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Background: Beyond survival of nowadays >80%, modern childhood cancer treatment strives to preserve long-term health and quality of life. However, the majority of today’s survivors suffer from short- and long-term adverse effects such as cardiovascular and pulmonary diseases, obesity, osteoporosis, fatigue, depression, and reduced physical fitness and quality of life. Regular exercise can play a major role to mitigate or prevent such late-effects. Despite this, there are no data on the effects of regular exercise in childhood cancer survivors from randomized controlled trials (RCTs). \(Primary\) \(outcome\) of the current RCT is therefore the effect of a 12-months exercise program on a composite cardiovascular disease risk score in childhood cancer survivors. \(Secondary\) \(outcomes\) are single cardiovascular disease risk factors, glycaemic control, bone health, body composition, physical fitness, physical activity, quality of life, mental health, fatigue and adverse events (safety).
Methods: A total of 150 childhood cancer survivors aged ≥16 years and diagnosed ≥5 years prior to the study are recruited from Swiss paediatric oncology clinics. Following the baseline assessments patients are randomized 1:1 into an intervention and control group. Thereafter, they are seen at month 3, 6 and 12 for follow-up assessments. The intervention group is asked to add ≥2.5 h of intense physical activity/week, including 30 min of strength building and 2 h of aerobic exercises. In addition, they are told to reduce screen time by 25%. Regular consulting by physiotherapists, individual web-based activity diaries, and pedometer devices are used as motivational tools for the intervention group. The control group is asked to keep their physical activity levels constant.
Discussion: The results of this study will show whether a partially supervised exercise intervention can improve cardiovascular disease risk factors, bone health, body composition, physical activity and fitness, fatigue, mental health and quality of life in childhood cancer survivors. If the program will be effective, all relevant information of the SURfit physical activity intervention will be made available to interested clinics that treat and follow-up childhood cancer patients to promote exercise in their patients.
A search is presented for the pair production of heavy vector-like \(T\) quarks, primarily targeting the \(T\) quark decays to a \(W\) boson and a \(b\)-quark. The search is based on 36.1 fb\(^{−1}\) of \(pp\) collisions at \(\sqrt{s}=13\) TeV recorded in 2015 and 2016 with the ATLAS detector at the CERN Large Hadron Collider. Data are analysed in the lepton-plus-jets final state, including at least one \(b\)-tagged jet and a large-radius jet identified as originating from the hadronic decay of a high-momentum \(W\) boson. No significant deviation from the Standard Model expectation is observed in the reconstructed \(T\) mass distribution. The observed 95% confidence level lower limit on the \(T\) mass are 1350 GeV assuming 100% branching ratio to \(Wb\). In the SU(2) singlet scenario, the lower mass limit is 1170 GeV. This search is also sensitive to a heavy vector-like \(B\) quark decaying to \(Wt\) and other final states. The results are thus reinterpreted to provide a 95% confidence level lower limit on the \(B\) quark mass at 1250 GeV assuming 100% branching ratio to \(Wt\); in the SU(2) singlet scenario, the limit is 1080 GeV. Mass limits on both \(T\) and \(B\) production are also set as a function of the decay branching ratios. The 100% branching ratio limits are found to be applicable to heavy vector-like \(Y\) and \(X\) production that decay to \(Wb\) and \(Wt\), respectively.
A search is conducted for new resonant and non-resonant high-mass phenomena in dielectron and dimuon final states. The search uses 36.1 fb\(^{−1}\) of proton-proton collision data, collected at \(\sqrt{s}=13\) TeV by the ATLAS experiment at the LHC in 2015 and 2016. No significant deviation from the Standard Model prediction is observed. Upper limits at 95% credibility level are set on the cross-section times branching ratio for resonances decaying into dileptons, which are converted to lower limits on the resonance mass, up to 4.1 TeV for the E\(_6\)-motivated \(Z^′_χ\). Lower limits on the \({qqℓℓ}\) contact interaction scale are set between 2.4 TeV and 40 TeV, depending on the model.
Purpose
To test quantitative functional lung MRI techniques in young adults with cystic fibrosis (CF) compared to healthy volunteers and to monitor immediate treatment effects of a single inhalation of hypertonic saline in comparison to clinical routine pulmonary function tests.
Materials and methods
Sixteen clinically stable CF patients and 12 healthy volunteers prospectively underwent two functional lung MRI scans and pulmonary function tests before and 2h after a single treatment of inhaled hypertonic saline or without any treatment. MRI-derived oxygen enhanced T1 relaxation measurements, fractional ventilation, first-pass perfusion parameters and a morpho-functional CF-MRI score were acquired.
Results
Compared to healthy controls functional lung MRI detected and quantified significantly increased ventilation heterogeneity in CF patients. Regional functional lung MRI measures of ventilation and perfusion as well as the CF-MRI score and pulmonary function tests could not detect a significant treatment effect two hours after a single treatment with hypertonic saline in young adults with CF (p>0.05).
Conclusion
This study shows the feasibility of functional lung MRI as a non-invasive, radiation-free tool for monitoring patients with CF.
Background
Depression is a common comorbidity in patients with chronic heart failure (HF) and linked to a wider range of symptoms which, in turn, are linked to a decreased health-related quality of life (HRQOL). Treatment of depression might improve HRQOL but detecting depression is difficult due to the symptom overlap between HF and depression. Therefore, clinical guidelines recommend to routinely screen for depression in HF patients. No studies have so far investigated the treatment after getting aware of a depressive symptomatology and its correlation with HRQOL in primary care HF patients. Therefore, we examined the factors linked to depression treatment and those linked to HRQOL in HF patients. We hypothesized that GPs’ awareness of depressive symptomatology was associated with depression treatment and HRQOL in HF patients.
Methods
For this observational study, HF patients were recruited in primary care practices and filled out a questionnaire including PHQ-9 and HADS. A total of 574 patients screened positive for depressive symptomatology. Their GPs were interviewed by phone regarding the patients’ comorbidities and potential depression treatment. Descriptive and regression analysis were performed.
Results
GPs reported various types of depression treatments (including dialogue/counselling by the GP him/herself in 31.8% of the patients). The reported rates differed considerably between GP-reported initiated treatment and patient-reported utilised treatment regarding psychotherapy (16.4% vs. 9.5%) and pharmacotherapy (61.2% vs. 30.3%). The GPs' awareness of depressive symptomatology was significantly associated with the likelihood of receiving pharmacotherapy (OR 2.8; p < 0.001) but not psychotherapy. The patient’s HRQOL was not significantly associated with the GPs' awareness of depression.
Conclusion
GPs should be aware of the gap between GP-initiated and patient-utilised depression treatments in patients with chronic HF, which might lead to an undersupply of depression treatment. It remains to be investigated why GPs’ awareness of depressive symptomatology is not linked to patients’ HRQOL. We hypothesize that GPs are aware of cases with reduced HRQOL (which improves under depression treatment) and unaware of cases whose depression do not significantly impair HRQOL, resulting in comparable levels of HRQOL in both groups. This hypothesis needs to be further investigated.
The cross section of a top-quark pair produced in association with a photon is measured in proton-proton collisions at a centre-of-mass energy of \(\sqrt{s} = 8\) TeV with 20.2 fb\(^{−1}\) of data collected by the ATLAS detector at the Large Hadron Collider in 2012. The measurement is performed by selecting events that contain a photon with transverse momentum \(p_T\) > 15 GeV, an isolated lepton with large transverse momentum, large missing transverse momentum, and at least four jets, where at least one is identified as originating from a \(b\)-quark. The production cross section is measured in a fiducial region close to the selection requirements. It is found to be 139 ± 7 (stat.) ± 17 (syst.) fb, in good agreement with the theoretical prediction at next-to-leading order of 151 ± 24 fb. In addition, differential cross sections in the fiducial region are measured as a function of the transverse momentum and pseudorapidity of the photon.
Measurements of differential cross-sections of top-quark pair production in fiducial phase-spaces are presented as a function of top-quark and \(t\overline{t}\) system kinematic observables in proton-proton collisions at a centre-of-mass energy of \(\sqrt{s}\) = 13 TeV. The data set corresponds to an integrated luminosity of 3.2 fb\(^{−1}\), recorded in 2015 with the ATLAS detector at the CERN Large Hadron Collider. Events with exactly one electron or muon and at least two jets in the final state are used for the measurement. Two separate selections are applied that each focus on different top-quark momentum regions, referred to as resolved and boosted topologies of the \(t\overline{t}\) final state. The measured spectra are corrected for detector effects and are compared to several Monte Carlo simulations by means of calculated \(χ^2\) and \(p\)-values.
Background
The lytic cycle of the protozoan parasite \(Toxoplasma\) \(gondii\), which involves a brief sojourn in the extracellular space, is characterized by defined transcriptional profiles. For an obligate intracellular parasite that is shielded from the cytosolic host immune factors by a parasitophorous vacuole, the brief entry into the extracellular space is likely to exert enormous stress. Due to its role in cellular stress response, we hypothesize that translational control plays an important role in regulating gene expression in \(Toxoplasma\) during the lytic cycle. Unlike transcriptional profiles, insights into genome-wide translational profiles of \(Toxoplasma\) \(gondii\) are lacking.
Methods
We have performed genome-wide ribosome profiling, coupled with high throughput RNA sequencing, in intracellular and extracellular \(Toxoplasma\) \(gondii\) parasites to investigate translational control during the lytic cycle.
Results
Although differences in transcript abundance were mostly mirrored at the translational level, we observed significant differences in the abundance of ribosome footprints between the two parasite stages. Furthermore, our data suggest that mRNA translation in the parasite is potentially regulated by mRNA secondary structure and upstream open reading frames.
Conclusion
We show that most of the \(Toxoplasma\) genes that are dysregulated during the lytic cycle are translationally regulated.
A search for the supersymmetric partners of the Standard Model bottom and top quarks is presented. The search uses 36.1 fb\(^{−1}\) of \(pp\) collision data at \(\sqrt{s}\) = 13 TeV collected by the ATLAS experiment at the Large Hadron Collider. Direct production of pairs of bottom and top squarks (\(\overline{b}_1\) and \(\overline{t}_1\)) is searched for in final states with \(b\)-tagged jets and missing transverse momentum. Distinctive selections are defined with either no charged leptons (electrons or muons) in the final state, or one charged lepton. The zero-lepton selection targets models in which the \(\overline{b}_1\) is the lightest squark and decays via \(\overline{b}_1\) → \(b\overline{χ}^0_1\), where \(\overline{χ}^0_1\) is the lightest neutralino. The one-lepton final state targets models where bottom or top squarks are produced and can decay into multiple channels, \(\overline{b}_1\) → \(b\overline{χ}^0_1\) and \(\overline{b}_1\) → \(t\overline{χ}^±_1\), or \(\overline{t}_1\) → \(t\overline{χ}^0_1\) and \(\overline{t}_1\) → \(b\overline{χ}^±_1\), where \(\overline{χ}^±_1\) is the lightest chargino and the mass difference \(m_{\overline{χ}^±_1}\) − \(m_{\overline{χ}^0_1}\) is set to 1 GeV. No excess above the expected Standard Model background is observed. Exclusion limits at 95% confidence level on the mass of third-generation squarks are derived in various supersymmetry-inspired simplified models.
Design and validation of a disease network of inflammatory processes in the NSG-UC mouse model
(2017)
Background: Ulcerative colitis (UC) is a highly progressive inflammatory disease that requires the interaction of epithelial, immune, endothelial and muscle cells and fibroblasts. Previous studies suggested two inflammatory conditions in UC-patients: ‘acute’ and ‘remodeling’ and that the design of a disease network might improve the understanding of the inflammatory processes. The objective of the study was to design and validate a disease network in the NOD-SCID IL2rγ\(^{null}\) (NSG)-UC mouse model to get a better understanding of the inflammatory processes.
