuff during walking and stance are located in the ulnar region and that the level of weight-bearing, forearm circumference and kinematic parameters influence peak pressure values and pressure distribution.
Methods
Ten healthy adults participated in a cross-sectional study. A pressure sensor array was attached to the forearm of each participant separating the forearm into four quadrants (lateral, ulnar, intermediate and medial). Measurements were taken during crutch gait and during partial and full weight-bearing stance. A three-dimensional motion analysis system with reflective markers attached to the subject’s body and to the crutches was used to obtain kinematic data.
Results
The mean pressure on the forearm during crutch gait was 37.5 kPa (SD 8.8 kPa). Highest mean pressure values were measured in the ulnar (41.0 kPa, SD 9.6 kPa) and intermediate (38.0 kPa, SD 9.0 kPa) quadrants. The center of pressure was mainly located in an oblique lamellar area in these two quadrants. With increasing weight-bearing on the crutches during stance, we observed a shift of the peak pressures towards the ulnar quadrant. The circumference of the forearm correlated with the peak pressure in the medial and intermediate quadrants during crutch gait (P < 0.05). Peak pressures on the forearm showed a trend towards correlation with crutch abduction, but no association with other kinematic parameters was detected.
Conclusion
The pressure load on the forearm during crutch-assisted gait is located predominantly over the ulna and may be linked to a range of secondary conditions caused by crutch use including hematoma formation and pain.
doi:10.1186/1743-0003-11-61
PMCID: PMC3996167  PMID: 24731773
Crutch gait; Forearm; Pressure distribution; Peak pressure; Center of pressure
22.  Saccadic body turns in walking Drosophila 
Drosophila melanogaster structures its optic flow during flight by interspersing translational movements with abrupt body rotations. Whether these “body saccades” are accompanied by steering movements of the head is a matter of debate. By tracking single flies moving freely in an arena, we now discovered that walking Drosophila also perform saccades. Movement analysis revealed that the flies separate rotational from translational movements by quickly turning their bodies by 15 degrees within a tenth of a second. Although walking flies moved their heads by up to 20 degrees about their bodies, their heads moved with the bodies during saccadic turns. This saccadic strategy contrasts with the head saccades reported for e.g., blowflies and honeybees, presumably reflecting optical constraints: modeling revealed that head saccades as described for these latter insects would hardly affect the retinal input in Drosophila because of the lower acuity of its compound eye. The absence of head saccades in Drosophila was associated with the absence of haltere oscillations, which seem to guide head movements in other flies. In addition to adding new twists to Drosophila walking behavior, our analysis shows that Drosophila does not turn its head relative to its body when turning during walking.
doi:10.3389/fnbeh.2014.00365
PMCID: PMC4205811  PMID: 25386124
Drosophila; saccades; optic flow; visual acuity; halteres; walking; head body coordination
23.  A Global In Vivo Drosophila RNAi Screen Identifies a Key Role of Ceramide Phosphoethanolamine for Glial Ensheathment of Axons 
PLoS Genetics  2013;9(12):e1003980.
Glia are of vital importance for all complex nervous system. One of the many functions of glia is to insulate and provide trophic and metabolic support to axons. Here, using glial-specific RNAi knockdown in Drosophila, we silenced 6930 conserved genes in adult flies to identify essential genes and pathways. Among our screening hits, metabolic processes were highly represented, and genes involved in carbohydrate and lipid metabolic pathways appeared to be essential in glia. One critical pathway identified was de novo ceramide synthesis. Glial knockdown of lace, a subunit of the serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathies in humans, resulted in ensheathment defects of peripheral nerves in Drosophila. A genetic dissection study combined with shotgun high-resolution mass spectrometry of lipids showed that levels of ceramide phosphoethanolamine are crucial for axonal ensheathment by glia. A detailed morphological and functional analysis demonstrated that the depletion of ceramide phosphoethanolamine resulted in axonal defasciculation, slowed spike propagation, and failure of wrapping glia to enwrap peripheral axons. Supplementing sphingosine into the diet rescued the neuropathy in flies. Thus, our RNAi study in Drosophila identifies a key role of ceramide phosphoethanolamine in wrapping of axons by glia.
