Carbon monoxide-releasing antibacterial molecules target respiration and global transcriptional regulators

Carbon monoxide, a classical respiratory inhibitor, also exerts vasodilatory, anti-inflammatory, and antiapoptotic effects. CO-releasing molecules have therapeutic value, increasing phagocytosis and reducing sepsis-induced lethality. Here we identify for the first time the bacterial targets of Ru(CO)(3)Cl(glycinate) (CORM-3), a ruthenium-based carbonyl that liberates CO rapidly under physiological conditions. Contrary to the expectation that CO would be preferentially inhibitory at low oxygen tensions or anaerobically, Escherichia coli cultures were also sensitive to CORM-3 at concentrations equimolar with oxygen. CORM-3, assayed as ruthenium, was taken up by bacteria and rapidly delivered CO intracellularly to terminal oxidases. Microarray analysis of CORM-3-treated cells revealed extensively modified gene expression, notably down-regulation of genes encoding key aerobic respiratory complexes. Genes involved in metal metabolism, homeostasis, or transport were also differentially expressed, and free intracellular zinc levels were elevated. Probabilistic modeling of transcriptomic data identified the global transcription regulators ArcA, CRP, Fis, FNR, Fur, BaeR, CpxR, and IHF as targets and potential CO sensors. Our discovery that CORM-3 is an effective inhibitor and global regulator of gene expression, especially under aerobic conditions, has important implications for administration of CO-releasing agents in sepsis and inflammatio

CD9 co-operation with syndecan-1 is required for a major staphylococcal adhesion pathway

Epithelial colonization is a critical first step in bacterial pathogenesis. Staphylococcus aureus can utilize several host factors to associate with cells, including α5β1 integrin and heparan sulfate proteoglycans, such as the syndecans. Here, we demonstrate that a partner protein of both integrins and syndecans, the host membrane adapter protein tetraspanin CD9, is essential for syndecan-mediated staphylococcal adhesion. Fibronectin is also essential in this process, while integrins are only critical for post-adhesion entry into human epithelial cells. Treatment of epithelial cells with CD9-derived peptide or heparin caused significant reductions in staphylococcal adherence, dependent on both CD9 and syndecan-1. Exogenous fibronectin caused a CD9-dependent increase in staphylococcal adhesion, whereas blockade of β1 integrins did not affect adhesion but did reduce the subsequent internalization of adhered bacteria. CD9 disruption or deletion increased β1 integrin-mediated internalization, suggesting that CD9 coordinates sequential staphylococcal adhesion and internalization. CD9 controls staphylococcal adhesion through syndecan-1, using a mechanism that likely requires CD9-mediated syndecan organization to correctly display fibronectin at the host cell surface. We propose that CD9-derived peptides or heparin analogs could be developed as anti-adhesion treatments to inhibit the initial stages of staphylococcal pathogenesis

Patterns of Mood and Personality Factors and Associations With STI/HIV-Related Drug and Sex Risk Among African American Male Inmates

Background: Research on the association between antisocial personality disorder (ASPD) with comorbid mental disorders and sexually transmitted infection (STI)/HIV risk among inmates is scant despite the high prevalence of psychopathology and of STI/HIV in this population. Methods: We used baseline data from Project DISRUPT, a cohort study conducted among incarcerated African American men (n = 207), to measure associations between ASPD and STI/HIV risk. We also conducted latent class analyses (LCAs) to identify subgroups defined by ASPD with comorbid stress, depression, and borderline personality disorder symptoms and measured associations between latent class membership and STI/HIV risk. Results: Approximately 15% had ASPD and 39% reported depression. Controlling for sociodemographics, stress, and depression, ASPD was independently associated with illicit [AOR = 3.23, 95% confidence interval (CI): 1.18–8.87] and injection drug use (AOR: 5.49, 95% CI: 1.23–24.42) but not with sexual risk. LCAs suggested that those at high risk of ASPD were likely to experience co-morbid mental disorders. ASPD comorbid with these disorders was linked to drug and sex risk. Conclusions: STI/HIV prevention for inmates should incorporate diagnosis and treatment of ASPD and comorbid disorders, and interventions to address ASPD-related factors (e.g., impulsivity) that drive STI/HIV risk

The Committed Intimate Partnerships of Incarcerated African-American Men: Implications for Sexual HIV Transmission Risk and Prevention Opportunities

Incarceration is thought to influence HIV transmission by disrupting partnerships that provide support and protect against sex risk-taking. Current correctional facility-based family-strengthening programs focus on marital partnerships, a minority of inmates’ partnerships. Research on the sex partnerships of incarcerated African-American men and the types of partnerships most likely to protect against HIV-related sex risk is limited. Improved understanding can inform expansion of correctional facility-based family-strengthening programs to a greater proportion of protective partnerships and HIV risk reduction programs to partnerships vulnerable to sex risk. Project DISRUPT is a cohort study of African-American men being released from prison in North Carolina who were in committed heterosexual partnerships at prison entry. Using baseline survey data (N = 189), we conducted latent class analysis (LCA) to identify subgroups of participants with distinct relationship profiles and measured associations between relationship characteristics and multiple partnerships of inmates and their partners in the six months before incarceration. LCA indicated a two-class solution, with relationships distinguished by satisfaction/stability (satisfied/stable class: 58.0%; dissatisfied/unstable class: 42.0%); each class had comparable relationship length and levels of marriage and cohabitation. Dissatisfied/unstable relationships were associated with multiple partnerships among participants (AOR 2.93, 95% CI 1.50, 5.72) and partners (AOR 4.95, 95% CI 1.68, 14.58). Satisfaction indicators—versus length, marriage, or cohabitation—were the strongest independent correlates of inmates’ and partners’ multiple partnerships. Pre-incarceration economic deprivation, mental disorder symptoms, substance use, and violence in relationships were associated with dissatisfaction/instability. Prison-based programs designed to maintain healthy partnerships, strengthen relationship skills, and reduce HIV risk-taking and violence in relationships are warranted and should be targeted to both marital and nonmarital partnerships. Programming also should address the poverty, mental illness, and substance use factors that threaten relationship satisfaction/stability and increase HIV risk