Methods: Leukocytes were isolated from the spleen of NSG-UC mice and subjected to flow cytometric analysis. RT-PCR and RNAseq analysis were performed from distal parts of the colon. Based on these analyses and the effects of interleukins, chemokines and growth factors described in the literature, a disease network was designed. To validate the disease network the effect of infliximab and pitrakinra was tested in the NSG-UC model. A clinical- and histological score, frequencies of human leukocytes isolated from spleen and mRNA expression levels from distal parts of the colon were determined.
Results: Analysis of leukocytes isolated from the spleen of challenged NSG-UC mice corroborated CD64, CD163 and CD1a expressing CD14+ monocytes, CD1a expressing CD11b+ macrophages and HGF, TARC, IFNγ and TGFß1 mRNA as inflammatory markers. The disease network suggested that a proinflammatory condition elicited by IL-17c and lipids and relayed by cytotoxic T-cells, Th17 cells and CD1a expressing macrophages and monocytes. Conversely, the remodeling condition was evoked by IL-34 and TARC and promoted by Th2 cells and M2 monocytes. Mice benefitted from treatment with infliximab as indicated by the histological- and clinical score. As predicted by the disease network infliximab reduced the proinflammatory response by suppressing M1 monocytes and CD1a expressing monocytes and macrophages and decreased levels of IFNγ, TARC and HGF mRNA. As predicted by the disease network inflammation aggravated in the presence of pitrakinra as indicated by the clinical and histological score, elevated frequencies of CD1a expressing macrophages and TNFα and IFNγ mRNA levels.
Conclusions: The combination of the disease network and the NSG-UC animal model might be developed into a powerful tool to predict efficacy or in-efficacy and potential mechanistic side effects.
A search is presented for particles that decay producing a large jet multiplicity and invisible particles. The event selection applies a veto on the presence of isolated electrons or muons and additional requirements on the number of \(b\)-tagged jets and the scalar sum of masses of large-radius jets. Having explored the full ATLAS 2015-2016 dataset of LHC proton-proton collisions at \(\sqrt{s}\) = 13 TeV, which corresponds to 36.1 fb\(^{−1}\) of integrated luminosity, no evidence is found for physics beyond the Standard Model. The results are interpreted in the context of simplified models inspired by R-parity-conserving and R-parity-violating supersymmetry, where gluinos are pair-produced. More generic models within the phenomenological minimal supersymmetric Standard Model are also considered.
Cholesterol-dependent cytolysins (CDCs) are protein toxins that originate from Gram-positive bacteria and contribute substantially to their pathogenicity. CDCs bind membrane cholesterol and build prepores and lytic pores. Some effects of the toxins are observed in non-lytic concentrations. Two pathogens, \(Streptococcus\) \(pneumoniae\) and \(Listeria\) \(monocytogenes\), cause fatal bacterial meningitis, and both produce toxins of the CDC family—pneumolysin and listeriolysin O, respectively. It has been demonstrated that pneumolysin produces dendritic varicosities (dendrite swellings) and dendritic spine collapse in the mouse neocortex, followed by synaptic loss and astrocyte cell shape remodeling without elevated cell death. We utilized primary glial cultures and acute mouse brain slices to examine the neuropathological effects of listeriolysin O and to compare it to pneumolysin with identical hemolytic activity. In cultures, listeriolysin O permeabilized cells slower than pneumolysin did but still initiated non-lytic astrocytic cell shape changes, just as pneumolysin did. In an acute brain slice culture system, listeriolysin O produced dendritic varicosities in an NMDA-dependent manner but failed to cause dendritic spine collapse and cortical astrocyte reorganization. Thus, listeriolysin O demonstrated slower cell permeabilization and milder glial cell remodeling ability than did pneumolysin and lacked dendritic spine collapse capacity but exhibited equivalent dendritic pathology.
A search for pair production of a scalar partner of the top quark in events with four or more jets plus missing transverse momentum is presented. An analysis of 36.1 fb\(^{−1}\) of \(\sqrt{s}\) = 13 TeV proton-proton collisions collected using the ATLAS detector at the LHC yields no significant excess over the expected Standard Model background. To interpret the results a simplified supersymmetric model is used where the top squark is assumed to decay via \(\tilde{t}_1\) → \(t^{(∗)}\)\(\tilde{χ}^0_1\) and \(\tilde{t}_1\) → \(b\tilde{χ}^±_1\) → \({bW}^{(∗)}\tilde{χ}^0_1\), where \(\tilde{χ}^0_1\) (\(\tilde{χ}^±_1\)) denotes the lightest neutralino (chargino). Exclusion limits are placed in terms of the top-squark and neutralino masses. Assuming a branching ratio of 100% to \(t\tilde{χ}^0_1\), top-squark masses in the range 450–1000 GeV are excluded for \(\tilde{χ}^0_1\) masses below 160 GeV. In the case where \(m_{\tilde{t}_1}\) ∼ \(m_t\) + \(m_{\tilde{χ}^0_1}\), top-squark masses in the range 235–590 GeV are excluded.
Advanced LIGO detected a significant gravitational wave signal (GW170104) originating from the coalescence of two black holes during the second observation run on January 4th, 2017. An all-sky high-energy neutrino follow-up search has been made using data from the Antares neutrino telescope, including both upgoing and downgoing events in two separate analyses. No neutrino candidates were found within ±500 s around the GW event time nor any time clustering of events over an extended time window of ±3 months. The non-detection is used to constrain isotropic-equivalent high-energy neutrino emission from GW170104 to less than ∼ 1.2 × \(10^{55}\) erg for a \(E^{−2}\) spectrum. This constraint is valid in the energy range corresponding to the 5–95% quantiles of the neutrino flux [3.2 TeV; 3.6 PeV], if the GW emitter was below the Antares horizon at the alert time.
This paper presents a measurement of the triple-differential cross section for the Drell-Yan process \({Z/γ^*}\) → ℓ\(^+\)ℓ\(^-\) where ℓ is an electron or a muon. The measurement is performed for invariant masses of the lepton pairs, \(m_{ℓℓ}\) , between 46 and 200 GeV using a sample of 20.2 fb\(^{−1}\) of \(pp\) collisions data at a centre-of-mass energy of \(\sqrt{s}\) = 8 TeV collected by the ATLAS detector at the LHC in 2012. The data are presented in bins of invariant mass, absolute dilepton rapidity, |\(y_{ℓℓ}\)|, and the angular variable cos \(θ^*\) between the outgoing lepton and the incoming quark in the Collins-Soper frame. The measurements are performed in the range |\(y_{ℓℓ}\)| < 2.4 in the muon channel, and extended to |\(y_{ℓℓ}\)| < 3.6 in the electron channel. The cross sections are used to determine the \(Z\) boson forward-backward asymmetry as a function of |\(y_{ℓℓ}\)| and \(m_{ℓℓ}\) . The measurements achieve high-precision, below the percent level in the pole region, excluding the uncertainty in the integrated luminosity, and are in agreement with predictions. These precision data are sensitive to the parton distribution functions and the effective weak mixing angle.
A search for the decay of the Standard Model Higgs boson into a \({b\overline{b}}\) pair when produced in association with a \(W\) or \(Z\) boson is performed with the ATLAS detector. The analysed data, corresponding to an integrated luminosity of 36.1 fb\(^{−1}\), were collected in proton-proton collisions in Run 2 of the Large Hadron Collider at a centre-of-mass energy of 13 TeV. Final states containing zero, one and two charged leptons (electrons or muons) are considered, targeting the decays \(Z\) → \({νν}\), \(W\) → \({ℓν}\) and \(Z\) → \({ℓℓ}\). For a Higgs boson mass of 125 GeV, an excess of events over the expected background from other Standard Model processes is found with an observed significance of 3.5 standard deviations, compared to an expectation of 3.0 standard deviations. This excess provides evidence for the Higgs boson decay into b-quarks and for its production in association with a vector boson. The combination of this result with that of the Run 1 analysis yields a ratio of the measured signal events to the Standard Model expectation equal to 0.90 ± 0.18(stat.)\(^{+0.21}_{−0.19}\)(syst.). Assuming the Standard Model production cross-section, the results are consistent with the value of the Yukawa coupling to \(b\)-quarks in the Standard Model.
Functional selectivity of G-protein-coupled receptors is believed to originate from ligand-specific conformations that activate only subsets of signaling effectors. In this study, to identify molecular motifs playing important roles in transducing ligand binding into distinct signaling responses, we combined in silico evolutionary lineage analysis and structure-guided site-directed mutagenesis with large-scale functional signaling characterization and non-negative matrix factorization clustering of signaling profiles. Clustering based on the signaling profiles of 28 variants of the β\(_2\)-adrenergic receptor reveals three clearly distinct phenotypical clusters, showing selective impairments of either the Gi or βarrestin/endocytosis pathways with no effect on Gs activation. Robustness of the results is confirmed using simulation-based error propagation. The structural changes resulting from functionally biasing mutations centered around the DRY, NPxxY, and PIF motifs, selectively linking these micro-switches to unique signaling profiles. Our data identify different receptor regions that are important for the stabilization of distinct conformations underlying functional selectivity.
The electroweak production and subsequent decay of single top quarks in the \(t\)-channel is determined by the properties of the \({Wtb}\) vertex, which can be described by the complex parameters of an effective Lagrangian. An analysis of a triple-differential decay rate in \(t\)-channel production is used to simultaneously determine five generalised helicity fractions and phases, as well as the polarisation of the produced top quark. The complex parameters are then constrained. This analysis is based on 20.2 fb\(^{−1}\) of proton-proton collision data at a centre-of-mass energy of 8 TeV collected with the ATLAS detector at the LHC. The fraction of decays containing transversely polarised \(W\) bosons is measured to be \(f_1\) = 0.30 ± 0.05. The phase between amplitudes for transversely and longitudinally polarised \(W\) bosons recoiling against left-handed \(b\)-quarks is measured to be \(\delta\)_ = 0.002\(\pi^{+0.016\pi}_{+0.017\pi}\), giving no indication of CP violation. The fractions of longitudinal or transverse \(W\) bosons accompanied by right-handed \(b\)-quarks are also constrained. Based on these measurements, limits are placed at 95% CL on the ratio of the complex coupling parameters Re [\({g_R/V_L}\) \(\in\) [−0.12, 0.17] and Im [\({g_R/V_L}\) \(\in\) [−0.07, 0.06]. Constraints are also placed on the ratios |\({V_R}/{V_L}\)| and |\({g_L}/{V_L}\)|. In addition, the polarisation of single top quarks in the \(t\)-channel is constrained to be \(P\) > 0.72 (95% CL). None of the above measurements make assumptions about the value of any of the other parameters or couplings and all of them are in agreement with the Standard Model.
proGenomes: a resource for consistent functional and taxonomic annotations of prokaryotic genomes
(2017)
The availability of microbial genomes has opened many new avenues of research within microbiology. This has been driven primarily by comparative genomics approaches, which rely on accurate and consistent characterization of genomic sequences. It is nevertheless difficult to obtain consistent taxonomic and integrated functional annotations for defined prokaryotic clades. Thus, we developed proGenomes, a resource that provides user-friendly access to currently 25 038 high-quality genomes whose sequences and consistent annotations can be retrieved individually or by taxonomic clade. These genomes are assigned to 5306 consistent and accurate taxonomic species clusters based on previously established methodology. proGenomes also contains functional information for almost 80 million protein-coding genes, including a comprehensive set of general annotations and more focused annotations for carbohydrate-active enzymes and antibiotic resistance genes. Additionally, broad habitat information is provided for many genomes. All genomes and associated information can be downloaded by user-selected clade or multiple habitat-specific sets of representative genomes. We expect that the availability of high-quality genomes with comprehensive functional annotations will promote advances in clinical microbial genomics, functional evolution and other subfields of microbiology. proGenomes is available at http://progenomes.embl.de.
