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Intrinsically disordered protein (IDP) duplexes composed of two IDP chains cross-linked by bivalent partner proteins form scaffolds for assembly of multiprotein complexes. The N-terminal domain of dynein intermediate chain (N-IC) is one such IDP that forms a bivalent scaffold with multiple dynein light chains including LC8, a hub protein that promotes duplex formation of diverse IDP partners. N-IC also binds a subunit of the dynein regulator, dynactin. Here we characterize interactions of a yeast ortholog of N-IC (N-Pac11) with yeast LC8 (Dyn2) or with the intermediate chain-binding subunit of yeast dynactin (Nip100). Residue level changes in Pac11 structure are monitored by NMR spectroscopy, and binding energetics are monitored by isothermal titration calorimetry (ITC). N-Pac11 is monomeric and primarily disordered except for a single α-helix (SAH) at the N terminus and a short nascent helix, LH, flanked by the two Dyn2 recognition motifs. Upon binding Dyn2, the only Pac11 residues making direct protein-protein interactions are in and immediately flanking the recognition motifs. Dyn2 binding also orders LH residues of Pac11. Upon binding Nip100, only Pac11 SAH residues make direct protein-protein interactions, but LH residues at a distant sequence position and L1 residues in an adjacent linker are also ordered. The long distance, ligand-dependent ordering of residues reveals new elements of dynamic structure within IDP linker regions.
Emerging evidence indicates that protein synthesis and degradation are necessary for the remodeling of synapses. These two processes govern cellular protein turnover, are tightly regulated, and are modulated by neuronal activity in time and space. The anisotropic anatomy of the neurons presents a challenge for the study of protein turnover, but the understanding of protein turnover in neurons and its modulation in response to activity can help us to unravel the fine-tuned changes that occur at synapses in response to activity. Here we review the key experimental evidence demonstrating the role of protein synthesis and degradation in synaptic plasticity, as well as the turnover rates of specific neuronal proteins.
Background: Tumor associated macrophages (TAMs) are known to support tumor progression and their accumulation is generally associated with poor prognosis. The shift from a tumor-attacking to a tumor-supportive macrophage phenotype is based on an educational program that, at least in part, is initiated by apoptotic tumor cells.
Aims: We explored the macrophage phenotype shift during tumor progression by analyzing the macrophage NO-output system and examining potential NO targets.
Methods: Biochemical and Molecular Biology-orientated cell culture experiments, in part using 3d-tumor spheroid models as well as animal experiments were used.
Results: Apoptotic cells polarize macrophages towards a healing, tumor-supportive phenotype. Soluble mediators released from apoptotic cells, among them the lipid sphingosine-1-phosphate (S1P), cause expression of arginase 2 in macrophages, thereby lowering citrulline/NO formation but enhancing ornithine production. Mechanistically, this is achieved via the S1P2 receptor and the CRE (cAMP-response element) binding site in the arginase 2 promoter. Reduced NO-formation is also seen in ex vivo macrophages from a xenograft model allowing restricted vs. unrestricted tumor growth based on tumor-associated S1P-formation. The theoretical ability of NO to target hypoxia-inducible factor-1 (HIF-1) and jumonji histone demethylases (JHDMs) in cells of the tumor microenvironment will be discussed in light of the iNOS/arginase balance. Moreover, data on the importance of HIF-1 in macrophages for their interaction with tumor cells, polarization, and angiogenic potential will be presented.
Conclusions: We hypothesize that apoptotic death of tumor cells and associated macrophage activation facilitates the progression of malignant disease. The macrophage polarization program affects the NO-output system and the capacity of macrophages to support or restrict tumor growth.
