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  • Publication . Article . Other literature type . Preprint . 2022
    Open Access English
    Authors: 
    Laura Sberna; Stanislav Babak; Sylvain Marsat; Andrea Caputo; Giulia Cusin; Alexandre Toubiana; Enrico Barausse; Chiara Caprini; Tito Dal Canton; Alberto Sesana; +1 more
    Project: EC | GRU (101007855), EC | LDMThExp (682676), EC | GRAMS (815673), EC | B Massive (818691)

    Binaries of relatively massive black holes like GW190521 have been proposed to form in dense gas environments, such as the disks of Active Galactic Nuclei (AGNs), and they might be associated with transient electromagnetic counterparts. The interactions of this putative environment with the binary could leave a significant imprint at the low gravitational wave frequencies observable with the Laser Interferometer Space Antenna (LISA). We show that LISA will be able to detect up to ten GW190521-like black hole binaries, with sky position errors $\lesssim1$ deg$^2$. Moreover, it will measure directly various effects due to the orbital motion around the supermassive black hole at the center of the AGN, especially the Doppler modulation and the Shapiro time delay. Thanks to a careful treatment of their frequency domain signal, we were able to perform the full parameter estimation of Doppler and Shapiro-modulated binaries as seen by LISA. We find that the Doppler and Shapiro effects will allow for measuring the AGN parameters (radius and inclination of the orbit around the AGN, central black hole mass) with up to percent-level precision. Properly modeling these low-frequency environmental effects is crucial to determine the binary formation history, as well as to avoid biases in the reconstruction of the source parameters and in tests of general relativity with gravitational waves. 13+4 pages, 7+1 figures v3: corrected typo in Fig 5

  • Open Access English
    Authors: 
    Irene Jiménez Guerrero; Francisco Pérez-Montaño; Gustavo Mateus da Silva; Naama Wagner; Dafna Shkedy; Mei Zhao; Lorena Pizarro; Maya Bar; Ron Walcott; Guido Sessa; +2 more
    Publisher: Cold Spring Harbor Laboratory

    AbstractMany Gram-negative plant and animal pathogenic bacteria employ a type III secretion system (T3SS) to secrete protein effectors into the cells of their hosts and promote disease. The plant pathogen Acidovorax citrulli requires a functional T3SS for pathogenicity. As with Xanthomonas and Ralstonia spp., an AraC-type transcriptional regulator, HrpX, regulates expression of genes encoding T3SS components and type III-secreted effectors (T3Es) in A. citrulli. A previous study reported eleven T3E genes in this pathogen, based on the annotation of a sequenced strain. We hypothesized that this was an underestimation. Guided by this hypothesis, we aimed at uncovering the T3E arsenal of the A. citrulli model strain, M6. We carried out a thorough sequence analysis searching for similarity to known T3Es from other bacteria. This analysis revealed 51 A. citrulli genes whose products are similar to known T3Es. Further, we combined machine learning and transcriptomics to identify novel T3Es. The machine learning approach ranked all A. citrulli M6 genes according to their propensity to encode T3Es. RNA-Seq revealed differential gene expression between wild-type M6 and a mutant defective in HrpX. Data combined from these approaches led to the identification of seven novel T3E candidates, that were further validated using a T3SS-dependent translocation assay. These T3E genes encode hypothetical proteins, do not show any similarity to known effectors from other bacteria, and seem to be restricted to plant pathogenic Acidovorax species. Transient expression in Nicotiana benthamiana revealed that two of these T3Es localize to the cell nucleus and one interacts with the endoplasmic reticulum. This study not only uncovered the arsenal of T3Es of an important pathogen, but it also places A. citrulli among the “richest” bacterial pathogens in terms of T3E cargo. It also revealed novel T3Es that appear to be involved in the pathoadaptive evolution of plant pathogenic Acidovorax species.Author summaryAcidovorax citrulli is a Gram-negative bacterium that causes bacterial fruit blotch (BFB) disease of cucurbits. This disease represents a serious threat to cucurbit crop production worldwide. Despite the agricultural importance of BFB, the knowledge about basic aspects of A. citrulli-plant interactions is rather limited. As many Gram-negative plant and animal pathogenic bacteria, A. citrulli employs a complex secretion system, named type III secretion system, to deliver protein virulence effectors into the host cells. In this work we aimed at uncovering the arsenal of type III-secreted effectors (T3Es) of this pathogen by combination of bioinformatics and experimental approaches. We found that this bacterium possesses at least 51 genes that are similar to T3E genes from other pathogenic bacteria. In addition, our study revealed seven novel T3Es that seem to occur only in A. citrulli strains and in other plant pathogenic Acidovorax species. We found that two of these T3Es localize to the plant cell nucleus while one partially interacts with the endoplasmic reticulum. Further characterization of the novel T3Es identified in this study may uncover new host targets of pathogen effectors and new mechanisms by which pathogenic bacteria manipulate their hosts.