The orthorhombic rare-earth manganite compounds \(R\)MnO\(_3\) show a global magnetic order for \(T\) < \(T\)\(_N\), and several representatives are multiferroic with a cycloidal spin ground state order for \(T\) < \(T\)\(_c\)\(_y\)\(_c\)\(_l\) < \(T\)\(_N\) \(\approx\) 40 K. We deduce from the temperature dependence of spin–phonon coupling in Raman spectroscopy for a series of \(R\)MnO\(_3\) compounds that their spin order locally persists up to about twice \(T\)\(_N\). Along the same line, our observation of the persistence of the electromagnon in GdMnO\(_3\) up to \(T\) \(\approx\) 100 K is attributed to a local cycloidal spin order for \(T\) > \(T\)\(_c\)\(_y\)\(_c\)\(_l\), in contrast to the hitherto assumed incommensurate sinusoidal phase in the intermediate temperature range. The development of the magnetization pattern can be described in terms of an order–disorder transition at \(T\)\(_c\)\(_y\)\(_c\)\(_l\) within a pseudospin model of localized spin cycloids with opposite chirality.
Surgical implantation of a biomaterial triggers foreign-body-induced fibrous encapsulation. Two major mechanisms of this complex physiological process are (I) chemotaxis of fibroblasts from surrounding tissue to the implant region, followed by (II) tissue remodeling. As an alternative to animal studies, we here propose a process-aligned \({in}\) \({vitro}\) test platform to investigate the material dependency of fibroblast chemotaxis and tissue remodeling mediated by material-resident macrophages.
Embedded in a biomimetic three-dimensional collagen hydrogel, chemotaxis of fibroblasts in the direction of macrophage-material-conditioned cell culture supernatant was analyzed by live cell imaging. A combination of statistical analysis with a complementary parameterized random walk model allowed quantitative and qualitative characterization of the cellular walk process. We thereby identified an increasing macrophage-mediated chemotactic potential ranking of biomaterials from glass over polytetrafluorethylene to titanium. To address long-term effects of biomaterial-resident macrophages on fibroblasts in a three-dimensional microenvironment, we further studied tissue remodeling by applying macrophage-material-conditioned medium on fibrous \({in}\) \({vitro}\) tissue models. A high correlation of the \({in}\) \({vitro}\) tissue model to state of the art \({in}\) \({vivo}\) study data was found. Titanium exhibited a significantly lower tissue remodeling capacity compared to polytetrafluorethylene. With this approach, we identified a material dependency of both chemotaxis and tissue remodeling processes, strengthening knowledge on their specific contribution to the foreign body reaction.
Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [\(^{68}\)Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies.
Thirty-five patients with MM underwent [\(^{68}\)Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [\(^{18}\)F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity.
[\(^{68}\)Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [\(^{18}\)F]FDG was available, [\(^{68}\)Ga]Pentixafor-PET detected more lesions in 4/19 (21%) subjects, [\(^{18}\)F]FDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions. [\(^{18}\)F]FDG-PET positivity correlated with [\(^{68}\)Ga]Pentixafor-PET positivity (p=0.018).
[\(^{68}\)Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.
[60]Fullerene hexakisadducts possessing 12 carboxylic acid side chains form crystalline hydrogen-bonding frameworks in the solid state. Depending on the length of the linker between the reactive sites and the malonate units, the distance of the [60]fullerene nodes and thereby the spacing of the frameworks can be controlled and for the most elongated derivative, continuous channels are obtained within the structure. Stability, structural integrity and porosity of the material were investigated by powder X-ray diffraction, thermogravimetry and sorption measurements.
West African summer monsoon precipitation is characterized by distinct decadal variability. Due to its welldocumented link to oceanic boundary conditions in various ocean basins it represents a paradigm for decadal predictability. In this study, we reappraise this hypothesis for several sub-regions of sub-Saharan West Africa using the new German contribution to the coupled model intercomparison project phase 5 (CMIP5) near-term prediction system.
In addition, we assume that dynamical downscaling of the global decadal predictions leads to an enhanced predictive skill because enhanced resolution improves the atmospheric response to oceanic forcing and landsurface feedbacks. Based on three regional climate models, a heterogeneous picture is drawn: none of the regional climate models outperforms the global decadal predictions or all other regional climate models in every region nor decade. However, for every test case at least one regional climate model was identified which outperforms the global predictions. The highest predictive skill is found in the western and central Sahel Zone with correlation coefficients and mean-square skill scores exceeding 0.9 and 0.8, respectively.
Hangover links nuclear RNA signaling to cAMP regulation via the phosphodiesterase 4d ortholog dunce
(2017)
The hangover gene defines a cellular stress pathway that is required for rapid ethanol tolerance in Drosophila melanogaster. To understand how cellular stress changes neuronal function, we analyzed Hangover function on a cellular and neuronal level. We provide evidence that Hangover acts as a nuclear RNA binding protein and we identified the phosphodiesterase 4d ortholog dunce as a target RNA. We generated a transcript-specific dunce mutant that is impaired not only in ethanol tolerance but also in the cellular stress response. At the neuronal level, Dunce and Hangover are required in the same neuron pair to regulate experience-dependent motor output. Within these neurons, two cyclic AMP (cAMP)-dependent mechanisms balance the degree of tolerance. The balance is achieved by feedback regulation of Hangover and dunce transcript levels. This study provides insight into how nuclear Hangover/RNA signaling is linked to the cytoplasmic regulation of cAMP levels and results in neuronal adaptation and behavioral changes.
Self-organization is a promising method within the framework of bottom-up architectures to generate nanostructures in an efficient way. The present work demonstrates that self- organization on the length scale of a few to several tens of nanometers can be achieved by a proper combination of a large (organic) molecule and a vicinal metal surface if the local bonding of the molecule on steps is significantly stronger than that on low-index surfaces. In this case thermal annealing may lead to large mass transport of the subjacent substrate atoms such that nanometer-wide and micrometer-long molecular stripes or other patterns are being formed on high-index planes. The formation of these patterns can be controlled by the initial surface orientation and adsorbate coverage. The patterns arrange self-organized in regular arrays by repulsive mechanical interactions over long distances accompanied by a significant enhancement of surface stress. We demonstrate this effect using the planar organic molecule PTCDA as adsorbate and Ag(10 8 7) and Ag(775)surfaces as substrate. The patterns are directly observed by STM, the formation of vicinal surfaces is monitored by highresolution electron diffraction, the microscopic surface morphology changes are followed by spectromicroscopy, and the macroscopic changes of surface stress are measured by a cantilever bending method. The in situ combination of these complementary techniques provides compelling evidence for elastic interaction and a significant stress contribution to long-range order and nanopattern formation.
In early spring, red wood ants Formica polyctena are often observed clustering on the nest surface in large numbers basking in the sun. It has been hypothesized that sun-basking behaviour may contribute to nest heating because of both heat carriage into the nest by sunbasking workers, and catabolic heat production from the mobilization of the workers’ lipid reserves. We investigated sun-basking behaviour in laboratory colonies of F. polyctena exposed to an artificial heat source. Observations on identified individuals revealed that not all ants bask in the sun. Sun-basking and non-sun-basking workers did not differ in body size nor in respiration rates. The number of sun-basking ants and the number of their visits to the hot spot depended on the temperature of both the air and the hot spot. To investigate whether sun basking leads to a physiological activation linked with increased lipolysis, we measured respiration rates of individual workers as a function of temperature, and compared respiration rates of sun-basking workers before and two days after they were allowed to expose themselves to a heat source over 10 days, at self-determined intervals. As expected for ectothermic animals, respiration rates increased with increasing temperatures in the range 5 to 35˚C. However, the respiration rates of sun-basking workers measured two days after a long-term exposure to the heat source were similar to those before sun basking, providing no evidence for a sustained increase of the basal metabolic rates after prolonged sun basking. Based on our measurements, we argue that self-heating of the nest mound in early spring has therefore to rely on alternative heat sources, and speculate that physical transport of heat in the ant bodies may have a significant effect.
The transcriptome is a powerful proxy for the physiological state of a cell, healthy or diseased. As a result, transcriptome analysis has become a key tool in understanding the molecular changes that accompany bacterial infections of eukaryotic cells. Until recently, such transcriptomic studies have been technically limited to analyzing mRNA expression changes in either the bacterial pathogen or the infected eukaryotic host cell. However, the increasing sensitivity of high-throughput RNA sequencing now enables “dual RNA-seq” studies, simultaneously capturing all classes of coding and noncoding transcripts in both the pathogen and the host. In the five years since the concept of dual RNA-seq was introduced, the technique has been applied to a range of infection models. This has not only led to a better understanding of the physiological changes in pathogen and host during the course of an infection but has also revealed hidden molecular phenotypes of virulence-associated small noncoding RNAs that were not visible in standard infection assays. Here, we use the knowledge gained from these recent studies to suggest experimental and computational guidelines for the design of future dual RNA-seq studies. We conclude this review by discussing prospective applications of the technique.
The empty p\(_z\)-orbital of a three-coordinate organoboron compound leads to its electron-deficient properties, which make it an excellent π-acceptor in conjugated organic chromophores. The empty p-orbital in such Lewis acids can be attacked by nucleophiles, so bulky groups are often employed to provide air-stable materials. However, many of these can still bind fluoride and cyanide anions leading to applications as anion-selective sensors. One electron reduction generates radical anions. The π-acceptor strength can be easily tuned by varying the organic substituents. Many of these compounds show strong two-photon absorption (TPA) and two-photon excited fluorescence (TPEF) behaviour, which can be applied for e.g. biological imaging. Furthermore, these chromophores can be used as emitters and electron transporters in OLEDs, and examples have recently been found to exhibit efficient thermally activated delayed fluorescence (TADF). The three-coordinate organoboron unit can also be incorporated into polycyclic aromatic hydrocarbons. Such boron-doped compounds exhibit very interesting properties, distinct from their all-carbon analogues. Significant developments have been made in all of these areas in recent years and new applications are rapidly emerging for this class of boron compounds.
Burkina Faso ranges amongst the fastest growing countries in the world with an annual population growth rate of more than three percent. This trend has consequences for food security since agricultural productivity is still on a comparatively low level in Burkina Faso. In order to compensate for the low productivity, the agricultural areas are expanding quickly. The mapping and monitoring of this expansion is difficult, even on the basis of remote sensing imagery, since the extensive farming practices and frequent cloud coverage in the area make the delineation of cultivated land from other land cover and land use types a challenging task. However, as the rapidly increasing population could have considerable effects on the natural resources and on the regional development of the country, methods for improved mapping of LULCC (land use and land cover change) are needed. For this study, we applied the newly developed ESTARFM (Enhanced Spatial and Temporal Adaptive Reflectance Fusion Model) framework to generate high temporal (8-day) and high spatial (30 m) resolution NDVI time series for all of Burkina Faso for the years 2001, 2007, and 2014. For this purpose, more than 500 Landsat scenes and 3000 MODIS scenes were processed with this automated framework. The generated ESTARFM NDVI time series enabled extraction of per-pixel phenological features that all together served as input for the delineation of agricultural areas via random forest classification at 30 m spatial resolution for entire Burkina Faso and the three years. For training and validation, a randomly sampled reference dataset was generated from Google Earth images and based on expert knowledge. The overall accuracies of 92% (2001), 91% (2007), and 91% (2014) indicate the well-functioning of the applied methodology. The results show an expansion of agricultural area of 91% between 2001 and 2014 to a total of 116,900 km\(^2\). While rainfed agricultural areas account for the major part of this trend, irrigated areas and plantations also increased considerably, primarily promoted by specific development projects. This expansion goes in line with the rapid population growth in most provinces of Burkina Faso where land was still available for an expansion of agricultural area. The analysis of agricultural encroachment into protected areas and their surroundings highlights the increased human pressure on these areas and the challenges of environmental protection for the future.
