Studies suggest that the efficacy of cancer chemotherapy and immunotherapy is influenced by intestinal bacteria. However, the influence of the microbiome on radiation therapy is not as well ...understood, and the microbiome comprises more than bacteria. Here, we find that intestinal fungi regulate antitumor immune responses following radiation in mouse models of breast cancer and melanoma and that fungi and bacteria have opposite influences on these responses. Antibiotic-mediated depletion or gnotobiotic exclusion of fungi enhances responsiveness to radiation, whereas antibiotic-mediated depletion of bacteria reduces responsiveness and is associated with overgrowth of commensal fungi. Further, elevated intratumoral expression of Dectin-1, a primary innate sensor of fungi, is negatively associated with survival in patients with breast cancer and is required for the effects of commensal fungi in mouse models of radiation therapy.
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•Commensal bacteria support antitumor T cell responses following radiation therapy•Depletion of intestinal bacteria leads to expansion of commensal fungal populations•Commensal fungi promote pro-tumor macrophage actions by impeding antitumor T cells•Tumor-associated macrophages sense fungi through a Dectin-1-mediated mechanism
Depletion of commensal bacteria leads to expansion of commensal fungi and reduced antitumor immunity following irradiation of tumors. Targeting commensal fungi enhanced the radiation-induced antitumor immune response by reducing macrophage-mediated immunosuppression. Thus, Shiao et al. demonstrate opposing effects of commensal bacteria and fungi on antitumor immunity following radiation.
Eddie Muller, the host of “Noir Alley” on Turner Classic Movies, has what just might be the ideal job. TCM is a cultural gem, a visual museum airing silent and foreign movies, curious travelogues, ...godawful comedies, and all the great movies as well—not to mention all those “B” noirs Muller shares with us. Muller's website calls him a “wordslinger,” “impresario,” and “noirchaeologist,” but even before TCM put him on the air, he had earned the nickname of “Czar of Noir.”
Studies of Leishmania donovani have shown that both ornithine decarboxylase and spermidine synthase, two enzymes of the polyamine biosynthetic pathway, are critical for promastigote proliferation and ...required for maximum infection in mice. However, the importance of arginase (ARG), the first enzyme of the polyamine pathway in Leishmania, has not been analyzed in L. donovani To test ARG function in intact parasites, we generated Δarg null mutants in L. donovani and evaluated their ability to proliferate in vitro and trigger infections in mice. The Δarg knockout was incapable of growth in the absence of polyamine supplementation, but the auxotrophic phenotype could be bypassed by addition of either millimolar concentrations of ornithine or micromolar concentrations of putrescine or by complementation with either glycosomal or cytosolic versions of ARG. Spermidine supplementation of the medium did not circumvent the polyamine auxotrophy of the Δarg line. Although ARG was found to be essential for ornithine and polyamine synthesis, ornithine decarboxylase appeared to be the rate-limiting enzyme for polyamine production. Mouse infectivity studies revealed that the Δarg lesion reduced parasite burdens in livers by an order of magnitude but had little impact on the numbers of parasites recovered from spleens. Thus, ARG is essential for proliferation of promastigotes but not intracellular amastigotes. Coupled with previous studies, these data support a model in which L. donovani amastigotes readily salvage ornithine and have some access to host spermidine pools, while host putrescine appears to be unavailable for salvage by the parasite.
Spx is a global transcriptional regulator that is conserved among Gram-positive bacteria, in which Spx is required for preventing oxidatively induced proteotoxicity. Upon stress induction, Spx ...engages RNA polymerase (RNAP) through interaction with the C-terminal domain of the
-encoded RNAP α subunit (αCTD). Previous mutational analysis of
revealed that substitutions of Y263 in αCTD severely impaired Spx-activated transcription. Attempts to substitute alanine for αCTD R261, R268, R289, E255, E298, and K294 were unsuccessful, suggesting that these residues are essential. To determine whether these RpoA residues were required for productive Spx-RNAP interaction, we ectopically expressed the putatively lethal
mutant alleles in the
mutant, where "
" indicates the amino acid change that results from mutation of the allele. By complementation analysis, we show that Spx-bound αCTD amino acid residues are not essential for Spx-activated transcription
but that R261A, E298A, and E255A mutants confer a partial defect in NaCl-stress induction of Spx-controlled genes. In addition, strains expressing
are defective in disulfide stress resistance and produce RNAP having a reduced affinity for Spx. The E255 residue corresponds to
αD259, which has been implicated in αCTD-σ
interaction (σ
R603, corresponding to R362 of
σ
). However, the combined
and
mutations have an additive negative effect on Spx-dependent expression, suggesting the residues' differing roles in Spx-activated transcription. Our findings suggest that, while αCTD is essential for Spx-activated transcription, Spx is the primary DNA-binding determinant of the Spx-αCTD complex.