  • Open Access English
    Authors: 
    Gal Dalal; Balázs Szörényi; Gugan Thoppe;
    Project: NSF | RoL: FELS: RAISE: Does ev... (1840223)

    Policy evaluation in reinforcement learning is often conducted using two-timescale stochastic approximation, which results in various gradient temporal difference methods such as GTD(0), GTD2, and TDC. Here, we provide convergence rate bounds for this suite of algorithms. Algorithms such as these have two iterates, $\theta_n$ and $w_n,$ which are updated using two distinct stepsize sequences, $\alpha_n$ and $\beta_n,$ respectively. Assuming $\alpha_n = n^{-\alpha}$ and $\beta_n = n^{-\beta}$ with $1 > \alpha > \beta > 0,$ we show that, with high probability, the two iterates converge to their respective solutions $\theta^*$ and $w^*$ at rates given by $\|\theta_n - \theta^*\| = \tilde{O}( n^{-\alpha/2})$ and $\|w_n - w^*\| = \tilde{O}(n^{-\beta/2});$ here, $\tilde{O}$ hides logarithmic terms. Via comparable lower bounds, we show that these bounds are, in fact, tight. To the best of our knowledge, ours is the first finite-time analysis which achieves these rates. While it was known that the two timescale components decouple asymptotically, our results depict this phenomenon more explicitly by showing that it in fact happens from some finite time onwards. Lastly, compared to existing works, our result applies to a broader family of stepsizes, including non-square summable ones.

  • Open Access English
    Authors: 
    Elisabeth Stelling; Melanie Ricke-Hoch; Sergej Erschow; Steve Hoffman; Anke K. Bergmann; Maren Heimerl; Stefan Pietzsch; Karin Battmer; Alexandra Haase; Britta Stapel; +4 more
    Publisher: Cold Spring Harbor Laboratory

    AbstractCardiac levels of the signal transducer and activator of transcription factor-3 (STAT3) decline with age, and male but not female mice with a cardiomyocyte-specific STAT3 deficiency (CKO) display premature age-related heart failure associated with reduced cardiac capillary density. In the present study isolated male and female CKO-cardiomyocytes exhibit increased prostaglandin (PG)-generating cyclooxygenase-2 (COX-2) expression. The PG-degrading hydroxyprostaglandin-dehydrogenase-15 (HPGD) expression is only reduced in male cardiomyocytes, which is associated with increased PGD2 secretion from isolated male but not female CKO-cardiomyocytes. Reduced HPGD expression in male cardiomyocytes derive from impaired androgen-receptor-(AR)-signaling due to loss of its co-factor STAT3. Elevated PGD2 secretion in males is associated with increased white adipocyte accumulation in aged male but not female hearts. Adipocyte differentiation is enhanced in isolated SCA-1+-cardiac-progenitor-cells (CPC) from young male CKO-mice compared to the adipocyte differentiation of male wildtype (WT)-CPC and CPC isolated from female mice. Epigenetic analysis in freshly isolated male CKO-CPC display hypermethylation in pro-angiogenic genes (Fgfr2, Epas1) and hypomethylation in the white adipocyte differentiation gene Zfp423 associated with upregulated ZFP423 expression and a shift from endothelial to white adipocyte differentiation compared to WT-CPC. The expression of the histone-methyltransferase EZH2 is reduced in male CKO-CPC compared to male WT-CPC whereas no differences in the EZH2 expression in female CPC were observed. Clonally expanded CPC can differentiate into endothelial cells or into adipocytes depending on the differentiation conditions. ZFP423 overexpression is sufficient to induce white adipocyte differentiation of clonal CPC. In isolated WT-CPC, PGD2 stimulation reduces the expression of EZH2 thereby upregulating ZFP423 expression and promoting white adipocyte differentiation.Thus, cardiomyocyte STAT3-deficiency leads to age-related and sex-specific cardiac remodeling and failure in part due to sex-specific alterations in PGD2 secretion and subsequent epigenetic impairment of the differentiation potential of CPC. Causally involved is the impaired AR signaling in absence of STAT3, which reduces the expression of the PG degrading enzyme HPGD.