Apolipoprotein-E4 (APOE-E4) is a major genetic risk factor for developing Alzheimer’s disease (AD). The verbal fluency task (VFT), especially the subtask category fluency, has shown to provide a good discrimination between cognitively normal controls and subjects with AD. Interestingly, APOE-E4 seems to have no effect on the behavioral performance during a VFT in healthy elderly. Thus, the purpose of the present study was to reveal possible compensation mechanisms by investigating the effect of APOE-E4 on the hemodynamic response in non-demented elderly during a VFT by using functional near-infrared spectroscopy (fNIRS). We compared performance and hemodynamic response of high risk APOE-E4/E4, -E3/E4 carriers with neutral APOE-E3/E3 non-demented subjects (N = 288; 70–77 years). No difference in performance was found. APOE-E4/E4, -E3/E4 carriers had a decreased hemodynamic response in the right inferior frontal junction (IFJ) with a corresponding higher response in the left middle frontal gyrus (MFG) during category fluency. Performance was correlated with the hemodynamic response in the MFG. We assume a compensation of decreased IFJ brain activation by utilizing the MFG during category fluency and thus resulting in no behavioral differences between APOE-groups during the performance of a VFT.
Livin/BIRC7 is a member of the inhibitors of apoptosis proteins family, which are involved in tumor development through the inhibition of caspases. Aim was to investigate the expression of livin and other members of its pathway in adrenocortical tumors and in the adrenocortical carcinoma (ACC) cell line NCI-H295R.
The mRNA expression of livin, its isoforms α and β, XIAP, CASP3 and DIABLO was evaluated by qRT-PCR in 82 fresh-frozen adrenal tissues (34 ACC, 25 adenomas = ACA, 23 normal adrenal glands = NAG). Livin protein expression was assessed by immunohistochemistry in 270 paraffin-embedded tissues (192 ACC, 58 ACA, 20 NAG). Livin, CASP3 and cleaved caspase-3 were evaluated in NCI-H295R after induction of livin overexpression.
Relative livin mRNA expression was significantly higher in ACC than in ACA and NAG (0.060 ± 0.116 vs 0.004 ± 0.014 and 0.002 ± 0.009, respectively, p < 0.01), being consistently higher in tumors than in adjacent NAG and isoform β more expressed than α. No significant differences in CASP3, XIAP and DIABLO levels were found among these groups. In immunohistochemistry, livin was localized in both cytoplasm and nuclei. The ratio between cytoplasmic and nuclear staining was significantly higher in ACC (1.51 ± 0.66) than in ACA (0.80 ± 0.35) and NAG (0.88 ± 0.27; p < 0.0001). No significant correlations were observed between livin expression and histopathological parameters or clinical outcome. In NCI-H295R cells, the livin overexpression slightly reduced the activation of CASP3, but did not correlate with cell viability.
In conclusion, livin is specifically over-expressed in ACC, suggesting that it might be involved in adrenocortical tumorigenesis and represent a new molecular marker of malignancy.
C-X-C-motif chemokine receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer. We have recently reported promising first-in-man experience with CXCR4-directed endoradiotherapy (ERT) in multiple myeloma (MM).
Eight heavily pretreated MM patients underwent a total of 10 ERT cycles (7 patients with 1 cycle and a single patient with 3 cycles). ERT was administered in combination with chemotherapy and autologous stem cell support. End points were occurrence and timing of adverse events, progression-free and overall survival.
ERT was overall well tolerated without any unexpected acute adverse events or changes in vital signs. With absorbed tumor doses >30-70 Gy in intra- or extramedullary lesions, significant anti-myeloma activity was observed with 1 patient achieving complete remission and 5/8 partial remission. Directly after ERT major infectious complications were seen in one patient who died from sepsis 22 days after ERT, another patient with high tumor burden experienced lethal tumor lysis syndrome. Median progression-free survival was 54 days (range, 13-175), median overall survival was 223 days (range, 13-313). During follow-up (6 patients available), one patient died from infectious complications, 2/8 from disease progression, the remaining 3/8 patients are still alive.
CXCR4-directed ERT was well-tolerated and exerted anti-myeloma activity even at very advanced stage MM with presence of extramedullary disease. Further assessment of this novel treatment option is highly warranted.
Next-to-leading-order electroweak corrections to the production of four charged leptons at the LHC
(2017)
We present a state-of-the-art calculation of the next-to leading-order electroweak corrections to ZZ production, including the leptonic decays of the Z bosons into μ\(^+\)μ\(^ −\)e\(^+\)e\(^−\) or μ\(^+\)μ\(^−\)μ\(^+\)μ\(^−\) final states. We use complete leading-order and next-to-leading-order matrix elements for four-lepton production, including contributions of virtual photons and all off-shell effects of Z bosons, where the finite Z-boson width is taken into account using the complex-mass scheme. The matrix elements are implemented into Monte Carlo programs allowing for the evaluation of arbitrary differential distributions. We present integrated and differential cross sections for the LHC at 13 TeV both for an inclusive setup where only lepton identification cuts are applied, and for a setup motivated by Higgs-boson analyses in the four-lepton decay channel. The electroweak corrections are divided into photonic and purely weak contributions. The former show the well-known pronounced tails near kinematical thresholds and resonances; the latter are generically at the level of ∼ −5% and reach several −10% in the high-energy tails of distributions. Comparing the results for μ\(^+\)μ\(^−\)e\(^+\)e\(^−\) and μ\(^+\)μ\(^−\)μ\(^+\)μ\(^−\) final states, we find significant differences mainly in distributions that are sensitive to the μ\(^+\)μ\(^−\) pairing in the μ\(^+\)μ\(^−\)μ\(^+\)μ\(^−\) final state. Differences between μ\(^+\)μ\(^−\)e\(^+\)e\(^−\) and μ\(^+\)μ\(^−\)μ\(^+\)μ\(^−\) channels due to interferences of equal-flavour leptons in the final state can reach up to 10% in off-shell-sensitive regions. Contributions induced by incoming photons, i.e. photon-photon and quark-photon channels, are included, but turn out to be phenomenologically unimportant.
A striking feature of the metabolite profile of \(Ancistrocladus\) \(likoko\) (Ancistrocladaceae) is the exclusive production of 5,8\('\)-linked naphthylisoquinoline alkaloids varying in their OMe/OH substitution patterns and in the hydrogenation degree in their isoquinoline portions. Here we present nine new compounds of this coupling type isolated from the twigs of this remarkable Central African liana. Three of them, the ancistrolikokines E (9), E\(_2\) (10), and F (11), are the first 5,8\('\)-linked naphthyldihydroisoquinolines found in nature with \(R\)-configuration at C-3. The fourth new metabolite, ancistrolikokine G (12), is so far the only representative of the 5,8\('\)-coupling type that belongs to the very rare group of alkaloids with a fully dehydrogenated isoquinoline portion. Moreover, five new \(N\)-methylated naphthyltetrahydroisoquinolines, named ancistrolikokines A\(_2\) (13), A\(_3\) (14), C\(_2\) (5), H (15), and H\(_2\) (16) are presented, along with six known 5,8\('\)-linked alkaloids, previously identified in related African \(Ancistrocladus\) species, now found for the first time in \(A.\) \(likoko\). The structural elucidation was achieved by spectroscopic analysis (HRESIMS, 1D and 2D NMR) and by chemical (oxidative degradation) and chiroptical (electronic circular dichroism) methods. The new ancistrolikokines showed moderate to good preferential cytotoxic activities towards pancreatic PANC-1 cells in nutrient-deprived medium (NDM), without causing toxicity under normal, nutrient-rich conditions, with ancistrolikokine H\(_2\) (16) being the most potent compound.
\(^{11}\)C-methionine-PET in multiple myeloma: a combined study from two different institutions
(2017)
\(^{11}\)C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to \(^{18}\)F-2`-deoxy-2`-fluoro-D-glucose (FDG).
78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of Würzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available.
MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases.
MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72).
This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM.
Higgs production in association with off-shell top-antitop pairs at NLO EW and QCD at the LHC
(2017)
We present NLO electroweak corrections to Higgs production in association with off-shell top-antitop quark pairs. The full process pp → e +νeµ −ν¯µbb¯H is considered, and hence all interference, off-shell, and non-resonant contributions are taken into account.
The electroweak corrections turn out to be below one per cent for the integrated cross section but can exceed 10% in certain phase-space regions. In addition to its phenomenological relevance, the computation constitutes a major technical achievement as the full NLO virtual corrections involving up to 9-point functions have been computed exactly. The results of the full computation are supported by two calculations in the double-pole approximation. These also allow to infer the effect of off-shell contributions and emphasise their importance especially for the run II of the LHC. Finally, we present combined predictions featuring both NLO electroweak and QCD corrections in a common set-up that will help the experimental collaborations in their quest of precisely measuring the aforementioned process.
The human ubiquitin ligase HUWE1 has key roles in tumorigenesis, yet it is unkown how its activity is regulated. We present the crystal structure of a C-terminal part of HUWE1, including the catalytic domain, and reveal an asymmetric auto-inhibited dimer. We show that HUWE1 dimerizes in solution and self-associates in cells, and that both occurs through the crystallographic dimer interface. We demonstrate that HUWE1 is inhibited in cells and that it can be activated by disruption of the dimer interface. We identify a conserved segment in HUWE1 that counteracts dimer formation by associating with the dimerization region intramolecularly. Our studies reveal, intriguingly, that the tumor suppressor p14ARF binds to this segment and may thus shift the conformational equilibrium of HUWE1 toward the inactive state. We propose a model, in which the activity of HUWE1 underlies conformational control in response to physiological cues—a mechanism that may be exploited for cancer therapy.
The MuvB multiprotein complex, together with B-MYB and FOXM1 (MMB-FOXM1), plays an essential role in cell cycle progression by regulating the transcription of genes required for mitosis and cytokinesis. In many tumors, B-MYB and FOXM1 are overexpressed as part of the proliferation signature. However, the transcriptional targets that are important for oncogenesis have not been identified. Given that mitotic kinesins are highly expressed in cancer cells and that selected kinesins have been reported as target genes of MMB-FOXM1, we sought to determine which mitotic kinesins are directly regulated by MMB-FOXM1. We demonstrate that six mitotic kinesins and two microtubule-associated non-motor proteins (MAPs) CEP55 and PRC1 are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cells.
Suppression of KIF23 and PRC1 strongly suppressed proliferation of MDA-MB-231 cells. The set of MMB-FOXM1 regulated kinesins genes and 4 additional kinesins which we referred to as the mitotic kinesin signature (MKS) is linked to poor outcome in breast cancer patients. Thus, mitotic kinesins could be used as prognostic biomarker and could be potential therapeutic targets for the treatment of breast cancer.
Marine sponge-derived Streptomyces sp SBT343 extract inhibits staphylococcal biofilm formation
(2017)
Staphylococcus epidermidis and Staphylococcus aureus are opportunistic pathogens that cause nosocomial and chronic biofilm-associated infections. Indwelling medical devices and contact lenses are ideal ecological niches for formation of staphylococcal biofilms. Bacteria within biofilms are known to display reduced susceptibilities to antimicrobials and are protected from the host immune system. High rates of acquired antibiotic resistances in staphylococci and other biofilm-forming bacteria further hamper treatment options and highlight the need for new anti-biofilm strategies. Here, we aimed to evaluate the potential of marine sponge-derived actinomycetes in inhibiting biofilm formation of several strains of S. epidermidis, S. aureus, and Pseudomonas aeruginosa. Results from in vitro biofilm-formation assays, as well as scanning electron and confocal microscopy, revealed that an organic extract derived from the marine sponge-associated bacterium Streptomyces sp. SBT343 significantly inhibited staphylococcal biofilm formation on polystyrene, glass and contact lens surfaces, without affecting bacterial growth. The extract also displayed similar antagonistic effects towards the biofilm formation of other S. epidermidis and S. aureus strains tested but had no inhibitory effects towards Pseudomonas biofilms. Interestingly the extract, at lower effective concentrations, did not exhibit cytotoxic effects on mouse fibroblast, macrophage and human corneal epithelial cell lines. Chemical analysis by High Resolution Fourier Transform Mass Spectrometry (HRMS) of the Streptomyces sp. SBT343 extract proportion revealed its chemical richness and complexity. Preliminary physico-chemical characterization of the extract highlighted the heat-stable and non-proteinaceous nature of the active component(s). The combined data suggest that the Streptomyces sp. SBT343 extract selectively inhibits staphylococcal biofilm formation without interfering with bacterial cell viability. Due to absence of cell toxicity, the extract might represent a good starting material to develop a future remedy to block staphylococcal biofilm formation on contact lenses and thereby to prevent intractable contact lens-mediated ocular infections.
