Long-Range Forces of QCD

We consider the scattering of two color dipoles (e.g., heavy quarkonium states) at low energy - a QCD analog of Van der Waals interaction. Even though the couplings of the dipoles to the gluon field can be described in perturbation theory, which leads to the potential proportional to (N_c^2-1)/R^{7}, at large distances R the interaction becomes totally non-perturbative. Low-energy QCD theorems are used to evaluate the leading long-distance contribution \sim (N_f^2-1)/(11N_c - 2N_f)^2 R^{-5/2} exp(-2 \mu R) (\mu is the Goldstone boson mass), which is shown to arise from the correlated two-boson exchange. The sum rule which relates the overall strength of the interaction to the energy density of QCD vacuum is derived. Surprisingly, we find that when the size of the dipoles shrinks to zero (the heavy quark limit in the case of quarkonia), the non-perturbative part of the interaction vanishes more slowly than the perturbative part as a consequence of scale anomaly. As an application, we evaluate elastic \pi J/\psi and \pi J/\psi \to \pi \psi' cross sections.Comment: 16pages, 9 eps figures; discussion extended, 2 new references added, to appear in Phys.Rev.

Strong Phases and Factorization for Color Suppressed Decays

We prove a factorization theorem in QCD for the color suppressed decays B0-> D0 M0 and B0-> D*0 M0 where M is a light meson. Both the color-suppressed and W-exchange/annihilation amplitudes contribute at lowest order in LambdaQCD/Q where Q={mb, mc, Epi}, so no power suppression of annihilation contributions is found. A new mechanism is given for generating non-perturbative strong phases in the factorization framework. Model independent predictions that follow from our results include the equality of the B0 -> D0 M0 and B0 -> D*0 M0 rates, and equality of non-perturbative strong phases between isospin amplitudes, delta(DM) = delta(D*M). Relations between amplitudes and phases for M=pi,rho are also derived. These results do not follow from large Nc factorization with heavy quark symmetry.Comment: 38 pages, 6 figs, typos correcte

Correlated Production of p and p^bar in Au+Au Collisions at sqrt(s_NN) = 200 GeV

Correlations between p and pbar's at transverse momenta typical of enhanced baryon production in Au+Au collisions are reported. The PHENIX experiment measures same and opposite sign baryon pairs in Au+Au collisions at sqrt(s_NN) = 200 GeV. Correlated production of p and p^bar with the trigger particle from the range 2.5 < p_T < 4.0 GeV/c and the associated particle with 1.8 < p_T < 2.5 GeV/c is observed to be nearly independent of the centrality of the collisions. Same sign pairs show no correlation at any centrality. The conditional yield of mesons triggered by baryons (and anti-baryons) and mesons in the same pT range rises with increasing centrality, except for the most central collisions, where baryons show a significantly smaller number of associated mesons. These data are consistent with a picture in which hard scattered partons produce correlated p and p^bar in the p_T region of the baryon excess.Comment: 420 authors from 58 institutions, 21 pages,5 figures. Submitted to Physics Letters B. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Caspase-8-dependent gasdermin D cleavage promotes antimicrobial defense but confers susceptibility to TNF-induced lethality.

Gasdermin D (GSDMD) is a pore-forming protein that promotes pyroptosis and release of proinflammatory cytokines. Recent studies revealed that apoptotic caspase-8 directly cleaves GSDMD to trigger pyroptosis. However, the molecular requirements for caspase-8-dependent GSDMD cleavage and the physiological impact of this signaling axis are unresolved. Here, we report that caspase-8-dependent GSDMD cleavage confers susceptibility to tumor necrosis factor (TNF)-induced lethality independently of caspase-1 and that GSDMD activation provides host defense against Yersinia infection. We further demonstrate that GSDMD inactivation by apoptotic caspases at aspartate 88 (D88) suppresses TNF-induced lethality but promotes anti-Yersinia defense. Last, we show that caspase-8 dimerization and autoprocessing are required for GSDMD cleavage, and provide evidence that the caspase-8 autoprocessing and activity on various complexes correlate with its ability to directly cleave GSDMD. These findings reveal GSDMD as a potential therapeutic target to reduce inflammation associated with mutations in the death receptor signaling machinery

Positive selection of mutations in the Helicobacter pylori katA 5′ untranslated region in a Mongolian Gerbil Model of gastric disease