  • Open Access English
    Authors: 
    Frédéric Paulin; Uri Shapira;
    Country: France
    Project: UKRI | Isaac Newton Institute fo... (EP/K032208/1), NSF | Mathematical Sciences Res... (1440140)

    Let $P$ be a prime polynomial in the variable $Y$ over a finite field and let $f$ be a quadratic irrational in the field of formal Laurant series in the variable $Y^{-1}$. We study the asymptotic properties of the degrees of the coefficients of the continued fraction expansion of quadratic irrationals such as $P^nf$ and prove results that are in sharp contrast to the analogue situation in zero characteristic.

  • Publication . Preprint . Conference object . Article . 2020
    Open Access English
    Authors: 
    Susanna F. de Rezende; Or Meir; Jakob Nordström; Toniann Pitassi; Robert Robere; Marc Vinyals;
    Project: EC | UTHOTP (279611), NSERC

    We significantly strengthen and generalize the theorem lifting Nullstellensatz degree to monotone span program size by Pitassi and Robere (2018) so that it works for any gadget with high enough rank, in particular, for useful gadgets such as equality and greater-than. We apply our generalized theorem to solve three open problems: •We present the first result that demonstrates a separation in proof power for cutting planes with unbounded versus polynomially bounded coefficients. Specifically, we exhibit CNF formulas that can be refuted in quadratic length and constant line space in cutting planes with unbounded coefficients, but for which there are no refutations in subexponential length and subpolynomial line space if coefficients are restricted to be of polynomial magnitude. •We give the first explicit separation between monotone Boolean formulas and monotone real formulas. Specifically, we give an explicit family of functions that can be computed with monotone real formulas of nearly linear size but require monotone Boolean formulas of exponential size. Previously only a non-explicit separation was known. •We give the strongest separation to-date between monotone Boolean formulas and monotone Boolean circuits. Namely, we show that the classical GEN problem, which has polynomial-size monotone Boolean circuits, requires monotone Boolean formulas of size $2^{\Omega(n/\text{polylog}(n))}$ . An important technical ingredient, which may be of independent interest, is that we show that the Nullstellensatz degree of refuting the pebbling formula over a DAG $G$ over any field coincides exactly with the reversible pebbling price of $G$ . In particular, this implies that the standard decision tree complexity and the parity decision tree complexity of the corresponding falsified clause search problem are equal. This is an extended abstract. The full version of the paper is available at https://arxiv.org/abs/2001.02144.

  • Open Access English
    Authors: 
    Mahdiar Sadeghi; M. Ali Al-Radhawi; Michael Margaliot; Eduardo D. Sontag;
    Publisher: Cold Spring Harbor Laboratory

    We consider a compartmental model for ribosome flow during RNA translation called the RFM. This model includes a set of positive transition rates that control the flow from every site to the consecutive site. It has been shown that when these rates are time-varying and jointly T-periodic every solution of the RFM converges to a unique periodic solution with period T. In other words, the RFM entrains to the periodic excitation. In particular, the protein production rate converges to a unique T-periodic pattern. From a biological point of view, one may argue that the average of the periodic production rate, and not the instantaneous rate, is the relevant quantity. Here, we study a problem that can be roughly stated as: can periodic rates yield a higher average production rate than constant rates? We rigorously formulate this question and show via simulations, and rigorous analysis in one simple case, that the answer is no.