Reproducibility and comparison of oxygen-enhanced T\(_1\) quantification in COPD and asthma patients
(2017)
T\(_1\) maps have been shown to yield useful diagnostic information on lung function in patients with chronic obstructive pulmonary disease (COPD) and asthma, both for native T\(_1\) and ΔT\(_1\), the relative reduction while breathing pure oxygen. As parameter quantification is particularly interesting for longitudinal studies, the purpose of this work was both to examine the reproducibility of lung T\(_1\) mapping and to compare T\(_1\) found in COPD and asthma patients using IRSnapShotFLASH embedded in a full MRI protocol. 12 asthma and 12 COPD patients (site 1) and further 15 COPD patients (site 2) were examined on two consecutive days. In each patient, T\(_1\) maps were acquired in 8 single breath-hold slices, breathing first room air, then pure oxygen. Maps were partitioned into 12 regions each to calculate average values. In asthma patients, the average T\(_{1,RA}\) = 1206ms (room air) was reduced to T\(_{1,O2}\) = 1141ms under oxygen conditions (ΔT\(_1\) = 5.3%, p < 5⋅10\(^{−4})\), while in COPD patients both native T\(_{1,RA}\) = 1125ms was significantly shorter (p < 10\(^{−3})\) and the relative reduction to T\(_{1,O2}\) = 1081ms on average ΔT\(_1\) = 4.2%(p < 10\(^{−5}\)). On the second day, with T\(_{1,RA}\) = 1186ms in asthma and T\(_{1,RA}\) = 1097ms in COPD, observed values were slightly shorter on average in all patient groups. ΔT\(_1\) reduction was the least repeatable parameter and varied from day to day by up to 23% in individual asthma and 30% in COPD patients. While for both patient groups T\(_1\) was below the values reported for healthy subjects, the T\(_1\) and ΔT\(_1\) found in asthmatics lies between that of the COPD group and reported values for healthy subjects, suggesting a higher blood volume fraction and better ventilation. However, it could be demonstrated that lung T\(_1\) quantification is subject to notable inter-examination variability, which here can be attributed both to remaining contrast agent from the previous day and the increased dependency of lung T\(_1\) on perfusion and thus current lung state.
Increased aortic stiffness is known to be associated with atherosclerosis and has a predictive value for cardiovascular events. This study aims to investigate the local distribution of early arterial stiffening due to initial atherosclerotic lesions. Therefore, global and local pulse wave velocity (PWV) were measured in ApoE\(^{-/-}\) and wild type (WT) mice using ultrahigh field MRI. For quantification of global aortic stiffness, a new multi-point transit-time (TT) method was implemented and validated to determine the global PWV in the murine aorta. Local aortic stiffness was measured by assessing the local PWV in the upper abdominal aorta, using the flow/area (QA) method. Significant differences between age matched ApoE\(^{-/-}\) and WT mice were determined for global and local PWV measurements (global PWV: ApoE\(^{-/-}\): 2.7 ±0.2m/s vs WT: 2.1±0.2m/s, P<0.03; local PWV: ApoE\(^{-/-}\): 2.9±0.2m/s vs WT: 2.2±0.2m/s, P<0.03). Within the WT mouse group, the global PWV correlated well with the local PWV in the upper abdominal aorta (R\(^2\) = 0.75, P<0.01), implying a widely uniform arterial elasticity.
In ApoE\(^{-/-}\) animals, however, no significant correlation between individual local and global PWV was present (R\(^2\) = 0.07, P = 0.53), implying a heterogeneous distribution of vascular stiffening in early atherosclerosis. The assessment of global PWV using the new multi-point TT measurement technique was validated against a pressure wire measurement in a vessel
phantom and showed excellent agreement. The experimental results demonstrate that vascular stiffening caused by early atherosclerosis is unequally distributed over the length of large vessels. This finding implies that assessing heterogeneity of arterial stiffness by multiple local measurements of PWV might be more sensitive than global PWV to identify early atherosclerotic lesions.
Introduction: Calciphylaxis/calcific uremic arteriolopathy affects mainly end-stage kidney disease patients but is also associated with malignant disorders such as myeloma, melanoma and breast cancer. Genetic risk factors of calciphylaxis have never been studied before.
Methods: We investigated 10 target genes using a tagging SNP approach: the genes encoding CD73/ ecto-5'-nucleotidase (purinergic pathway), Matrix Gla protein, Fetuin A, Bone Gla protein, VKORC1 (all related to intrinsic calcification inhibition), calcium-sensing receptor, FGF23, Klotho, vitamin D receptor, stanniocalcin 1 (all related to CKD-MBD). 144 dialysis patients from the German calciphylaxis registry were compared with 370 dialysis patients without history of CUA. Genotyping was performed using iPLEX Gold MassARRAY(Sequenom, San Diego, USA), KASP genotyping chemistry (LGC, Teddington, Middlesex, UK) or sequencing. Statistical analysis comprised logistic regression analysis with adjustment for age and sex.
Results: 165 SNPs were finally analyzed and 6 SNPs were associated with higher probability for calciphylaxis (OR>1) in our cohort. Nine SNPs of three genes (CD73, FGF23 and Vitamin D receptor) reached nominal significance (p< 0.05), but did not reach statistical significance after correction for multiple testing. Of the CD73 gene, rs4431401 (OR = 1.71, 95%CI 1.08-2.17, p = 0.023) and rs9444348 (OR = 1.48, 95% CI 1.11-1.97, p = 0.008) were associated with a higher probability for CUA. Of the FGF23 and VDR genes, rs7310492, rs11063118, rs13312747 and rs17882106 were associated with a higher probability for CUA.
Conclusion: Polymorphisms in the genes encoding CD73, vitamin D receptor and FGF23 may play a role in calciphylaxis development. Although our study is the largest genetic study on calciphylaxis, it is limited by the low sample sizes. It therefore requires replication in other cohorts if available.
Objective: Perception of time as well as rhythm in musical structures rely on complex brain mechanisms and require an extended network of multiple neural sources. They are therefore sensitive to impairment. Several psychophysical studies have shown that patients with Parkinson's disease (PD) have deficits in perceiving time and rhythms due to a malfunction of the basal ganglia (BG) network.
Method: In this study we investigated the time perception of PD patients during music perception by assessing their just noticeable difference (JND) in the time perception of a complex musical Gestalt. We applied a temporal discrimination task using a short melody with a clear beat-based rhythm. Among the subjects, 26 patients under L-Dopa administration and 21 age-matched controls had to detect an artificially delayed time interval in the range between 80 and 300 ms in the middle of the musical period. We analyzed the data by (a) calculating the detection threshold directly, (b) by extrapolating the JNDs, (c) relating it to musical expertise.
Results: Patients differed from controls in the detection of time-intervals between 220 and 300 ms (*p = 0.0200, n = 47). Furthermore, this deficit depended on the severity of the disease (*p = 0.0452; n = 47). Surprisingly, PD patients did not show any deficit of their JND compared to healthy controls, although the results showed a trend (*p = 0.0565, n = 40). Furthermore, no significant difference of the JND was found according to the severity of the disease. Additionally, musically trained persons seemed to have lower thresholds in detecting deviations in time and syntactic structures of music (*p = 0.0343, n = 39).
Conclusion: As an explanation of these results, we would like to propose the hypothesis of a time-syntax-congruency in music perception suggesting that processing of time and rhythm is a Gestalt process and that cortical areas involved in processing of musical syntax may compensate for impaired BG circuits that are responsible for time processing and rhythm perception. This mechanism may emerge more strongly as the deficits in time processing and rhythm perception progress. Furthermore, we presume that top-down-bottom-up-processes interfere additionally and interact in this context of compensation.
In this article, we present approaches to interactive simulations of biohybrid systems. These simulations are comprised of two major computational components: (1) agent-based developmental models that retrace organismal growth and unfolding of technical scaffoldings and (2) interfaces to explore these models interactively. Simulations of biohybrid systems allow us to fast forward and experience their evolution over time based on our design decisions involving the choice, configuration and initial states of the deployed biological and robotic actors as well as their interplay with the environment. We briefly introduce the concept of swarm grammars, an agent-based extension of L-systems for retracing growth processes and structural artifacts. Next, we review an early augmented reality prototype for designing and projecting biohybrid system simulations into real space. In addition to models that retrace plant behaviors, we specify swarm grammar agents to braid structures in a self-organizing manner. Based on this model, both robotic and plant-driven braiding processes can be experienced and explored in virtual worlds. We present an according user interface for use in virtual reality. As we present interactive models concerning rather diverse description levels, we only ensured their principal capacity for interaction but did not consider efficiency analyzes beyond prototypic operation. We conclude this article with an outlook on future works on melding reality and virtuality to drive the design and deployment of biohybrid systems.
This essay argues that Orwell’s representation of animals as companion species offers a strikingly new, as-yet largely neglected view of animal agency and interiority in his work. In “Shooting an Elephant”, Burmese Days and “Marrakech”, the writer’s focus on the social reject is supplemented by a marked sense of community implying human tragedy yet framing it within precariously situated human-animal, colonial or urban-imperial transitions that visualise animals as agents of change and co-shaping species interdependent with the lives of the humans that utilize and domineer them. Animals are required whenever Orwell aspires to shift from isolation to communality, from the self-conscious outsider to the larger realm of ideas framing the world in which his characters strive to overstep the accepted lines of social performance and conformity. Read in and around disciplinary structures of rationalization, Orwell’s animals appear to secure themselves, quite paradoxically, a place within the normative anthropocentric framework excluding them. They extend beyond anthropomorphising or allegorical modes of description and open up bio-political perspectives within and across regimes of knowledge and empathy. Orwell’s writings thus present a challenge to the culturally accredited fantasy of human exceptionalism, collapsing any epistemic space between humans and animals and burying the idea of sustaining radical species distinction.
Für Menschen ohne Religionszugehörigkeit und religiöses Selbstverständnis liegt kaum eine Beschreibung jenseits negativer Abgrenzungen von traditioneller Religion vor, wie sie in den Begriffen „nichtreligiös“ und „konfessionslos“ zum Ausdruck kommen. Der Aufsatz untersucht die Option eines säkularen „worldview“ und fragt, ob und in welchem Maß religiöse und nichtreligiöse Studienteilnehmer sich in ihrer Haltung zu Menschenrechten unterscheiden. Die empirische Studie (N=2244) zeigt, dass Menschenrechte bei jungen Menschen bei unterschiedlichen Akzentsetzungen durchweg auf Zustimmung stoßen. In Umrissen tritt dabei ein gemeinsamer „worldview“ oder eine „Weltanschauung“ der säkularen Befragten hervor, die in der Anerkennung des intrinsischen Wertes des Anderen und gesellschaftlich gesetzter Normen besteht.