Combination chemotherapy with gemcitabine and cisplatin in patients with metastatic urothelial cancer of the bladder frequently results in the development of acquired drug resistance. Availability of cell culture models with acquired resistance could help to identify candidate treatments for an efficient second-line therapy. Six cisplatin- and six gemcitabine-resistant cell lines were established. Cell viability assays were performed to evaluate the sensitivity to 16 different chemotherapeutic substances. The activity of the drug transporter ATP-binding cassette transporter, subfamily B, member 1 (ABCB1, a critical mediator of multidrug resistance in cancer) was evaluated using fluorescent ABCB1 substrates. For functional assessment, cells overexpressing ABCB1 were generated by transduction with a lentiviral vector encoding for ABCB1, while zosuquidar was used for selective inhibition. In this study, 8 of 12 gemcitabine- or cisplatin-resistant cell lines were cross-resistant to carboplatin, 5 to pemetrexed, 4 to methotrexate, 3 to oxaliplatin, 5-fluorouracil, and paclitaxel, and 2 to cabazitaxel, larotaxel, docetaxel, topotecan, doxorubicin, and mitomycin c, and 1 of 12 cell lines was cross-resistant to vinflunine and vinblastine. In one cell line with acquired resistance to gemcitabine (TCC-SUPrGEMCI20), cross-resistance seemed to be mediated by ABCB1 expression. Our model identified the vinca alkaloids vinblastine and vinflunine, in Europe an already approved second-line therapeutic for metastatic bladder cancer, as the most effective compounds in urothelial cancer cells with acquired resistance to gemcitabine or cisplatin. These results demonstrate that this in vitro model can reproduce clinically relevant results and may be suitable to identify novel substances for the treatment of metastatic bladder cancer.
We present an angular thin-lens formula giving the angle of refraction β for arbitrary values of the angle of incidence α. With this formula, we find analytical results for the focal length f of a thin-lens system. The number of lenses n and their focal lengths f1,f2,…,fn are abitrary, as are the mutual distances D12,…,D(n−1)n between the lenses. All these results are exact, i.e. not restricted to small or even paraxial angles. In the literature, the 2-lens and 3-lens versions (the last one without proof or derivation) are known [1]. We present the general result for n lenses and for (the positions of) its principal planes.
Linking mathematics with reality is not new. It is also not new to use outdoor activities to learn mathematics. It seems to be new, to combine such mathematical outdoor activities with mobile technology, like the geocache community which makes use of GPS technology to guide their members to special places and points of interest. The use of mobile technologies to learn at any time and any location is known as “mobile learning”. This type of learning can be seen as an extension of eLearning. Considering the definition of O’Malley one notices that this definition does not exactly match with the idea of the MathCityMap-Project (MCM), because the learning environment in the MCM-Project is predetermined. Combined with the math trail method the project enables mobile learning within math trails with latest technology.In the MCM-Project students experience mathematics at real places and within real situations in out-of-school activities,with help of GPS-enabled smartphones and special math problems. In contrast to the paper versions of math trails we are able to give direct feedback on the solutions by using “mobile devices” such as smartphones or tablets. If the user has difficulties in solving the modeling task, stepped hints can be provided. The teacher is able to use the MCM-Portal to upload tasks developed by himself or by his students and he is also able to build a personal math trail for his students.
The hepatitis C virus (HCV) was discovered in the late 1980s. Interferon (IFN)-α was proposed as an antiviral treatment for chronic hepatitis C at about the same time. Successive improvements in IFN-α-based therapy (dose finding, pegylation, addition of ribavirin) increased the rates of sustained virologic response, i.e. the rates of curing HCV infection. These rates were further improved by adding the first available direct-acting antiviral (DAA) drugs to the combination of pegylated IFN-α and ribavirin. An IFN-free era finally started in 2014, yielding rates of sustained virologic response over 90% in patients treated for 8 to 24 weeks with all-oral regimens. Major challenges however remain in implementation of these new treatment strategies, not only in low- to middle-income countries, but also in high-income countries where the price of these therapies is still prohibitive. Elimination of HCV infection through treatment in certain areas is possible but raises major public health issues.