Though extensively studied in
, the role of αCTD in activator-stimulated transcription is largely uncharacterized in
Here, we conduct phenotypic analyses of putatively lethal αCTD alanine codon substitution mutants to determine whether these residues function in specific DNA binding at the Spx-αCTD-DNA interface. Our findings suggest that multisubunit RNAP contact to Spx is optimal for activation while Spx fulfills the most stringent requirement of upstream promoter binding. Furthermore, several αCTD residues targeted for mutagenesis in this study are conserved among many bacterial species and thus insights on their function in other regulatory systems may be suggested herein.
Ghosts in the White House Davis, J. Madison
World Literature Today,
09/2018, Letnik:
92, Številka:
5
Journal Article, Book Review
Recenzirano
Personally, I felt sorry for Patterson in the media interviews, awkwardly sitting beside Clinton while the ex-president fielded questions about Monica Lewinsky, but I'm sure Patterson's attitude was ...buoyed by the thought of all those presidents marching into his bank account. ...he turned out to be more prolific in death than in life. According to his nephew, Stona Fitch (aka novelist Rory Flynn), Harrington was an old-fashioned, hard-drinking, knock-out-pages kind of novelist who oversexualized everything and could ruin any family dinner. From 1980 to 2016, nearly thirty books appeared in the "Capital Crimes" mystery series, with titles such as Murder in the White House, Murder in the Supreme Court, Murder in the CIA, and Murder in Ford's Theater (ahem!). According to his nephew, Stona Fitch (aka novelist Rory Flynn), Harrington was an oldfashioned, hard-drinking, knock-out-pages kind of novelist who oversexualized everything and could ruin any family dinner.
Hired to write an original Law and Order novel, I was told that the novelist's challenge was that the show was characterless; that is to say, unlike many other television series (like the spin-off ...Law and Order: Special Victims Unit), the internal struggles of the characters were of little or no consequence. Nonetheless, fear of the "Yellow Peril" unfortunately lingers, and images of leering Hispanic drug lords have recently become part of our national political discourse, drawing on the echoes of characterization in movies like The Magnificent Seven (1960) and The Treasure of the Sierra Madre (1948). Fear of the viral storms released as a reaction to racism inhibits the creation of many of these oldfashioned criminal masterminds, which is good, but it also might explain why so many of our movies have bad-guy robots or aliens or comic-book mutants. J. Madison Davis is the author of eight mystery novels, including The Murder of Frau Schütz, an Edgar nominee, and Law and Order: Dead Line.
After the family moved to Cleveland, Chester mixed in Mafia circles and picked up a taste for drink, gambling, prostitution, con games, and other vices, largely financed by a worker's compensation ...allowance he was granted after a two-story tumble down an elevator shaft. Because of the back injury from his fall, he was allowed to write in his cell, sheltering him from much of the prison violence, though he was forever tormented by the horror of the Ohio Penitentiary fire in 1930. Anger is the justifiable reaction to the betrayals, torture, and killings that African Americans have endured in their history. J. Madison Davis is the author of eight mystery novels, including The Murder of Frau Schütz, an Edgar nominee, and Law and Order: Dead Line.
...it is a nearly perfect film, and utterly, utterly boring." Daughters who died of drug overdoses, marriages falling apart, despair nigh onto suicide, anger issues, pressure from the mayor's office, ...officious supervisors who somehow were put in charge even though they know nothing of real police work-all are common as dandelions. ...life is quite predictable, but it's the quirky details and events that give us pause, that make us look more closely and feel the wonder. J. Madison Davis is the author of eight mystery novels, including The Murder of Frau Schütz, an Edgar nominee, and Law and Order: Dead Line.
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