Schule als Lern- und Lebensort zukünftiger Generationen partizipiert an global sich vollziehenden medialen Transformationsprozessen. Religionspädagogik und -didaktik sind, wie alle anderen Fachwissenschaften auch, herausgefordert, die Integration digitaler Medien in Theorie und Praxis zu reflektieren und konzeptionieren. Dies hat in mindestens drei Dimensionen zu erfolgen: beim Lernen mit digitalen Medien, beim Lernen über digitale Medien sowie in der Einübung in eine konstruktiv-kritische Medienbildung. Das Projekt ist der Entwicklung, Erprobung und Evaluation von Lernszenarien im Religionsunterricht und im Austausch mit außerschulischen religiösen Bildungsorten gewidmet.
In den 125 Jahren seit ihrer Einführung im Jahre 1892 hat die deutsche GmbH einerseits einen Siegeszug um die ganze Welt angetreten und musste sich andererseits im eigenen Heimatland der scharfen Konkurrenz der englischen Limited erwehren. Dieser Wettbewerb setzte im Internationalen Gesellschaftsrecht einen Wechsel von der Sitz- zur Gründungstheorie voraus. Seine negativen Auswirkungen lassen sich, wie die jüngere EuGH-Rechtsprechung zeigt, durch eine am Sachproblem orientierte Anwendung inländischer Drittschutzregeln zielgerichtet eingrenzen. Im europäischen Ideenwettbewerb ist das deutsche GmbH-Recht derweil deutlich zurückgefallen. Das liegt weniger an der vermeintlichen Dominanz des englischen Rechts als am Ideenreichtum der kleineren EU-Staaten, denen es mit gut durchdachten Reformprojekten gelingt, international Aufmerksamkeit auf sich zu ziehen.
Die europäische Konzernorganisation und die „Europa GmbH“ (SPE) bilden zwei wichtige Forschungsschwerpunkte im Werk von Peter Hommelhoff. Beide Projekte haben sich über die Jahre als außerordentlich dicke Bretter erwiesen. Doch davon lässt sich der Jubilar nicht beirren. Rückschläge und Umwege gehören in der Wissenschaft zum kollektiven Lernprozess, der neue Erkenntnisse bringt. Ganz in diesem Sinne münden die Erfahrungen aus der Diskussion um ein europäisches Konzernrecht und um die SPE im vorliegenden Beitrag in die Konzeption eines supranationalen Konzernbausteins für europäische Unternehmensgruppen.
Rezension zu Deutsche Reichstagsakten, Deutsche Reichstagsakten. Reichsversammlungen 1556–1662. Hrsg. v. der Historischen Kommission bei der Bayerischen Akademie der Wissenschaften durch Maximilian Lanzinner. Der Reichstag zu Regensburg 1556/57. 2 Teilbde. Bearb. v. Josef Leeb. München, Oldenbourg Wissenschaftsverlag 2013
Rezension zu Weiß, Katja:Ägyptische Tier- und Götterbronzen aus Unterägypten. Untersuchungen zu Typus, Ikonographie und Funktion sowie der Bedeutung innerhalb der Kulturkontakte zu Griechenland. Wiesbaden: Harrassowitz 2012. XXXVI, 1171 S., 2 Teile, 7 Abb., 79 Taf., 145 Tab., 1 Kart. 4° = Ägypten und Altes Testament 81. Hartbd. € 198,00. ISBN 978-3-447-06719-5
An den Grenzen der Pragmatik
(2017)
The Old Babylonian Ištar ritual from Mari (FM 3, no. 2) has been the focus of much discussion since its primary edition in 1938 by G. Dossin. This article offers a new analysis of the passage mentioning the balaĝ-deity Ninigizibara, which leads to identifying this balaĝ as a huge upright lyre as tall as a human played by two persons from both sides. Similar musical instruments are known from Anatolia and Egypt. Especially the Egyptian examples, which are attested only for the time of Echnaton, show striking parallels to the musical performance described in the Old Babylonian Ištar ritual. After discussing the possible background of cultural exchange, this article closes with a revaluation and new interpretation of the term balaĝ.
Although the Letter of Aristeas mentions the translation of the Jewish nomos into Greek, it is striking that worship is not a fundamental theme of this writing. Nevertheless, six passages present acts of worship, which recount worship from different perspectives: Aristeas prays to God and explains his “Greek” idea of worship (Let. Aris. 17), whereas in Let. Aris. 132-140 the high priest explains the Jewish concept of worship. Sacrifices and prayers at the temple in Jerusalem for the Ptolemaic royal house are told in Let. Aris. 45, while at the Ptolemaic court in Alexandria one of the Jewish scholars prays at the beginning of the symposium (Let. Aris. 184-186). Then the daily prayer of the Jewish scholars are recounted in Let. Aris. 305-306 and finally the Ptolemaic king performs a proskynesis before the law at the end of the letter and thereby accepts the translation (Let. Aris. 317).
The three-dimensional cuneiform script is one of the oldest known writing systems and a central object of research in Ancient Near Eastern Studies and Hittitology. An important step towards the understanding of the cuneiform script is the provision of opportunities and tools for joint analysis. This paper presents an approach that contributes to this challenge: a collaborative compatible web-based scientific exploration and analysis of 3D scanned cuneiform fragments. The WebGL -based concept incorporates methods for compressed web-based content delivery of large 3D datasets and high quality visualization. To maximize accessibility and to promote acceptance of 3D techniques in the field of Hittitology, the introduced concept is integrated into the Hethitologie-Portal Mainz, an established leading online research resource in the field of Hittitology, which until now exclusively included 2D content. The paper shows that increasing the availability of 3D scanned archaeological data through a web-based interface can provide significant scientific value while at the same time finding a trade-off between copyright induced restrictions and scientific usability.
Echinocandin antifungals represent one of the most important drug classes for the treatment of invasive fungal infections. The mode of action of the echinocandins relies on inhibition of the β-1,3-glucan synthase, an enzyme essentially required for the synthesis of the major fungal cell wall carbohydrate β-1,3-glucan. Depending on the species, echinocandins may exert fungicidal or fungistatic activity. Apparently independent of this differential activity, a surprising in vitro phenomenon called the “paradoxical effect” can be observed. The paradoxical effect is characterized by the ability of certain fungal isolates to reconstitute growth in the presence of higher echinocandin concentrations, while being fully susceptible at lower concentrations. The nature of the paradoxical effect is not fully understood and has been the focus of multiple studies in the last two decades. Here we concisely review the current literature and propose an updated model for the paradoxical effect, taking into account recent advances in the field.
Although recent developmental studies exploring the predictive power of intelligence and working memory (WM) for educational achievement in children have provided evidence for the importance of both variables, findings concerning the relative impact of IQ and WM on achievement have been inconsistent. Whereas IQ has been identified as the major predictor variable in a few studies, results from several other developmental investigations suggest that WM may be the stronger predictor of academic achievement. In the present study, data from the Munich Longitudinal Study on the Genesis of Individual Competencies (LOGIC) were used to explore this issue further. The secondary data analysis included data from about 200 participants whose IQ and WM was first assessed at the age of six and repeatedly measured until the ages of 18 and 23. Measures of reading, spelling, and math were also repeatedly assessed for this age range. Both regression analyses based on observed variables and latent variable structural equation modeling (SEM) were carried out to explore whether the predictive power of IQ and WM would differ as a function of time point of measurement (i.e., early vs. late assessment). As a main result of various regression analyses, IQ and WM turned out to be reliable predictors of academic achievement, both in early and later developmental stages, when previous domain knowledge was not included as additional predictor. The latter variable accounted for most of the variance in more comprehensive regression models, reducing the impact of both IQ and WM considerably. Findings from SEM analyses basically confirmed this outcome, indicating IQ impacts on educational achievement in the early phase, and illustrating the strong additional impact of previous domain knowledge on achievement at later stages of development.
Past and the projected future climate change in Afghanistan has been analyzed systematically and differentiated with respect to its different climate regions to gain some first quantitative insights into Afghanistan’s vulnerability to ongoing and future climate changes. For this purpose, temperature, precipitation and five additional climate indices for extremes and agriculture assessments (heavy precipitation; spring precipitation; growing season length (GSL), the Heat Wave Magnitude Index (HWMI); and the Standardized Precipitation Evapotranspiration Index (SPEI)) from the reanalysis data were examined for their consistency to identify changes in the past (data since 1950). For future changes (up to the year 2100), the same parameters were extracted from an ensemble of 12 downscaled regional climate models (RCM) of the Coordinated Regional Climate Downscaling Experiment (CORDEX)-South Asia simulations for low and high emission scenarios (Representative Concentration Pathways 4.5 and 8.5). In the past, the climatic changes were mainly characterized by a mean temperature increase above global level of 1.8 °C from 1950 to 2010; uncertainty with regard to reanalyzed rainfall data limited a thorough analysis of past changes. Climate models projected the temperature trend to accelerate in the future, depending strongly on the global carbon emissions (2006–2050 Representative Concentration Pathways 4.5/8.5: 1.7/2.3 °C; 2006–2099: 2.7/6.4 °C, respectively). Despite the high uncertainty with regard to precipitation projections, it became apparent that the increasing evapotranspiration is likely to exacerbate Afghanistan’s already existing water stress, including a very strong increase of frequency and magnitude of heat waves. Overall, the results show that in addition to the already extensive deficiency in adaptation to current climate conditions, the situation will be aggravated in the future, particularly in regard to water management and agriculture. Thus, the results of this study underline the importance of adequate adaptation to climate change in Afghanistan. This is even truer taking into account that GSL is projected to increase substantially by around 20 days on average until 2050, which might open the opportunity for extended agricultural husbandry or even additional harvests when water resources are properly managed.
What does it mean to take animal autobiography seriously and how can we account for the representation of life-narrating animals? The article investigates animal autobiographies as ‘literary autozoographies’, drawing attention to both the generic contexts and the epistemological premises of these texts. Adopting a double-bind approach stemming from autobiographical research as well as cultural animal studies, the article focuses on early nineteenth-century equine autozoographies from the German-speaking tradition. These texts are discussed exemplarily in relation to the parameters of fictional autobiographies, before they are contextualized with historical discourses regarding horses in natural history and so-called ‘horse-science’. Due to the fact that the poetics and aesthetics of the genre are modeled on the templates of factual autobiographies, the article argues that literary autozoographies can be read as fictional autobiographies as well as meta-auto/biographical discourse undermining autobiographical conventions. Furthermore, it shows that literary autozoography and zoology share a common historical and ideological epistemology accounting for the representation of animals in both fields. Literary autozoographies thus participate in the negotiation and production of species-specific knowledge. Reading Life of the Mecklenburg Mare Amante (1804), Life of a Job Horse (1807) and Life of a Worn-Out Hack (1819) alongside equine-centric discourses around 1800, the article demonstrates in what ways these texts can be regarded as part of a regime of knowledge attributing emotions and cognitive capacities to horses, while simultaneously arguing for humane treatment on the basis of interspecies homologies.
Blazars like Markarian 421 or Markarian 501 are active galactic nuclei (AGN), with their jets orientated towards the observer. They are among the brightest objects in the very high energy (VHE) gamma ray regime (>100 GeV). Their emitted gamma-ray fluxes are extremely variable, with changing activity levels on timescales between minutes, months, and even years. Several questions are part of the current research, such as the question of the emission regions or the engine of the AGN and the particle acceleration. A dedicated longterm monitoring program is necessary to investigate the properties of blazars in detail. A densely sampled and unbiased light curve allows for observation of both high and low states of the sources, and the combination with multi-wavelength observation could contribute to the answer of several questions mentioned above. FACT (First G-APD Cherenkov Telescope) is the first operational telescope using silicon photomultiplier (SiPM, also known as Geigermode—Avalanche Photo Diode, G-APD) as photon detectors. SiPM have a very homogenous and stable longterm performance, and allow operation even during full moon without any filter, leading to a maximal duty cycle for an Imaging Air Cherenkov Telescope (IACT). Hence, FACT is an ideal device for such a longterm monitoring of bright blazars. A small set of sources (e.g., Markarian 421, Markarian 501, 1ES 1959+650, and 1ES 2344+51.4) is currently being monitored. In this contribution, the FACT telescope and the concept of longterm monitoring of bright blazars will be introduced. The results of the monitoring program will be shown, and the advantages of densely sampled and unbiased light curves will be discussed.
