Rapid evolution of protein kinase PKR alters sensitivity to viral inhibitors.

Protein kinase PKR (also known as EIF2AK2) is activated during viral infection and phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (eIF2), leading to inhibition of translation and viral replication. We report fast evolution of the PKR kinase domain in vertebrates, coupled with positive selection of specific sites. Substitution of positively selected residues in human PKR with residues found in related species altered sensitivity to PKR inhibitors from different poxviruses. Species-specific differences in sensitivity to poxviral pseudosubstrate inhibitors were identified between human and mouse PKR, and these differences were traced to positively selected residues near the eIF2alpha binding site. Our findings indicate how an antiviral protein evolved to evade viral inhibition while maintaining its primary function. Moreover, the identified species-specific differences in the susceptibility to viral inhibitors have important implications for studying human infections in nonhuman model systems

Improving Food Safety Knowledge Through an Online Training Program

Foodborne illness is a major public health concern in the U.S. The CDC estimates that approximately 48 million Americans become ill, 128,000 hospitalized, and 3,000 die of foodborne illnesses annually. Most of these illnesses are attributed to improper food handling. To meet the growing demand for food safety training, the Texas A&M AgriLife Extension Service developed an online course to educate food handlers in food safety best practices. Since 2008, over 7,200 food service workers have completed the online course, demonstrating that such a tool can be can used to expand Extension\u27s outreach to this important audience

b-quark decay in the collinear approximation

The semileptonic decay of a b-quark, b--> c l nu, is considered in the relativistic limit where the decay products are approximately collinear. Analytic results for the double differential lepton energy distributions are given for finite charm-quark mass. Their use for the fast simulation of isolated lepton backgrounds from heavy quark decays is discussed.Comment: 7 pages, 1 figure, submitted to Phys.Rev.

Gluon-induced W-boson pair production at the LHC

Pair production of W bosons constitutes an important background to Higgs boson and new physics searches at the Large Hadron Collider LHC. We have calculated the loop-induced gluon-fusion process gg -> W*W* -> leptons, including intermediate light and heavy quarks and allowing for arbitrary invariant masses of the W bosons. While formally of next-to-next-to-leading order, the gg -> W*W* -> leptons process is enhanced by the large gluon flux at the LHC and by experimental Higgs search cuts, and increases the next-to-leading order WW background estimate for Higgs searches by about 30%. We have extended our previous calculation to include the contribution from the intermediate top-bottom massive quark loop and the Higgs signal process. We provide updated results for cross sections and differential distributions and study the interference between the different gluon scattering contributions. We describe important analytical and numerical aspects of our calculation and present the public GG2WW event generator.Comment: 20 pages, 4 figure

Co-cultivation of murine BMDCs with 67NR mouse mammary carcinoma cells give rise to highly drug resistant cells

<p>Abstract</p> <p>Background</p> <p>Tumor tissue resembles chronically inflamed tissue. Since chronic inflammatory conditions are a strong stimulus for bone marrow-derived cells (BMDCs) it can be assumed that recruitment of BMDCs into cancer tissue should be a common phenomenon. Several data have outlined that BMDC can influence tumor growth and metastasis, e.g., by inducing a paracrine acting feedback loop in tumor cells. Likewise, cell fusion and horizontal gene transfer are further mechanisms how BMDCs can trigger tumor progression.</p> <p>Results</p> <p>Hygromycin resistant murine 67NR-Hyg mammary carcinoma cells were co-cultivated with puromycin resistant murine BMDCs from Tg(GFPU)5Nagy/J mice. Isolation of hygromycin/puromycin resistant mBMDC/67NR-Hyg cell clones was performed by a dual drug selection procedure. PCR analysis revealed an overlap of parental markers in mBMDC/67NR-Hyg cell clones, suggesting that dual resistant cells originated by cell fusion. By contrast, both STR and SNP data analysis indicated that only parental 67NR-Hyg alleles were found in mBMDC/67NR-Hyg cell clones favoring horizontal gene transfer as the mode of origin. RealTime-PCR-array analysis showed a marked up-regulation of Abcb1a and Abcb1b ABC multidrug transporters in mBMDC/67NR-Hyg clones, which was verified by Western Blot analysis. Moreover, the markedly increased Abcb1a/Abcb1b expression was correlated to an efficient Rhodamine 123 efflux, which was completely inhibited by verapamil, a well-known Abcb1a/Abcb1b inhibitor. Likewise, mBMDCs/67NR-Hyg clones revealed a marked resistance towards chemotherapeutic drugs including 17-DMAG, doxorubicin, etoposide and paclitaxel. In accordance to Rhodamine 123 efflux data, chemotherapeutic drug resistance of mBMDC/67NR-Hyg cells was impaired by verapamil mediated blockage of Abc1a/Abcb1b multidrug transporter function.</p> <p>Conclusion</p> <p>Co-cultivation of mBMDCs and mouse 67NR-Hyg mammary carcinoma cells gave rise to highly drug resistant cells. Even though it remains unknown whether mBMDC/67NR-Hyg clones originated by cell fusion or horizontal gene transfer, our data indicate that the exchange of genetic information between two cellular entities is crucial for the origin of highly drug resistant cancer (hybrid) cells, which might be capable to survive chemotherapy.</p