  • Open Access English
    Authors: 
    Ivano Baronchelli; G. Rodighiero; Harry I. Teplitz; Claudia Scarlata; Alberto Franceschini; S. Berta; Laia Barrufet; Mattia Vaccari; Matteo Bonato; Laure Ciesla; +15 more
    Publisher: HAL CCSD
    Countries: United States, France, Italy
    Project: EC | HELP (607254)

    For a sample of star forming galaxies in the redshift interval 0.15$<$z$<$0.3, we study how both the relative strength of the AGN infra-red emission, compared to that due to the star formation (SF), and the numerical fraction of AGNs, change as a function of the total stellar mass of the hosting galaxy group (M$^{*}_{\mathrm{group}}$), between $10^{10.25}$ and $10^{11.9}$M$_{\odot}$. Using a multi-component SED fitting analysis, we separate the contribution of stars, AGN torus and star formation to the total emission at different wavelengths. This technique is applied to a new multi-wavelength data-set in the SIMES field (23 not redundant photometric bands), spanning the wavelength range from the UV (GALEX) to the far-IR (Herschel) and including crucial AKARI and WISE mid-IR observations (4.5 \mu m$<\lambda<$24 \mu m), where the BH thermal emission is stronger. This new photometric catalog, that includes our best photo-z estimates, is released through the NASA/IPAC Infrared Science Archive (IRSA). Groups are identified through a friends of friends algorithm ($\sim$62% purity, $\sim$51% completeness). We identified a total of 45 galaxies requiring an AGN emission component, 35 of which in groups and 10 in the field. We find BHAR$\propto ($M$^{*}_{\mathrm{group}})^{1.21\pm0.27}$ and (BHAR/SFR)$\propto ($M$^{*}_{\mathrm{group}})^{1.04\pm0.24}$ while, in the same range of M$^{*}_{\mathrm{group}}$, we do not observe any sensible change in the numerical fraction of AGNs. Our results indicate that the nuclear activity (i.e. the BHAR and the BHAR/SFR ratio) is enhanced when galaxies are located in more massive and richer groups. Comment: 31 pages, 23 figures

  • Open Access English
    Authors: 
    Gurel-Gurevich, Ori; Jerison, Daniel C.; Nachmias, Asaf;
    Project: EC | RANDGEOM (676970)

    Given a finite simple triangulation, we estimate the sizes of circles in its circle packing in terms of Cannon's vertex extremal length. Our estimates provide control over the size of the largest circle in the packing. We use them, combined with results from [12], to prove that in a proper circle packing of the discrete mating-of-trees random map model of Duplantier, Gwynne, Miller and Sheffield, the size of the largest circle goes to zero with high probability. 13 pages, 3 figures

  • Open Access English
    Authors: 
    Joshua M. Borin; Sarit Avrani; Jeffrey E. Barrick; Katherine L. Petrie; Justin R. Meyer;
    Publisher: National Academy of Sciences

    AbstractThe evolution of antibiotic resistant bacteria threatens to become the leading cause of worldwide mortality. This crisis has renewed interest in the practice of phage therapy. Yet, bacteria’s capacity to evolve resistance is likely to debilitate this therapy as well. To combat the evolution of phage resistance and improve treatment outcomes, many have suggested leveraging phages’ ability to counter resistance by evolving phages on target hosts before using them in therapy (phage training). We found that during in vitro experiments, a phage trained for 28 days suppressed bacteria ∼1000-fold for 3-8 times longer than its untrained ancestor. This extension was due to a delay in the evolution of resistance. Several factors contributed to this prolonged suppression. Mutations that confer resistance to trained phages are ∼100× less common and, while the target bacterium can evolve complete resistance to the untrained phage in a single step, multiple mutations are required to evolve complete resistance to trained phages. Mutations that confer resistance to trained phages are more costly than mutations for untrained phage resistance. And when resistance does evolve, trained phages are better able to suppress these forms of resistance. One way the trained phage improved was through recombination with a gene in a defunct prophage in the host genome, which doubled phage fitness. This direct transfer of information encoded by the host but originating from a relict phage provides a previously unconsidered mode of training phage. Overall, we provide a case study for successful phage training and uncover mechanisms underlying its efficacy.Significance StatementThe evolution of antibiotic resistant bacteria threatens to claim over 10 million lives annually by 2050. This crisis has renewed interest in phage therapy, the use of bacterial viruses to treat infections. A major barrier to successful phage therapy is that bacteria readily evolve phage resistance. One idea proposed to combat resistance is “training” phages by using their natural capacity to evolve to counter resistance. Here, we show that training phages by coevolving them with their host for one month enhanced their capacity for suppressing bacterial growth and delayed the emergence of resistance. Enhanced suppression was caused by several mechanisms, suggesting that the coevolutionary training protocol produces a robust therapeutic that employs complementary modes of action.

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