In many neural systems anatomical motifs are present repeatedly, but despite their structural similarity they can serve very different tasks. A prime example for such a motif is the canonical microcircuit of six-layered neo-cortex, which is repeated across cortical areas, and is involved in a number of different tasks (e.g. sensory, cognitive, or motor tasks). This observation has spawned interest in finding a common underlying principle, a ‘goal function’, of information processing implemented in this structure. By definition such a goal function, if universal, cannot be cast in processing-domain specific language (e.g. ‘edge filtering’, ‘working memory’). Thus, to formulate such a principle, we have to use a domain-independent framework. Information theory offers such a framework. However, while the classical framework of information theory focuses on the relation between one input and one output (Shannon’s mutual information), we argue that neural information processing crucially depends on the combination of multiple inputs to create the output of a processor. To account for this, we use a very recent extension of Shannon Information theory, called partial information decomposition (PID). PID allows to quantify the information that several inputs provide individually (unique information), redundantly (shared information) or only jointly (synergistic information) about the output. First, we review the framework of PID. Then we apply it to reevaluate and analyze several earlier proposals of information theoretic neural goal functions (predictive coding, infomax and coherent infomax, efficient coding). We find that PID allows to compare these goal functions in a common framework, and also provides a versatile approach to design new goal functions from first principles. Building on this, we design and analyze a novel goal function, called ‘coding with synergy’, which builds on combining external input and prior knowledge in a synergistic manner. We suggest that this novel goal function may be highly useful in neural information processing.
Sleep has been shown to subtly disrupt the spatial organization of functional connectivity networks in the brain, but in a way that largely preserves the connectivity within sensory cortices. Here we evaluated the hypothesis that sleep does impact sensory cortices, but through alteration of activity dynamics. We therefore examined the impact of sleep on hemodynamics using a method for quantifying non-random, high frequency signatures of the blood-oxygen-level dependent (BOLD) signal (amplitude variance asymmetry; AVA). We found that sleep was associated with the elimination of these dynamics in a manner that is restricted to auditory, motor and visual cortices. This elimination was concurrent with increased variance of activity in these regions. Functional connectivity between regions showing AVA during wakefulness maintained a relatively consistent hierarchical structure during wakefulness and N1 and N2 sleep, despite a gradual reduction of connectivity strength as sleep progressed. Thus, sleep is related to elimination of high frequency non-random activity signatures in sensory cortices that are robust during wakefulness. The elimination of these AVA signatures conjointly with preservation of the structure of functional connectivity patterns may be linked to the need to suppress sensory inputs during sleep while still maintaining the capacity to react quickly to complex multimodal inputs.
Dilatometric studies on single crystalline barlowite – a structurally perfect spin-1/2 Kagome system
(2015)
We present results of high-resolution thermal expansion measurements on single crystalline barlowite – a structurally perfect spin-1/2 kagome system. The data reveal strongly pronounced and anisotropic second-order phase transition anomalies at the Néel transition at TN = 16K. From these data, together with literature results on the specific heat, the uniaxial-pressure dependences of TN are derived. We find a rather large positive pressure coefficient for uniaxial pressure along the hexagonal c axis of ∂TN/∂pc = (2.3 ± 0.2) K/GPa and smaller negative in-plane pressure coefficient of ∂TN/∂pin-plane = -(0.6 ± 0.03) K/GPa. These effects result in a small positive pressure coefficient under hydrostatic-pressure conditions of ∂TN/∂phydr = (1.1 ± 0.2) K/GPa. Bond-lengths considerations indicate that inter-layer Cu-O bonds, being larger than those typically found in stable Cu-O complexes, are responsible for this behavior.