Evaluation of the Impact of an Antibiotic Time-out for Transition of IV Vancomycin to Oral Linezolid in Hospitalized Patients

Background: Oral linezolid is a broad-spectrum oxazolidinone antibiotic that offers advantages compared to intravenous (IV) vancomycin including no requirement for therapeutic drug monitoring, no need for home health or peripherally inserted central catheter (PICC) line placement, and opportunities for earlier hospital discharge due to the ease of continuing therapy outpatient. A medication use evaluation investigated if opportunities existed for oral linezolid over IV vancomycin among a randomized cohort of 100 patients initiated on IV vancomycin. Reviewers identified 15 patients who were candidates for transition to oral linezolid and calculated a potential cost avoidance of $125 per day of antibiotic therapy. The purpose of this study is to assess the feasibility of implementing an interdisciplinary approach for transitioning IV vancomycin to oral linezolid based on pharmacist-led transition criteria. Methods: This is an IRB-reviewed, single-center, quasi-experimental study at Baptist Hospital of Miami, a 900-bed tertiary community hospital. Included patients were \u3e18 years old, receiving IV vancomycin for \u3e48 hours, and admitted between January 10, 2023 and March 31, 2023. Patients were excluded if they had an active vasopressor order, were immunocompromised, or if the patient was receiving antibiotics for meningitis, endocarditis, febrile neutropenia, or surgical prophylaxis. A pharmacy resident was on-call to assess for oral linezolid candidates using antibiotic timeout criteria and intervened as appropriate. Continuous and categorical variables were evaluated using the Mann-Whitney U test and Fisher’s exact test, respectively. The primary outcome was total cost avoidance in patients transitioned from IV vancomycin to oral linezolid. Secondary outcomes included median hospital length of stay, median antibiotic treatment days, and incidence of thrombocytopenia and acute kidney injury, and pharmacist intervention acceptance rate. Results: Investigators screened 317 patients for study inclusion and 94 patients met criteria. 66 (70$5,538, with a total of $21 and$70 saved per inpatient and outpatient antibiotic treatment day, respectively. Median length of antibiotic treatment days was 6 days between both groups (p=0.3524). No statistically significant differences were observed between length of stay, length of antibiotic treatment days, or safety outcomes between the 2 groups. Acute kidney injury occurred in 1 patient receiving linezolid and 1 patient receiving IV vancomycin. Thrombocytopenia, defined as a \u3e50% drop in platelet count from baseline, occurred in 1 patient receiving provider-driven linezolid therapy. Conclusion: Pharmacist-driven transition criteria from IV vancomycin to linezolid therapy resulted in a positive cost avoidance strategy, with similar effect on hospital antibiotic treatment days and no difference in incidence of adverse effects. These results demonstrate the practicality of a pharmacist prospective antibiotic timeout and intervention strategy for patients receiving empiric or targeted Methicillin-resistant Staphylococcus aureus (MRSA) therapy

Combining Monte Carlo generators with next-to-next-to-leading order calculations: event reweighting for Higgs boson production at the LHC

