Exotic dynamic behavior of the forced FitzHugh-Nagumo equations

AbstractSpace-clamped FitzHugh-Nagumo nerve model subjected to a stimulating electrical current of form Io + I cos γt is investigated via Poincaré map and numerical continuation. If I = 0, it is known that Hopf bifurcation occurs when Io is neither too small nor too large. Given such an Io. If γ is chosen close to the natural frequency of the Hopf bifurcated oscillation, a series of exotic phenomena varying with I are observed numerically. Let 2πλγ denote the generic period we watched. Then the scenario consists of two categories of period-adding bifurcation. The first category consists of a sequence of hysteretic, λ → λ + 2 period-adding starting with λ = 1 at I = 0+, and ending at some finite I, say I∗, as λ → ∞. The second category contains multiple levels of period-adding bifurcation. The top level consists of a sequence of λ → λ + 1, period-adding starting with λ = 2 at I = I∗. From this sequence, a hierarchy of m → m + n → n, period-adding in between are derived. Such a regular pattern is sometimes interrupted by a series of chaos. This category of bifurcation also terminates at some finite I. Harmonic resonance sets in afterwards. Lyapunov exponents, power spectra, and fractal dimensions are used to assist these observations

Elemental topological Dirac semimetal: {\alpha}-Sn on InSb(111)

Three-dimensional (3D) topological Dirac semimetals (TDSs) are rare but important as a versatile platform for exploring exotic electronic properties and topological phase transitions. A quintessential feature of TDSs is 3D Dirac fermions associated with bulk electronic states near the Fermi level. Using angle-resolved photoemission spectroscopy (ARPES), we have observed such bulk Dirac cones in epitaxially-grown {\alpha}-Sn films on InSb(111), the first such TDS system realized in an elemental form. First-principles calculations confirm that epitaxial strain is key to the formation of the TDS phase. A phase diagram is established that connects the 3D TDS phase through a singular point of a zero-gap semimetal phase to a topological insulator (TI) phase. The nature of the Dirac cone crosses over from 3D to 2D as the film thickness is reduced

Dynamical and statistical downscaling of seasonal temperature forecasts in Europe: Added value for user applications

This work describes the results of a comprehensive intercomparison experiment of dynamical and statistical downscaling methods performed in the framework of the SPECS (http://www.specs-fp7.eu) and EUPORIAS (http://www.euporias.eu) projects for seasonal forecasting over Europe, a region which exhibits low-to-moderate seasonal forecast skill. We considered a 15-member hindcast provided by the ECEARTH global model (similar to ECMWF System 4, but using bias corrected SST) for the period 1991-2012. In particular, we focus on summer mean temperature and evaluate the added value of downscaling for representation of the local climatology (mean values and extremes), improvement of model skill and performance in particular heatwave episodes. Whereas the suitability of dynamical downscaling for reducing the orographic biases of the global model depends on the region and model considered, statistical downscaling can systematically reduce errors in different order moments, from the mean to the extremes (as represented by the 95th percentile here). However, both dynamical and statistical methods lead to similar skill patterns with about the same overall performance as the global model, which shows higher values in south-eastern Europe. Therefore, no relevant added value is found in terms of model skill improvement. Finally, when focusing on the heatwaves of 2003, 2006, 2010 and 2012, the limitations of the global model to detect these hot episodes are inherited by all dynamical and statistical downscaling methods so no added value is neither found in this aspect. This work provides, to our knowledge, the largest and most comprehensive intercomparison of statistical and dynamical downscaling for seasonal forecasting over Europe.This study was supported by the SPECS and EUPORIAS projects, funded by the European Commission through the Seventh Framework Programme for Research under grant agreements 308378 and 308291, respectively. We are also grateful to the E-OBS dataset from the EU-FP6 project ENSEMBLES and the data providers in the ECA&D project. One of the authors (EvM) wants to thank Michael Kolax from SMHI (Norrköping, Sweden) for making available the full EC-EARTH hindcast ensemble for dynamical downscaling at KNMI. Finally, for the WRF simulations, the authors acknowledge the access provided to the Altamira Supercomputer at the Institute of Physics of Cantabria (IFCA-CSIC), member of the Spanish Supercomputing Network (http://grid.ifca.es/wiki/Supercomputing)

Dihydroartemisinin Enhances Apo2L/TRAIL-Mediated Apoptosis in Pancreatic Cancer Cells via ROS-Mediated Up-Regulation of Death Receptor 5