Long-term slash-and-burn experiments, when compared with intensive tillage without manuring, resulted in a huge data set relating to potential crop yields, depending on soil quality, crop type, and agricultural measures. Cultivation without manuring or fallow phases did not produce satisfying yields, and mono-season cropping on freshly cleared and burned plots resulted in rather high yields, comparable to those produced during modern industrial agriculture - at least ten-fold the ones estimated for the medieval period. Continuous cultivation on the same plot, using imported wood from adjacent areas as fuel, causes decreasing yields over several years. The high yield of the first harvest of a slash-and-burn agriculture is caused by nutrient input through the ash produced and mobilization from the organic matter of the topsoil, due to high soil temperatures during the burning process and higher topsoil temperatures due to the soil’s black surface. The harvested crops are pure, without contamination of any weeds. Considering the amount of work required to fight weeds without burning, the slash-and-burn technique yields much better results than any other tested agricultural approach. Therefore, in dense woodland, without optimal soils and climate, slash-and-burn agriculture seems to be the best, if not the only, feasible method to start agriculture, for example, during the Late Neolithic, when agriculture expanded from the loess belt into landscapes less suitable for agriculture. Extensive and cultivation with manuring is more practical in an already-open landscape and with a denser population, but its efficiency in terms of the ratio of the manpower input to food output, is worse. Slash-and-burn agriculture is not only a phenomenon of temperate European agriculture during the Neolithic, but played a major role in land-use in forested regions worldwide, creating anthromes on a huge spatial scale.
A commentary on: Feeling the Conflict: The Crucial Role of Conflict Experience in Adaptationby Desender, K., Van Opstal, F., and Van den Bussche, E. (2014). Psychol. Sci. 25, 675–683. doi:10.1177/0956797613511468
Conflict adaptation in masked priming has recently been proposed to rely not on successful conflictresolution but rather on conflict experience (Desender et al., 2014). We re-assessed this proposal ina direct replication and also tested a potential confound due toconflict strength. The data supported this alternative view, but also failed to replicate basic conflict adaptation effects of the original studydespite considerable power.
When More Is Better – Consumption Priming Decreases Responders’ Rejections in the Ultimatum Game
(2017)
During the past decades, economic theories of rational choice have been exposed to outcomes that were severe challenges to their claim of universal validity. For example, traditional theories cannot account for refusals to cooperate if cooperation would result in higher payoffs. A prominent illustration are responders’ rejections of positive but unequal payoffs in the Ultimatum Game. To accommodate this anomaly in a rational framework one needs to assume both a preference for higher payoffs and a preference for equal payoffs. The current set of studies shows that the relative weight of these preference components depends on external conditions and that consumption priming may decrease responders’ rejections of unequal payoffs. Specifically, we demonstrate that increasing the accessibility of consumption-related information accentuates the preference for higher payoffs. Furthermore, consumption priming increased responders’ reaction times for unequal payoffs which suggests an increased conflict between both preference components. While these results may also be integrated into existing social preference models, we try to identify some basic psychological processes underlying economic decision making. Going beyond the Ultimatum Game, we propose that a distinction between comparative and deductive evaluations may provide a more general framework to account for various anomalies in behavioral economics.
This paper proposes an attitude determination system for small Unmanned Aerial Vehicles (UAV) with a weight limit of 5 kg and a small footprint of 0.5m x 0.5 m. The system is realized by coupling single-frequency Global Positioning System (GPS) code and carrier-phase measurements with the data acquired from a Micro-Electro-Mechanical System (MEMS) Inertial Measurement Unit (IMU) using consumer-grade Components-Off-The-Shelf (COTS) only. The sensor fusion is accomplished using two Extended Kalman Filters (EKF) that are coupled by exchanging information about the currently estimated baseline. With a baseline of 48 cm, the static heading accuracy of the proposed system is comparable to the one of a commercial single-frequency GPS heading system with an accuracy of approximately 0.25°/m. Flight testing shows that the proposed system is able to obtain a reliable and stable GPS heading estimation without an aiding magnetometer.
Social immunity is a key factor for honeybee health, including behavioral defense strategies such as the collective use of antimicrobial plant resins (propolis). While laboratory data repeatedly show significant propolis effects, field data are scarce, especially at the colony level. Here, we investigated whether propolis, as naturally deposited in the nests, can protect honeybees against ectoparasitic mites Varroa destructor and associated viruses, which are currently considered the most serious biological threat to European honeybee subspecies, Apis mellifera, globally. Propolis intake of 10 field colonies was manipulated by either reducing or adding freshly collected propolis. Mite infestations, titers of deformed wing virus (DWV) and sacbrood virus (SBV), resin intake, as well as colony strength were recorded monthly from July to September 2013. We additionally examined the effect of raw propolis volatiles on mite survival in laboratory assays. Our results showed no significant effects of adding or removing propolis on mite survival and infestation levels. However, in relation to V. destructor, DWV titers increased significantly less in colonies with added propolis than in propolis-removed colonies, whereas SBV titers were similar. Colonies with added propolis were also significantly stronger than propolis-removed colonies. These findings indicate that propolis may interfere with the dynamics of V. destructor-transmitted viruses, thereby further emphasizing the importance of propolis for honeybee health.
Numerous studies revealed a positive relationship between biodiversity and ecosystem functioning, suggesting that biodiverse environments may not only enhance ecosystem processes, but also benefit individual ecosystem members by, for example, providing a higher diversity of resources. Whether and how the number of available resources affects resource collection and subsequently consumers (e.g., through impacting functions associated with resources) have, however, been little investigated, although a better understanding of this relationship may help explain why the abundance and richness of many animal species typically decline with decreasing plant (resource) diversity. Using a social bee species as model (Tetragonula carbonaria), we investigated how plant species richness—recorded for study sites located in different habitats—and associated resource abundance affected the diversity and functionality (here defined as nutritional content and antimicrobial activity) of resources (i.e., pollen, nectar, and resin) collected by a generalist herbivorous consumer. The diversity of both pollen and resin collected strongly increased with increasing plant/tree species richness, while resource abundance was only positively correlated with resin diversity. These findings suggest that bees maximize resource diversity intake in (resource) diverse habitats. Collecting more diverse resources did, however, not increase their functionality, which appeared to be primarily driven by the surrounding (plant) source community in our study. In generalist herbivores, maximizing resource diversity intake may therefore primarily secure collection of sufficient amounts of resources across the entire foraging season, but it also ensures that the allocated resources meet all functional needs. Decreasing available resource diversity may thus impact consumers primarily by reduced resource abundance, but also by reduced resource functionality, particularly when resources of high functionality (e.g., from specific plant species) become scarce.
The Sox pathway found in many sulfur bacteria oxidizes thiosulfate to sulfate. Pathway intermediates are covalently bound to a cysteine residue in the carrier protein SoxYZ. We have used biochemical complementation by SoxYZ-conjugates to probe the identity of the intermediates in the Sox pathway. We find that unconjugated SoxYZ and SoxYZ-S-sulfonate are unlikely to be intermediates during normal turnover in disagreement with current models. By contrast, conjugates with multiple sulfane atoms are readily metabolised by the Sox pathway. The most parsimonious interpretation of these data is that the true carrier species in the Sox pathway is a SoxYZ-S-sulfane adduct.
We develop the formalism of holographic renormalization to compute two-point functions in a holographic Kondo model. The model describes a (0 + 1)-dimensional impurity spin of a gauged SU(N ) interacting with a (1 + 1)-dimensional, large-N , strongly-coupled Conformal Field Theory (CFT). We describe the impurity using Abrikosov pseudo-fermions, and define an SU(N )-invariant scalar operator O built from a pseudo-fermion and a CFT fermion. At large N the Kondo interaction is of the form O\(^{†}\)O, which is marginally relevant, and generates a Renormalization Group (RG) flow at the impurity. A second-order mean-field phase transition occurs in which O condenses below a critical temperature, leading to the Kondo effect, including screening of the impurity. Via holography, the phase transition is dual to holographic superconductivity in (1 + 1)-dimensional Anti-de Sitter space. At all temperatures, spectral functions of O exhibit a Fano resonance, characteristic of a continuum of states interacting with an isolated resonance. In contrast to Fano resonances observed for example in quantum dots, our continuum and resonance arise from a (0 + 1)-dimensional UV fixed point and RG flow, respectively. In the low-temperature phase, the resonance comes from a pole in the Green’s function of the form −i〈O〉\(^{2}\), which is characteristic of a Kondo resonance.
The CCHC-type zinc finger nucleic acid-binding protein (CNBP/ZNF9) is conserved in eukaryotes and is essential for embryonic development in mammals. It has been implicated in transcriptional, as well as post-transcriptional, gene regulation; however, its nucleic acid ligands and molecular function remain elusive. Here, we use multiple systems-wide approaches to identify CNBP targets and function. We used photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) to identify 8,420 CNBP binding sites on 4,178 mRNAs. CNBP preferentially bound G-rich elements in the target mRNA coding sequences, most of which were previously found to form G-quadruplex and other stable structures in vitro. Functional analyses, including RNA sequencing, ribosome profiling, and quantitative mass spectrometry, revealed that CNBP binding did not influence target mRNA abundance but rather increased their translational efficiency. Considering that CNBP binding prevented G-quadruplex structure formation in vitro, we hypothesize that CNBP is supporting translation by resolving stable structures on mRNAs.
Background
The aim of this 4D flow cardiovascular magnetic resonance (CMR) follow-up study was to investigate longitudinal changes in aortic hemodynamics in adolescent patients with Marfan syndrome (MFS).
Methods
4D flow CMR for the assessment of in-vivo 3D blood flow with full coverage of the thoracic aorta was performed twice (baseline scan t1/follow-up scan t2) in 19 adolescent MFS patients (age at t1: 12.7 ± 3.6 years, t2: 16.2 ± 4.3 years) with a mean follow-up duration of 3.5 ± 1.2 years. Ten healthy volunteers (24 ± 3.8 years) served as a control group. Data analysis included aortic blood flow visualization by color-coded 3D pathlines, and grading of flow patterns (helices/vortices) on a 3-point scale (none, moderate, severe; blinded reading, 2 observers). Regional aortic peak systolic velocities and systolic 3D wall shear stress (WSS) along the entire aortic wall were quantified. Z-Scores of the aortic root and proximal descending aorta (DAo) were assessed.
Results
Regional systolic WSS was stable over the follow-up duration, except for a significant decrease in the proximal inner DAo segment (p = 0.02) between t1 and t2. MFS patients revealed significant lower mean systolic WSS in the proximal inner DAo compared with volunteers (0.78 ± 0.15 N/m\(^{2}\)) at baseline t1 (0.60 ± 0.18 N/m\(^{2}\); p = 0.01) and follow-up t2 (0.55 ± 0.16 N/m\(^{2}\); p = 0.001). There were significant relationships (p < 0.01) between the segmental WSS in the proximal inner DAo, DAo Z-scores (r = −0.64) and helix/vortex pattern grading (r = −0.55) at both t1 and t2. The interobserver agreement for secondary flow patterns assessment was excellent (Cohen’s k = 0.71).
Conclusions
MFS patients have lower segmental WSS in the inner proximal DAo segment which correlates with increased localized aberrant vortex/helix flow patterns and an enlarged diameter at one of the most critical sites for aortic dissection. General aortic hemodynamics are stable but these subtle localized DAo changes are already present at young age and tend to be more pronounced in the course of time.
