Avalanche of Bifurcations and Hysteresis in a Model of Cellular Differentiation

Cellular differentiation in a developping organism is studied via a discrete bistable reaction-diffusion model. A system of undifferentiated cells is allowed to receive an inductive signal emenating from its environment. Depending on the form of the nonlinear reaction kinetics, this signal can trigger a series of bifurcations in the system. Differentiation starts at the surface where the signal is received, and cells change type up to a given distance, or under other conditions, the differentiation process propagates through the whole domain. When the signal diminishes hysteresis is observed

Topoisomerase II inhibitors induce DNA damage-dependent interferon responses circumventing Ebola virus immune evasion

Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs. These compounds were demonstrated to induce IFN responses in an ATM kinase-dependent manner and to also trigger the DNA-sensing cGAS-STING pathway of IFN induction. These compounds also suppress EBOV replication in vitro and induce IFN in the presence of IFN-antagonist proteins from multiple negative-sense RNA viruses. These findings provide new insights into signaling pathways activated by important chemotherapy drugs and identify a novel therapeutic approach for IFN induction that may be exploited to inhibit RNA virus replication

Singular values of the Dirac operator in dense QCD-like theories

We study the singular values of the Dirac operator in dense QCD-like theories at zero temperature. The Dirac singular values are real and nonnegative at any nonzero quark density. The scale of their spectrum is set by the diquark condensate, in contrast to the complex Dirac eigenvalues whose scale is set by the chiral condensate at low density and by the BCS gap at high density. We identify three different low-energy effective theories with diquark sources applicable at low, intermediate, and high density, together with their overlapping domains of validity. We derive a number of exact formulas for the Dirac singular values, including Banks-Casher-type relations for the diquark condensate, Smilga-Stern-type relations for the slope of the singular value density, and Leutwyler-Smilga-type sum rules for the inverse singular values. We construct random matrix theories and determine the form of the microscopic spectral correlation functions of the singular values for all nonzero quark densities. We also derive a rigorous index theorem for non-Hermitian Dirac operators. Our results can in principle be tested in lattice simulations.Comment: 3 references added, version published in JHE

Type VI Secretion System and Its Effectors PdpC, PdpD, and OpiA Contribute to; Francisella; Virulence in Galleria mellonella Larvae

Francisella tularensis causes the deadly zoonotic disease tularemia in humans and is able to infect a broad range of organisms including arthropods, which are thought to play a major role in; Francisella; transmission. However, while mammalian; in vitro; and; in vivo; infection models are widely used to investigate; Francisella; pathogenicity, a detailed characterization of the major; Francisella; virulence factor, a noncanonical type VI secretion system (T6SS), in an arthropod; in vivo; infection model is missing. Here, we use Galleria mellonella larvae to analyze the role of the; Francisella; T6SS and its corresponding effectors in F. tularensis subsp.; novicida; virulence. We report that G. mellonella larvae killing depends on the functional T6SS and infectious dose. In contrast to other mammalian; in vivo; infection models, even one of the T6SS effectors PdpC, PdpD, or OpiA is sufficient to kill G. mellonella larvae, while sheath recycling by ClpB is dispensable. We further demonstrate that treatment by polyethylene glycol (PEG) activates; Francisella; T6SS in liquid culture and that this is independent of the response regulator PmrA. PEG-activated IglC secretion is dependent on T6SS structural component PdpB but independent of putative effectors PdpC, PdpD, AnmK, OpiB; 1; , OpiB; 2; , and OpiB; 3; . The results of larvae infection and secretion assay suggest that AnmK, a putative T6SS component with unknown function, interferes with OpiA-mediated toxicity but not with general T6SS activity. We establish that the easy-to-use G. mellonella larvae infection model provides new insights into the function of T6SS and pathogenesis of; Francisella;