Experimentally validated reconstruction and analysis of a genome-scale metabolic model of an anaerobic Neocallimastigomycota fungus

Anaerobic gut fungi in the phylum Neocallimastigomycota typically inhabit the digestive tracts of large mammalian herbivores, where they play an integral role in the decomposition of raw lignocellulose into its constitutive sugar monomers. However, quantitative tools to study their physiology are lacking, partially due to their complex and unresolved metabolism that includes the largely uncharacterized fungal hydrogenosome. Modern omics approaches combined with metabolic modeling can be used to establish an understanding of gut fungal metabolism and develop targeted engineering strategies to harness their degradation capabilities for lignocellulosic bioprocessing. Here, we introduce a high-quality genome of the anaerobic fungus Neocallimastix lanati from which we constructed the first genome-scale metabolic model of an anaerobic fungus. Relative to its size (200 Mbp, sequenced at 62× depth), it is the least fragmented publicly available gut fungal genome to date. Of the 1,788 lignocellulolytic enzymes annotated in the genome, 585 are associated with the fungal cellulosome, underscoring the powerful lignocellulolytic potential of N. lanati. The genome-scale metabolic model captures the primary metabolism of N. lanati and accurately predicts experimentally validated substrate utilization requirements. Additionally, metabolic flux predictions are verified by 13C metabolic flux analysis, demonstrating that the model faithfully describes the underlying fungal metabolism. Furthermore, the model clarifies key aspects of the hydrogenosomal metabolism and can be used as a platform to quantitatively study these biotechnologically important yet poorly understood early-branching fungi

Measurement of the ratios of the Z/G* + >= n jet production cross sections to the total inclusive Z/G* cross section in ppbar collisions at sqrt(s) = 1.96 TeV

We present a study of events with Z bosons and jets produced at the Fermilab Tevatron Collider in ppbar collisions at a center of mass energy of 1.96 TeV. The data sample consists of nearly 14,000 Z/G* -> e+e- candidates corresponding to the integrated luminosity of 0.4 fb-1 collected using the D0 detector. Ratios of the Z/G* + >= n jet cross sections to the total inclusive Z/G* cross section have been measured for n = 1 to 4 jet events. Our measurements are found to be in good agreement with a next-to-leading order QCD calculation and with a tree-level QCD prediction with parton shower simulation and hadronization.Comment: 7 pages, 2 figures, slightly modified, submitted to Phys. Lett.

Measurement of the Isolated Photon Cross Section in p-pbar Collisions at sqrt{s}=1.96 TeV

The cross section for the inclusive production of isolated photons has been measured in p anti-p collisions at sqrt{s}=1.96 TeV with the D0 detector at the Fermilab Tevatron Collider. The photons span transverse momenta 23 to 300 GeV and have pseudorapidity |eta|<0.9. The cross section is compared with the results from two next-to-leading order perturbative QCD calculations. The theoretical predictions agree with the measurement within uncertainties.Comment: 7 pages, 5 figures, submitted to Phys.Lett.

High mass exclusive diffractive dijet production in ppˉ\mathbf{p\bar{p}} collisions at s\mathbf{\sqrt{s}} = 1.96 TeV

We present evidence for diffractive exclusive dijet production with an invariant dijet mass greater than 100 GeV in data collected with the D0 experiment at the Fermilab Tevatron Collider. A discriminant based on calorimeter information is used to measure a significant number of events with little energy (typically less than 10 GeV) outside the dijet system, consistent with the diffractive exclusive dijet production topology. The probability for these events to be explained by other dijet production processes is $2 \times 10^{-5}$, corresponding to a 4.1 standard deviation significance.Comment: submitted to Phys. Lett.

Search for scalar leptoquarks in the acoplanar jet topology in ppbar collisions at sqrt(s)=1.96 TeV

A search for leptoquarks has been performed in 310 pb-1 of data from ppbar collisions at a center-of-mass energy of 1.96 TeV, collected by the D0 detector at the Fermilab Tevatron Collider. The topology analyzed consists of acoplanar jets with missing transverse energy. The data show good agreement with standard model expectations, and a lower mass limit of 136 GeV has been set at the 95% C.L. for a scalar leptoquark decaying exclusively into a quark and a neutrino.Comment: Minor changes in v2 to match the published version, 8 pages, 5 figure

Measurement of B(t->Wb)/B(t->Wq) at sqrt(s) = 1.96 TeV

We present the measurement of R = B(t->Wb)/B(t->Wq) in ppbar collisions at sqrt(s) = 1.96 TeV, using 230 pb-1 of data collected by the DO experiment at the Fermilab Tevatron Collider. We fit simultaneously R and the number of selected top quark pairs (ttbar), to the number of identified b-quark jets in events with one electron or one muon, three or more jets, and high transverse energy imbalance. To improve sensitivity, kinematical properties of events with no identified b-quark jets are included in the fit. We measure R = 1.03 +0.19 -0.17 (stat+syst), in good agreement with the standard model. We set lower limits of R > 0.61 and |V_tb| > 0.78 at 95% confidence level.Comment: 7 pages, 1 figure submitted to Phys. Rev. Let