We study a phenomenological ansatz for merging next-to-next-to-leading order (NNLO) calculations with Monte Carlo event generators. We reweight them to match bin-integrated NNLO differential distributions. To test this procedure, we study the Higgs boson production cross-section at the LHC, for which a fully differential partonic NNLO calculation is available. We normalize PYTHIA and MC@NLO Monte Carlo events for Higgs production in the gluon fusion channel to reproduce the bin integrated NNLO double differential distribution in the transverse momentum and rapidity of the Higgs boson. These events are used to compute differential distributions for the photons in the pp \to H \to \gamma \gamma decay channel, and are compared to predictions from fixed-order perturbation theory at NNLO. We find agreement between the reweighted generators and the NNLO result in kinematic regions where we expect a good description using fixed-order perturbation theory. Kinematic boundaries where resummation is required are also modeled correctly using this procedure. We then use these events to compute distributions in the pp \to H \to W^+W^- \to l^+l^- \nu\bar{\nu} channel, for which an accurate description is needed for measurements at the LHC. We find that the final state lepton distributions obtained from PYTHIA are not significantly changed by the reweighting procedure.Comment: 18 pages, 14 fig

Does the `Higgs' have Spin Zero?

The Higgs boson is predicted to have spin zero. The ATLAS and CMS experiments have recently reported of an excess of events with mass ~ 125 GeV that has some of the characteristics expected for a Higgs boson. We address the questions whether there is already any evidence that this excess has spin zero, and how this possibility could be confirmed in the near future. The excess observed in the gamma gamma final state could not have spin one, leaving zero and two as open possibilities. We calculate the angular distribution of gamma gamma pairs from the decays of a spin-two boson produced in gluon-gluon collisions, showing that is unique and distinct from the spin-zero case. We also calculate the distributions for lepton pairs that would be produced in the W W* decays of a spin-two boson, which are very different from those in Higgs decays, and note that the kinematics of the event selection used to produce the excess observed in the W W* final state have reduced efficiency for spin two.Comment: 22 pages, 22 figures, Version accepted for publication in JHEP, includes additional plots of dilepton mass distribution

Phosphate limitation triggers the dissolution of precipitated iron by the marine bacterium Pseudovibrio sp. FO-BEG1

Phosphorus is an essential nutrient for all living organisms. In bacteria, the preferential phosphorus source is phosphate, which is often a limiting macronutrient in many areas of the ocean. The geochemical cycle of phosphorus is strongly interconnected with the cycles of other elements and especially iron, because phosphate tends to adsorb onto iron minerals, such as iron oxide formed in oxic marine environments. Although the response to either iron or phosphate limitation has been investigated in several bacterial species, the metabolic interplay between these two nutrients has rarely been considered. In this study we evaluated the impact of phosphate limitation on the iron metabolism of the marine bacterium Pseudovibrio sp. FO-BEG1. We observed that phosphate limitation led to an initial decrease of soluble iron in the culture up to three times higher than under phosphate surplus conditions. Similarly, a decrease in soluble cobalt was more pronounced under phosphate limitation. These data point toward physiological changes induced by phosphate limitation that affect either the cellular surface and therefore the metal adsorption onto it or the cellular metal uptake. We discovered that under phosphate limitation strain FO-BEG1, as well as selected strains of the Roseobacter clade, secreted iron-chelating molecules. This leads to the hypothesis that these bacteria might release such molecules to dissolve iron minerals, such as iron-oxyhydroxide, in order to access the adsorbed phosphate. As the adsorption of phosphate onto iron minerals can significantly decrease phosphate concentrations in the environment, the observed release of iron-chelators might represent an as yet unrecognized link between the biogeochemical cycle of phosphorus and iron, and it suggests another biological function of iron-chelating molecules in addition to metal-scavenging

Effective K-factors for gg -> H -> WW -> lnu lnu at the LHC

A simulation of the search for the Standard Model Higgs boson at the LHC, in the channel gg -> H -> WW -> lnu lnu, is described. Higher-order QCD corrections are taken into account by using a reweighting procedure, which allows us to combine event rates obtained with the PYTHIA Monte Carlo program with the most up-to-date theoretical predictions for the transverse-momentum spectra of the Higgs signal and its corresponding WW background. With this method the discovery potential for Higgs masses between 140 and 180 GeV is recalculated and the potential statistical significance of this channel is found to increase considerably. For a Higgs mass of 165 GeV a signal-to-background ratio of almost 2:1 can be obtained. A statistical significance of five standard deviations might already be achieved with an integrated luminosity close to 0.4 fb^{-1}. Using this approach, an experimental effective K-factor of about 2.04 is obtained for the considered Higgs signature, which is only about 15 % smaller than the theoretical inclusive K-factor.Comment: 16 pages, 8 eps figures, comparison of jet veto efficiencies between PYTHIA and HERWIG added, to appear on JHE