BACKGROUND: Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, has recently shown antitumor activity in various cancer cells. Apo2 ligand or tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is regarded as a promising anticancer agent, but chemoresistance affects its efficacy as a treatment strategy. Apoptosis induced by the combination of DHA and Apo2L/TRAIL has not been well documented, and the mechanisms involved remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that DHA enhances the efficacy of Apo2L/TRAIL for the treatment of pancreatic cancer. We found that combined therapy using DHA and Apo2L/TRAIL significantly enhanced apoptosis in BxPC-3 and PANC-1 cells compared with single-agent treatment in vitro. The effect of DHA was mediated through the generation of reactive oxygen species, the induction of death receptor 5 (DR5) and the modulation of apoptosis-related proteins. However, N-acetyl cysteine significantly reduced the enhanced apoptosis observed with the combination of DHA and Apo2L/TRAIL. In addition, knockdown of DR5 by small interfering RNA also significantly reduced the amount of apoptosis induced by DHA and Apo2L/TRAIL. CONCLUSIONS/SIGNIFICANCE: These results suggest that DHA enhances Apo2L/TRAIL-mediated apoptosis in human pancreatic cancer cells through reactive oxygen species-mediated up-regulation of DR5

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

Structural Basis for Type VI Secretion Effector Recognition by a Cognate Immunity Protein

The type VI secretion system (T6SS) has emerged as an important mediator of interbacterial interactions. A T6SS from Pseudomonas aeruginosa targets at least three effector proteins, type VI secretion exported 1–3 (Tse1–3), to recipient Gram-negative cells. The Tse2 protein is a cytoplasmic effector that acts as a potent inhibitor of target cell proliferation, thus providing a pronounced fitness advantage for P. aeruginosa donor cells. P. aeruginosa utilizes a dedicated immunity protein, type VI secretion immunity 2 (Tsi2), to protect against endogenous and intercellularly-transferred Tse2. Here we show that Tse2 delivered by the T6SS efficiently induces quiescence, not death, within recipient cells. We demonstrate that despite direct interaction of Tsi2 and Tse2 in the cytoplasm, Tsi2 is dispensable for targeting the toxin to the secretory apparatus. To gain insights into the molecular basis of Tse2 immunity, we solved the 1.00 Å X-ray crystal structure of Tsi2. The structure shows that Tsi2 assembles as a dimer that does not resemble previously characterized immunity or antitoxin proteins. A genetic screen for Tsi2 mutants deficient in Tse2 interaction revealed an acidic patch distal to the Tsi2 homodimer interface that mediates toxin interaction and immunity. Consistent with this finding, we observed that destabilization of the Tsi2 dimer does not impact Tse2 interaction. The molecular insights into Tsi2 structure and function garnered from this study shed light on the mechanisms of T6 effector secretion, and indicate that the Tse2–Tsi2 effector–immunity pair has features distinguishing it from previously characterized toxin–immunity and toxin–antitoxin systems

Exploiting members of the BAHD acyltransferase family to synthesize multiple hydroxycinnamate and benzoate conjugates in yeast

BACKGROUND: BAHD acyltransferases, named after the first four biochemically characterized enzymes of the group, are plant-specific enzymes that catalyze the transfer of coenzyme A-activated donors onto various acceptor molecules. They are responsible for the synthesis in plants of a myriad of secondary metabolites, some of which are beneficial for humans either as therapeutics or as specialty chemicals such as flavors and fragrances. The production of pharmaceutical, nutraceutical and commodity chemicals using engineered microbes is an alternative, green route to energy-intensive chemical syntheses that consume petroleum-based precursors. However, identification of appropriate enzymes and validation of their functional expression in heterologous hosts is a prerequisite for the design and implementation of metabolic pathways in microbes for the synthesis of such target chemicals. RESULTS: For the synthesis of valuable metabolites in the yeast Saccharomyces cerevisiae, we selected BAHD acyltransferases based on their preferred donor and acceptor substrates. In particular, BAHDs that use hydroxycinnamoyl-CoAs and/or benzoyl-CoA as donors were targeted because a large number of molecules beneficial to humans belong to this family of hydroxycinnamate and benzoate conjugates. The selected BAHD coding sequences were synthesized and cloned individually on a vector containing the Arabidopsis gene At4CL5, which encodes a promiscuous 4-coumarate:CoA ligase active on hydroxycinnamates and benzoates. The various S. cerevisiae strains obtained for co-expression of At4CL5 with the different BAHDs effectively produced a wide array of valuable hydroxycinnamate and benzoate conjugates upon addition of adequate combinations of donors and acceptor molecules. In particular, we report here for the first time the production in yeast of rosmarinic acid and its derivatives, quinate hydroxycinnamate esters such as chlorogenic acid, and glycerol hydroxycinnamate esters. Similarly, we achieved for the first time the microbial production of polyamine hydroxycinnamate amides; monolignol, malate and fatty alcohol hydroxycinnamate esters; tropane alkaloids; and benzoate/caffeate alcohol esters. In some instances, the additional expression of Flavobacterium johnsoniae tyrosine ammonia-lyase (FjTAL) allowed the synthesis of p-coumarate conjugates and eliminated the need to supplement the culture media with 4-hydroxycinnamate. CONCLUSION: We demonstrate in this study the effectiveness of expressing members of the plant BAHD acyltransferase family in yeast for the synthesis of numerous valuable hydroxycinnamate and benzoate conjugates

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data