Injury of the sciatic nerve results in regulations of pro- and anti-oxidative enzymes at sites of nociceptive signaling including the injured nerve, dorsal root ganglia (DRGs), dorsal horn of the spinal cord, thalamus and somatosensory cortex (Valek et al., 2015) [1]. The present DiB paper shows immunohistochemistry of redoxins including peroxiredoxins (Prdx1–6), glutaredoxins (Glrx1, 2, 3, 5), thioredoxins (Txn1, 2) and thioredoxin reductases (Txnrd1, 2) in the DRGs, spinal cord and sciatic nerve and thalamus in naïve mice and 7 days after Spared sciatic Nerve Injury (SNI) in control mice (Hif1α-flfl) and in mice with a specific deletion of hypoxia inducible factor 1 alpha (SNS-HIF1α−/−) in DRG neurons. The sciatic nerves were immunostained for the respective redoxins and counterstained with hematoxylin. The redoxin immunoreactivity was quantified with ImageJ. For the DRGs and spinal cord the data show the quantitative assessment of the intensity of redoxin immunoreactivity transformed to rainbow pseudocolors. In addition, some redoxin examples of the ipsi and contralateral dorsal and ventral horns of the lumbar spinal cord and some redoxin examples of the thalamus are presented.
We have performed the first measurement of the coherent ψ(2S) photo-production cross section in ultra-peripheral PbPb collisions at the LHC. This charmonium excited state is reconstructed via the ψ(2S)→l+l− and ψ(2S)→J/ψπ+π− decays, where the J/ψ decays into two leptons. The analysis is based on an event sample corresponding to an integrated luminosity of about 22 μb−1. The cross section for coherent ψ(2S) production in the rapidity interval −0.9<y<0.9 is dσψ(2S)coh/dy=0.83±0.19(stat+syst) mb. The ψ(2S) to J/ψ coherent cross section ratio is 0.34−0.07+0.08(stat+syst). The obtained results are compared to predictions from theoretical models.
We present measurements of the azimuthal dependence of charged jet production in central and semi-central √sNN=2.76 TeV Pb–Pb collisions with respect to the second harmonic event plane, quantified as v2ch jet. Jet finding is performed employing the anti-kT algorithm with a resolution parameter R=0.2 using charged tracks from the ALICE tracking system. The contribution of the azimuthal anisotropy of the underlying event is taken into account event-by-event. The remaining (statistical) region-to-region fluctuations are removed on an ensemble basis by unfolding the jet spectra for different event plane orientations independently. Significant non-zero v2ch jet is observed in semi-central collisions (30–50% centrality) for 20<pTch jet<90 GeV/c. The azimuthal dependence of the charged jet production is similar to the dependence observed for jets comprising both charged and neutral fragments, and compatible with measurements of the v2 of single charged particles at high pT. Good agreement between the data and predictions from JEWEL, an event generator simulating parton shower evolution in the presence of a dense QCD medium, is found in semi-central collisions.
The production of electrons from heavy-flavour hadron decays was measured as a function of transverse momentum (pT) in minimum-bias p–Pb collisions at sNN=5.02 TeV using the ALICE detector at the LHC. The measurement covers the pT interval 0.5<pT<12 GeV/c and the rapidity range −1.065<ycms<0.135 in the centre-of-mass reference frame. The contribution of electrons from background sources was subtracted using an invariant mass approach. The nuclear modification factor RpPb was calculated by comparing the pT-differential invariant cross section in p–Pb collisions to a pp reference at the same centre-of-mass energy, which was obtained by interpolating measurements at s=2.76 TeV and s=7 TeV. The RpPb is consistent with unity within uncertainties of about 25%, which become larger for pT below 1 GeV/c. The measurement shows that heavy-flavour production is consistent with binary scaling, so that a suppression in the high-pT yield in Pb–Pb collisions has to be attributed to effects induced by the hot medium produced in the final state. The data in p–Pb collisions are described by recent model calculations that include cold nuclear matter effects.
We present results of a search for two hypothetical strange dibaryon states, i.e. the H-dibaryon and the possible Λn‾ bound state. The search is performed with the ALICE detector in central (0–10%) Pb–Pb collisions at √sNN=2.76 TeV, by invariant mass analysis in the decay modes Λn‾→d‾π+ and H-dibaryon →Λpπ−. No evidence for these bound states is observed. Upper limits are determined at 99% confidence level for a wide range of lifetimes and for the full range of branching ratios. The results are compared to thermal, coalescence and hybrid UrQMD model expectations, which describe correctly the production of other loosely bound states, like the deuteron and the hypertriton.