PAAR-repeat proteins sharpen and diversify the Type VI secretion system spike

The bacterial type VI secretion system (T6SS) is a large multi-component, dynamic macromolecular machine that plays an important role in the ecology of many Gram negative bacteria. T6SS is responsible for translocation of a wide range of toxic effector molecules allowing predatory cells to kill both prokaryotic as well as eukaryotic prey cells1-5. The T6SS organelle is functionally analogous to contractile tails of bacteriophages and is thought to attack cells by initially penetrating them with a trimeric protein complex called the VgrG spike6,7. Neither the exact protein composition of the T6SS organelle nor the mechanisms of effector selection and delivery are known. Here we report that proteins from the PAAR (Proline-Alanine-Alanine-aRginine) repeat superfamily form a sharp conical extension on the VgrG spike, which is further involved in attaching effector domains to the spike. The crystal structures of two PAAR-repeat proteins bound to VgrG-like partners show that these proteins function to sharpen the tip of the VgrG spike. We demonstrate that PAAR proteins are essential for T6SS- mediated secretion and target cell killing by Vibrio cholerae and Acinetobacter baylyi. Our results suggest a new model of the T6SS organelle in which the VgrG-PAAR spike complex is decorated with multiple effectors that are delivered simultaneously into target cells in a single contraction-driven translocation event

The identification of QTL controlling ergot sclerotia size in hexaploid wheat implicates a role for the Rht dwarfing alleles

The fungal pathogen Claviceps purpurea infects ovaries of a broad range of temperate grasses and cereals, including hexaploid wheat, causing a disease commonly known as ergot. Sclerotia produced in place of seed carry a cocktail of harmful alkaloid compounds that result in a range of symptoms in humans and animals, causing ergotism. Following a field assessment of C. purpurea infection in winter wheat, two varieties ‘Robigus’ and ‘Solstice’ were selected which consistently produced the largest differential effect on ergot sclerotia weights. They were crossed to produce a doubled haploid mapping population, and a marker map, consisting of 714 genetic loci and a total length of 2895 cM was produced. Four ergot reducing QTL were identified using both sclerotia weight and size as phenotypic parameters; QCp.niab.2A and QCp.niab.4B being detected in the wheat variety ‘Robigus’, and QCp.niab.6A and QCp.niab.4D in the variety ‘Solstice’. The ergot resistance QTL QCp.niab.4B and QCp.niab.4D peaks mapped to the same markers as the known reduced height (Rht) loci on chromosomes 4B and 4D, Rht-B1 and Rht-D1, respectively. In both cases, the reduction in sclerotia weight and size was associated with the semi-dwarfing alleles, Rht-B1b from ‘Robigus’ and Rht-D1b from ‘Solstice’. Two-dimensional, two-QTL scans identified significant additive interactions between QTL QCp.niab.4B and QCp.niab.4D, and between QCp.niab.2A and QCp.niab.4B when looking at sclerotia size, but not between QCp.niab.2A and QCp.niab.4D. The two plant height QTL, QPh.niab.4B and QPh.niab.4D, which mapped to the same locations as QCp.niab.4B and QCp.niab.4D, also displayed significant genetic interactions

Effects of soil warming and nitrogen foliar applications on bud burst of black spruce

Key message: In mature black spruce, bud burst process is anticipated by soil warming, while delayed by foliar applications of nitrogen; however, the effects depend on growth conditions at the site. Abstract: The observation of phenological events can be used as biological indicator of environmental changes, especially from the perspective of climate change. In boreal forests, the onset of the bud burst is a key factor in the length of the growing season. With current climate change, the major factors limiting the growth of boreal trees (i.e., temperature and nitrogen availability) are changing and studies on mature trees are limited. The aim of this study was to investigate the effects of soil warming and increased nitrogen (N) deposition on bud burst of mature black spruce [Picea mariana (Mill.) BSP]. From 2008 onwards, an experimental manipulation of these environmental growth conditions was conducted in two stands (BER and SIM) at different altitudes in the boreal forest of Quebec, Canada. An increase in soil temperature (H treatment) and a canopy application of artificial rain enriched with nitrogen (N treatment) were performed. Observations of bud phenology were made during May–July 2012 and 2013. In BER, H treatment caused an anticipation (estimated as 1–3 days); while N treatment, a delay (estimated as 1–2 days but only in 2012) in bud burst. No treatments effect was significant in SIM. It has been demonstrated that soil temperature and N availability can play an important role in affecting bud burst in black spruce but the effects of these environmental factors on growth are closely linked with site conditions