Background
Aortic valve stenosis is a common finding diagnosed with high sensitivity in transthoracic echocardiography, but the examiner often finds himself confronted with uncertain results in patients with moderate pressure gradients and concomitant systolic heart failure. While patients with true-severe low-gradient aortic valve stenosis with either reduced or preserved left ventricular systolic function are primarily candidates for valve replacement, there is a relevant proportion of patients with pseudo-severe aortic valve stenosis anticipated not to benefit but actually rather deteriorate by interventional therapy or surgery.
Case presentation
In this article we present a case report of a male patient with pseudo-severe aortic valve stenosis due to cardiac amyloidosis highlighting the diagnostic schedule. The patient underwent stress echocardiography because of discrepant findings in transthoracic echocardiography and cardiac catheterization regarding the severity of aortic valve stenosis. After evaluation of the results, it became clear that he had a need for optimum heart failure medication and implantation of a cardiac resynchronization therapy defibrillator.
Conclusion
Due to the pitfalls in conventional as well as invasive diagnostics at rest, Stress echocardiography should be considered part of the standard optimum diagnostic spectrum in all unclear or borderline cases in order to confirm the correct diagnosis and constitute optimal therapy.
Background
Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology.
Methods and results
We generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D-echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age.
Conclusion
Cardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy.
Obligate intracellular Chlamydia trachomatis replicate in a membrane-bound vacuole called inclusion, which serves as a signaling interface with the host cell. Here, we show that the chlamydial deubiquitinating enzyme (Cdu) 1 localizes in the inclusion membrane and faces the cytosol with the active deubiquitinating enzyme domain. The structure of this domain revealed high similarity to mammalian deubiquitinases with a unique α-helix close to the substrate-binding pocket. We identified the apoptosis regulator Mcl-1 as a target that interacts with Cdu1 and is stabilized by deubiquitination at the chlamydial inclusion. A chlamydial transposon insertion mutant in the Cdu1-encoding gene exhibited increased Mcl-1 and inclusion ubiquitination and reduced Mcl-1 stabilization. Additionally, inactivation of Cdu1 led to increased sensitivity of C. trachomatis for IFNγ and impaired infection in mice. Thus, the chlamydial inclusion serves as an enriched site for a deubiquitinating activity exerting a function in selective stabilization of host proteins and protection from host defense.
Colorectal carcinoma (CRC) is the most common cancer of the gastrointestinal tract with frequently dysregulated intracellular signaling pathways, including p53 signaling. The mainstay of chemotherapy treatment of CRC is 5-fluorouracil (5FU) and oxaliplatin. The two anticancer drugs mediate their therapeutic effect via DNA damage-triggered signaling. The small molecule reactivating p53 and inducing tumor apoptosis (RITA) is described as an activator of wild-type and reactivator of mutant p53 function, resulting in elevated levels of p53 protein, cell growth arrest, and cell death. Additionally, it has been shown that RITA can induce DNA damage signaling. It is expected that the therapeutic benefits of 5FU and oxaliplatin can be increased by enhancing DNA damage signaling pathways. Therefore, we highlighted the antiproliferative response of RITA alone and in combination with 5FU or oxaliplatin in human CRC cells. A panel of long-term established CRC cell lines (n = 9) including p53 wild-type, p53 mutant, and p53 null and primary patient-derived, low-passage cell lines (n = 5) with different p53 protein status were used for this study. A substantial number of CRC cells with pronounced sensitivity to RITA (IC\(_{50}\)< 3.0 μmol/l) were identified within established (4/9) and primary patient-derived (2/5) CRC cell lines harboring wild-type or mutant p53 protein. Sensitivity to RITA appeared independent of p53 status and was associated with an increase in antiproliferative response to 5FU and oxaliplatin, a transcriptional increase of p53 targets p21 and NOXA, and a decrease in MYC mRNA. The effect of RITA as an inducer of DNA damage was shown by a strong elevation of phosphorylated histone variant H2A.X, which was restricted to RITA-sensitive cells. Our data underline the primary effect of RITA, inducing DNA damage, and demonstrate the differential antiproliferative effect of RITA to CRC cells independent of p53 protein status. We found a substantial number of RITA-sensitive CRC cells within both panels of established CRC cell lines and primary patient-derived CRC cell lines (6/14) that provide a rationale for combining RITA with 5FU or oxaliplatin to enhance the antiproliferative response to both chemotherapeutic agents.
Becker naevus syndrome is a rare epidermal naevus syndrome defined by the co-occurrence of a Becker naevus with various cutaneous, muscular and skeletal anomalies. In the majority of cases, abnormalities exclusively consist of ipsilateral hypoplasia of the breast, areola and/or nipple in addition to the naevus. Here, we report on a 42-year-old woman with an extensive Becker naevus reaching from the left buttock to the left calf verified on histological examination. In addition, there was marked hypoplasia of the fatty tissue of the left thigh confirmed by magnetic resonance imaging in contrast to hyperplasia of the fatty tissue of the left gluteal area. Underlying muscles and bones were not affected. There was no difference in leg lengths. In addition, we review and discuss the features of Becker naevus syndrome with emphasis on 10 reported cases with involvement of the lower body.
Dicalcium phosphate cement preparation requires the addition of setting retarders to meet clinical requirements regarding handling time and processability. Previous studies have focused on the influence of different setting modifiers on material properties such as mechanical performance or injectability, while ignoring their influence on biological cement properties as they are used in low concentrations in the cement pastes and the occurrence of most compounds in human tissues. Here, analyses of both material and biological behavior were carried out on samples with common setting retardants (citric acid, sodium pyrophosphate, sulfuric acid) and novel (phytic acid). Cytocompatibility was evaluated by in vitro tests with osteoblastic (hFOB 1.19) and osteoclastic (RAW 264.7) cells. We found cytocompatibility was better for sodium pyrophosphate and phytic acid with a three-fold cell metabolic activity by WST-1 test, whereas samples set with citric acid showed reduced cell number as well as cell activity. The compressive strength (CS) of cements formed with phytic acid (CS = 13 MPa) were nearly equal to those formed with citric acid (CS = 15 MPa) and approximately threefold higher than for other setting retardants. Due to a proven cytocompatibility and high mechanical strength, phytic acid seems to be a candidate replacement setting retardant for dicalcium phosphate cements.
The effects of circuit-like functional high-intensity training (Circuit\(_{HIIT}\)) alone or in combination with high-volume low-intensity exercise (Circuit\(_{combined}\)) on selected cardio-respiratory and metabolic parameters, body composition, functional strength and the quality of life of overweight women were compared. In this single-center, two-armed randomized, controlled study, overweight women performed 9-weeks (3 sessions·wk\(^{−1}\)) of either Circuit\(_{HIIT}\) (n = 11), or Circuit\(_{combined}\) (n = 8). Peak oxygen uptake and perception of physical pain were increased to a greater extent (p < 0.05) by Circuit\(_{HIIT}\), whereas Circuit\(_{combined}\) improved perception of general health more (p < 0.05). Both interventions lowered body mass, body-mass-index, waist-to-hip ratio, fat mass, and enhanced fat-free mass; decreased ratings of perceived exertion during submaximal treadmill running; improved the numbers of push-ups, burpees, one-legged squats, and 30-s skipping performed, as well as the height of counter-movement jumps; and improved physical and social functioning, role of physical limitations, vitality, role of emotional limitations, and mental health to a similar extent (all p < 0.05). Either forms of these multi-stimulating, circuit-like, multiple-joint training can be employed to improve body composition, selected variables of functional strength, and certain dimensions of quality of life in overweight women. However, Circuit\(_{HIIT}\) improves peak oxygen uptake to a greater extent, but with more perception of pain, whereas Circuit\(_{Combined}\) results in better perception of general health.
Niemann–Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty.
Intercellular adhesion plays a major role in tissue development and homeostasis. Yet, technologies to measure mature cell-cell contacts are not available. We introduce a methodology based on fluidic probe force microscopy to assess cell-cell adhesion forces after formation of mature intercellular contacts in cell monolayers. With this method we quantify that L929 fibroblasts exhibit negligible cell-cell adhesion in monolayers whereas human endothelial cells from the umbilical artery (HUAECs) exert strong intercellular adhesion forces per cell. We use a new in vitro model based on the overexpression of Muscle Segment Homeobox 1 (MSX1) to induce Endothelial-to-Mesenchymal Transition (EndMT), a process involved in cardiovascular development and disease. We reveal how intercellular adhesion forces in monolayer decrease significantly at an early stage of EndMT and we show that cells undergo stiffening and flattening at this stage. This new biomechanical insight complements and expands the established standard biomolecular analyses. Our study thus introduces a novel tool for the assessment of mature intercellular adhesion forces in a physiological setting that will be of relevance to biological processes in developmental biology, tissue regeneration and diseases like cancer and fibrosis.
In vitro models of the human blood-brain barrier (BBB) are highly desirable for drug development. This study aims to analyze a set of ten different BBB culture models based on primary cells, human induced pluripotent stem cells (hiPSCs), and multipotent fetal neural stem cells (fNSCs). We systematically investigated the impact of astrocytes, pericytes, and NSCs on hiPSC-derived BBB endothelial cell function and gene expression. The quadruple culture models, based on these four cell types, achieved BBB characteristics including transendothelial electrical resistance (TEER) up to 2,500 Ω cm\(^{2}\) and distinct upregulation of typical BBB genes. A complex in vivo-like tight junction (TJ) network was detected by freeze-fracture and transmission electron microscopy. Treatment with claudin-specific TJ modulators caused TEER decrease, confirming the relevant role of claudin subtypes for paracellular tightness. Drug permeability tests with reference substances were performed and confirmed the suitability of the models for drug transport studies.
In their role as second messengers, cyclic nucleotides such as cAMP have a variety of intracellular effects. These complex tasks demand a highly organized orchestration of spatially and temporally confined cAMP action which should be best achieved by compartmentalization of the latter. A great body of evidence suggests that cAMP compartments may be established and maintained by cAMP degrading enzymes, e.g. phosphodiesterases (PDEs). However, the molecular and biophysical details of how PDEs can orchestrate cAMP gradients are entirely unclear. In this paper, using fusion proteins of cAMP FRET-sensors and PDEs in living cells, we provide direct experimental evidence that the cAMP concentration in the vicinity of an individual PDE molecule is below the detection limit of our FRET sensors (<100nM). This cAMP gradient persists in crude cytosol preparations. We developed mathematical models based on diffusion-reaction equations which describe the creation of nanocompartments around a single PDE molecule and more complex spatial PDE arrangements. The analytically solvable equations derived here explicitly determine how the capability of a single PDE, or PDE complexes, to create a nanocompartment depend on the cAMP degradation rate, the diffusive mobility of cAMP, and geometrical and topological parameters. We apply these generic models to our experimental data and determine the diffusive mobility and degradation rate of cAMP. The results obtained for these parameters differ by far from data in literature for free soluble cAMP interacting with PDE. Hence, restricted cAMP diffusion in the vincinity of PDE is necessary to create cAMP nanocompartments in cells.
Frequency analysis of the rf emission of oscillating Josephson supercurrent is a powerful passive way of probing properties of topological Josephson junctions. In particular, measurements of the Josephson emission enable the detection of topological gapless Andreev bound states that give rise to emission at half the Josephson frequency f\(_{J}\) rather than conventional emission at f\(_{J}\). Here, we report direct measurement of rf emission spectra on Josephson junctions made of HgTe-based gate-tunable topological weak links. The emission spectra exhibit a clear signal at half the Josephson frequency f\(_{J}\)/2. The linewidths of emission lines indicate a coherence time of 0.3–4 ns for the f\(_{J}\)/2 line, much shorter than for the f\(_{J}\) line (3–4 ns). These observations strongly point towards the presence of topological gapless Andreev bound states and pave the way for a future HgTe-based platform for topological quantum computation.