To evaluate potential effects of gastric inflammation on Helicobacter pylori diversification and evolution within the stomach, we experimentally infected Mongolian gerbils with an H. pylori strain in which Cag type IV secretion system (T4SS) activity is controlled by a TetR/tetO system. Gerbils infected with H. pylori under conditions in which Cag T4SS activity was derepressed had significantly higher levels of gastric inflammation than gerbils infected under conditions with repressed Cag T4SS activity. Mutations in the 5′ untranslated region (UTR) of katA (encoding catalase) were detected in strains cultured from 8 of the 17 gerbils infected with Cag T4SS-active H. pylori and none of the strains from 17 gerbils infected with Cag T4SS-inactive H. pylori. Catalase enzymatic activity, steady-state katA transcript levels, and katA transcript stability were increased in strains with these single nucleotide polymorphisms (SNPs) compared to strains in which these SNPs were absent. Moreover, strains harboring these SNPs exhibited increased resistance to bactericidal effects of hydrogen peroxide, compared to control strains. Experimental introduction of the SNPs into the wild-type katA 5′ UTR resulted in increased katA transcript stability, increased katA steady-state levels, and increased catalase enzymatic activity. Based on site-directed mutagenesis and modeling of RNA structure, increased katA transcript levels were correlated with higher predicted thermal stability of the katA 5′ UTR secondary structure. These data suggest that high levels of gastric inflammation positively select for H. pylori strains producing increased levels of catalase, which may confer survival advantages to the bacteria in an inflammatory gastric environment

RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signaling.

Injection of effector proteins to block host innate immune signaling is a common strategy used by many pathogenic organisms to establish an infection. For example, pathogenic Yersinia species inject the acetyltransferase YopJ into target cells to inhibit NF-κB and MAPK signaling. To counteract this, detection of YopJ activity in myeloid cells promotes the assembly of a RIPK1-caspase-8 death-inducing platform that confers antibacterial defense. While recent studies revealed that caspase-8 cleaves the pore-forming protein gasdermin D to trigger pyroptosis in macrophages, whether RIPK1 activates additional substrates downstream of caspase-8 to promote host defense is unclear. Here, we report that the related gasdermin family member gasdermin E (GSDME) is activated upon detection of YopJ activity in a RIPK1 kinase-dependent manner. Specifically, GSDME promotes neutrophil pyroptosis and IL-1β release, which is critical for anti-Yersinia defense. During in vivo infection, IL-1β neutralization increases bacterial burden in wild-type but not Gsdme-deficient mice. Thus, our study establishes GSDME as an important mediator that counteracts pathogen blockade of innate immune signaling

Genetic targeting of Card19 is linked to disrupted NINJ1 expression, impaired cell lysis, and increased susceptibility to Yersinia infection.

Cell death plays a critical role in inflammatory responses. During pyroptosis, inflammatory caspases cleave Gasdermin D (GSDMD) to release an N-terminal fragment that generates plasma membrane pores that mediate cell lysis and IL-1 cytokine release. Terminal cell lysis and IL-1β release following caspase activation can be uncoupled in certain cell types or in response to particular stimuli, a state termed hyperactivation. However, the factors and mechanisms that regulate terminal cell lysis downstream of GSDMD cleavage remain poorly understood. In the course of studies to define regulation of pyroptosis during Yersinia infection, we identified a line of Card19-deficient mice (Card19lxcn) whose macrophages were protected from cell lysis and showed reduced apoptosis and pyroptosis, yet had wild-type levels of caspase activation, IL-1 secretion, and GSDMD cleavage. Unexpectedly, CARD19, a mitochondrial CARD-containing protein, was not directly responsible for this, as an independently-generated CRISPR/Cas9 Card19 knockout mouse line (Card19Null) showed no defect in macrophage cell lysis. Notably, Card19 is located on chromosome 13, immediately adjacent to Ninj1, which was recently found to regulate cell lysis downstream of GSDMD activation. RNA-seq and western blotting revealed that Card19lxcn BMDMs have significantly reduced NINJ1 expression, and reconstitution of Ninj1 in Card19lxcn immortalized BMDMs restored their ability to undergo cell lysis in response to caspase-dependent cell death stimuli. Card19lxcn mice exhibited increased susceptibility to Yersinia infection, whereas independently-generated Card19Null mice did not, demonstrating that cell lysis itself plays a key role in protection against bacterial infection, and that the increased infection susceptibility of Card19lxcn mice is attributable to loss of NINJ1. Our findings identify genetic targeting of Card19 being responsible for off-target effects on the adjacent gene Ninj1, disrupting the ability of macrophages to undergo plasma membrane rupture downstream of gasdermin cleavage and impacting host survival and bacterial control during Yersinia infection