The pseudorapidity (η) and transverse-momentum (pT) distributions of charged particles produced in proton–proton collisions are measured at the centre-of-mass energy √s=13 TeV. The pseudorapidity distribution in |η|<1.8 is reported for inelastic events and for events with at least one charged particle in |η|<1. The pseudorapidity density of charged particles produced in the pseudorapidity region |η|<0.5 is 5.31±0.18 and 6.46±0.19 for the two event classes, respectively. The transverse-momentum distribution of charged particles is measured in the range 0.15<pT<20 GeV/c and |η|<0.8 for events with at least one charged particle in |η|<1. The evolution of the transverse momentum spectra of charged particles is also investigated as a function of event multiplicity. The results are compared with calculations from PYTHIA and EPOS Monte Carlo generators.
We construct net baryon number and strangeness susceptibilities as well as correlations between electric charge, strangeness and baryon number from experimental data at midrapidity of the ALICE Collaboration at CERN. The data were taken in central Pb–Pb collisions at sNN=2.76 TeV and cover one unit of rapidity. The resulting fluctuations and correlations are consistent with Lattice QCD results at the chiral crossover pseudocritical temperature Tc≃155 MeV. This agreement lends strong support to the assumption that the fireball created in these collisions is of thermal origin and exhibits characteristic properties expected in QCD at the transition from the quark gluon plasma to the hadronic phase. The volume of the fireball for one unit of rapidity at Tc is found to exceed 3000 fm3. A detailed discussion on uncertainties in the temperature and volume of the fireball is presented. The results are linked to pion interferometry measurements and predictions from percolation theory.
Background. Bile leakage testing may help to detect and reduce the incidence of biliary leakage after hepatic resection. This review was performed to investigate the value of the White-test in identifying intraoperative biliary leakage and avoiding postoperative leakage.
Material and methods. A systematic review and meta-analysis was performed. Two researchers performed literature research. Primary outcome measure was the incidence of post-hepatectomy biliary leakage; secondary outcome measure was the ability of detecting intraoperative biliary leakage with the help of the White-test.
Results. A total of 4 publications (including original data from our center) were included in the analysis. Evidence levels of the included studies had medium quality of 2b (individual cohort studies including low quality randomized controlled trials). Use of the White-test led to a significant reduction of post-operative biliary leakage [OR: 0.3 (95% CI: 0.14, 0.63), p = 0.002] and led to a significant higher intraoperative detection of biliary leakages [OR: 0.03 (95%CI: 0.02, 0.07), p < 0.00001].
Conclusion. Existing evidence implicates the use of the White-test after hepatic resection to identify bile leaks intraoperatively and thus reduce incidence of post-operative biliary leakage. Nonetheless, there is a requirement for a high-quality randomized controlled trial with adequately powered sample-size to confirm findings from the above described studies and further increase evidence in this field.
Hepatology highlights
(2015)
Previous study showed that kaffir lime leaf contains alkaloid, flavonoid, terpenoid, tannin and saponin. The objective of this study was to examine the cytotoxic effect of kaffir lime leaf extract on cervical cancer and neuroblastoma cell lines. The method used for this research to determine cell viability was an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Results showed that an ethyl acetate extract had an IC50 for HeLa cells, UKF-NB3, IMR-5 and SK-N-AS parental cells of 40.7 μg · mL–1, 28.4 μg · mL–1, 14.1 μg · mL–1, and 25.2 μg · mL–1 respectively. Furthermore, the IC50 of chloroform extracts for HeLa cells, UKF-NB3, IMR-5 and SK-N-AS parental were 17.6 μg · mL–1, 18.9 μg · mL–1, 6.4 μg · mL–1, and 9.4 μg · mL–1 respectively. These data showed that kaffir lime extract reduces the viability of cervical and neuroblastoma cell lines and may have potential as anti-cancer compounds.