Author Summary
Glia are essential for the function of any nervous system. The number of glia correlates with the complexity of the nervous system. Important functions of glia include maintaining ionic homeostasis, supporting neurotransmission, and insulating axons to speed up nerve conduction. The biomedical relevance of glia is highlighted by an increasing number of neurological diseases, in which glia appear to play an essential role, ranging from neuropathies to schizophrenia. Here, we performed a global in vivo glial-specific RNAi screen of evolutionary conserved genes in Drosophila. With this approach, we identified 736 candidate genes that resulted in lethality or motor deficits when knocked down specifically in glia. One essential pathway identified was ceramide phosphoethanolamine biosynthesis, which was found to be important for wrapping glia to extend their membrane around axons of the peripheral nerve. Our study illustrates that a large-scale screen in Drosophila, in combination with morphological analysis is able to dissect the basic mechanism of neuron-glia communication and identify candidate genes in human neuropathies.
doi:10.1371/journal.pgen.1003980
PMCID: PMC3861124  PMID: 24348263
24.  Improved luminosity determination in pp collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt {s} = 7\ \mathrm{TeV}$\end{document} using the ATLAS detector at the LHC 
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The luminosity calibration for the ATLAS detector at the LHC during pp collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s} = 7~\mathrm{TeV}$\end{document} in 2010 and 2011 is presented. Evaluation of the luminosity scale is performed using several luminosity-sensitive detectors, and comparisons are made of the long-term stability and accuracy of this calibration applied to the pp collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s} = 7~\mathrm{TeV}$\end{document}. A luminosity uncertainty of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\delta\mathcal{L}/ \mathcal{L} = \pm 3.5~\%$\end{document} is obtained for the 47 pb−1 of data delivered to ATLAS in 2010, and an uncertainty of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\delta\mathcal{L}/ \mathcal{L} = \pm1.8~\%$\end{document} is obtained for the 5.5 fb−1 delivered in 2011.
doi:10.1140/epjc/s10052-013-2518-3
PMCID: PMC4370906  PMID: 25814867
25.  Measurement of the inclusive jet cross-section in pp collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s}=2.76\ \mbox{TeV}$\end{document} and comparison to the inclusive jet cross-section at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s} =7\ \mbox{TeV}$\end{document} using the ATLAS detector 
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The inclusive jet cross-section has been measured in proton–proton collisions at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s} = 2.76~\mbox{TeV}$\end{document} in a dataset corresponding to an integrated luminosity of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$0.20~\mbox {pb$^{-1}$}$\end{document} collected with the ATLAS detector at the Large Hadron Collider in 2011. Jets are identified using the anti-kt algorithm with two radius parameters of 0.4 and 0.6. The inclusive jet double-differential cross-section is presented as a function of the jet transverse momentum pT and jet rapidity y, covering a range of 20≤pT<430 GeV and |y|<4.4. The ratio of the cross-section to the inclusive jet cross-section measurement at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s} = 7~\mbox{TeV}$\end{document}, published by the ATLAS Collaboration, is calculated as a function of both transverse momentum and the dimensionless quantity \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$x_{\mathrm{T}} = 2 p_{\mathrm{T}} / \sqrt{s}$\end{document}, in bins of jet rapidity. The systematic uncertainties on the ratios are significantly reduced due to the cancellation of correlated uncertainties in the two measurements. Results are compared to the prediction from next-to-leading order perturbative QCD calculations corrected for non-perturbative effects, and next-to-leading order Monte Carlo simulation. Furthermore, the ATLAS jet cross-section measurements at \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s} = 2.76~\mbox{TeV}$\end{document} and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\sqrt{s}=7~\mbox{TeV}$\end{document} are analysed within a framework of next-to-leading order perturbative QCD calculations to determine parton distribution functions of the proton, taking into account the correlations between the measurements.
doi:10.1140/epjc/s10052-013-2509-4
PMCID: PMC4400855  PMID: 25904819

Results 1-25 (55)