The role of chaperone-subunit usher domain interactions in the mechanism of bacterial pilus biogenesis revealed by ESI-MS

The PapC usher is a β-barrel outer membrane protein essential for assembly and secretion of P pili that are required for adhesion of pathogenic E. coli, which cause the development of pyelonephritis. Multiple protein subunits form the P pilus, the highly specific assembly of which is coordinated by the usher. Despite a wealth of structural knowledge, how the usher catalyzes subunit polymerization and orchestrates a correct and functional order of subunit assembly remain unclear. Here, the ability of the soluble N-terminal (UsherN), C-terminal (UsherC2), and Plug (UsherP) domains of the usher to bind different chaperone-subunit (PapDPapX) complexes is investigated using noncovalent electrospray ionization mass spectrometry. The results reveal that each usher domain is able to bind all six PapDPapX complexes, consistent with an active role of all three usher domains in pilus biogenesis. Using collision induced dissociation, combined with competition binding experiments and dissection of the adhesin subunit, PapG, into separate pilin and adhesin domains, the results reveal why PapG has a uniquely high affinity for the usher, which is consistent with this subunit always being displayed at the pilus tip. In addition, we show how the different soluble usher domains cooperate to coordinate and control efficient pilus assembly at the usher platform. As well as providing new information about the protein-protein interactions that determine pilus biogenesis, the results highlight the power of noncovalent MS to interrogate biological mechanisms, especially in complex mixtures of species

Socioeconomic differences in cancer survival: The Norwegian Women and Cancer Study

<p>Abstract</p> <p>Background</p> <p>Cancer survival has been observed to be poorer in low socioeconomic groups, but the knowledge about the underlying causal factors is limited. The purpose of this study was to examine how cancer survival varies by socioeconomic status (SES) among women in Norway, and to identify factors that explain this variation. SES was measured by years of education and gross household income, respectively.</p> <p>Methods</p> <p>We used data from The Norwegian Women and Cancer Study, a prospective cohort study including 91 814 women who responded to an extensive questionnaire between 1996 and 1998. A total of 3 899 incident cancer cases were diagnosed during follow-up, of whom 1 089 women died, 919 of them from cancer. Cox Proportional Hazards Model was used to calculate relative risks (RR) of mortality and 95% confidence intervals.</p> <p>Results</p> <p>We observed an overall negative socioeconomic gradient in cancer survival, which was most evident in the site specific analyses for survival of ovarian cancer by years of education. For colorectal cancer, mortality increased with years of education, but not with income. After adjustment for household size, marital status, disease stage, and smoking status the SES variation in cancer survival became non-significant. We found that the unequal socioeconomic distribution of smoking status prior to diagnosis contributed considerably to the poorer survival in low SES groups.</p> <p>Conclusion</p> <p>We found an overall negative socioeconomic gradient in cancer survival when SES is measured as years of education or gross household income. Smoking status prior to diagnosis was an important predictive factor for socioeconomic variation in survival.</p

Identification of Novel Methylation Markers in Hepatocellular Carcinoma using a Methylation Array

Promoter CpG island hypermethylation has become recognized as an important mechanism for inactivating tumor suppressor genes or tumor-related genes in human cancers of various tissues. Gene inactivation in association with promoter CpG island hypermethylation has been reported to be four times more frequent than genetic changes in human colorectal cancers. Hepatocellular carcinoma is also one of the human cancer types in which aberrant promoter CpG island hypermethylation is frequently found. However, the number of genes identified to date as hypermethylated for hepatocellular carcinoma (HCC) is fewer than that for colorectal cancer or gastric cancer, which can be attributed to fewer attempts to perform genome-wide methylation profiling for HCC. In the present study, we used bead-array technology and coupled methylation-specific PCR to identify new genes showing cancer-specific methylation in HCC. Twenty-four new genes have been identified as hypermethylated at their promoter CpG island loci in a cancer-specific manner. Of these, TNFRSF10C, HOXA9, NPY, and IRF5 were frequently hypermethylated in hepatocellular carcinoma tissue samples and their methylation was found to be closely associated with inactivation of gene expression. Further study will be required to elucidate the clinicopathological implications of these newly found DNA methylation markers in hepatocellular carcinoma

Occupational physical activity and risk for prostate cancer in a nationwide cohort study in Sweden

We investigated effects of occupational physical activity on relative risk for prostate cancer. From Swedish nationwide censuses in 1960 and 1970, we defined two cohorts of men whose occupational titles allowed classification of physical activity levels at work in 1960 (n=1 348 971) and in 1970 (n=1 377 629). A third cohort included only men whose jobs required a similar level of physical activity in both 1960 and 1970 (n=673 443). The incidence of prostate cancer between 1971 and 1989 was ascertained through record linkage to the Swedish Cancer Register. A total of 43 836, 28 702, and 19 670 prostate cancers, respectively, occurred in the three cohorts. In all three cohorts, the relative risk for prostate cancer increased with decreasing level of occupational physical activity (P<0.001), using Poisson regression. Among men with the same physical activity levels in 1960 and 1970, the rate ratio was 1.11 for men with sedentary jobs as compared with those whose jobs had very high/high activity levels after adjustment for age at follow-up, calendar year of follow-up and place of residence (95% CI 1.05–1.17; P for trend <0.001). There was no association between occupational activity and prostate cancer mortality. Since we had no data on other potential risk factors the observed associations for both incidence and mortality might have been confounded. Further studies are needed to better understand the potential role of physical activity for prostate cancer

Development of the retinofugal projections in the embryonic and larval zebrafish ( Brachydanio rerio )

Studies of the projection from the vertebrate retina have contributed significantly to current concepts of neural development. The zebrafish has recently become a favored system for the study of development in general and neural development in particular. Although the development of both the optic nerve and the retinotectal projection of the zebrafish has been described, the retinofugal projection in its entirety has not. This paper describes it and also addresses the issue of projectional exuberance: i. e., transient projections to targets that are not innervated in the adult. The retinofugal projection of embryonic and larval zebrafish (32 hours to 7 days post-fertilization) was labeled by intraocular injection of DiI (1,1′-dioctadecyl-3,3,3′,3′, tetramethylindocarbocyanine perchlorate) and then studied in wholemounts and sections. The first optic axons crossed the chiasm at 32 hours post-fertilization and projected in a straight line to reach the tectum at about 44 hours. At 48 hours, a few optic axons deviated along either the tract of the posterior commissure or the tract of the postoptic commissure. By 72 hours (about the time of hatching) optic axons arborized in ten distinct regions, termed arborization fields. At 6–7 days post-fertilization, the same ten arborization fields (nine contralateral, one bilater) were evident. Most of the arborization fields were located in the superficial neuropil and were not associated with morphologically identifiable clusters of somata. On the basis of various landmarks, the ten arborization fields are identified as precursors of retinorecipient nuclei previously described in other adult cypriniform fishes. The development was characterized by the nearly complete absence of any transient projections. Thus, the idea that axonal outgrowth is initially exuberant and trimmed back later is not supported by these results. © 1994 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50063/1/903460410_ftp.pd

Improved Limits on B0B^{0} decays to invisible (+γ)(+\gamma) final states

We establish improved upper limits on branching fractions for B0 decays to final States 10 where the decay products are purely invisible (i.e., no observable final state particles) and for final states where the only visible product is a photon. Within the Standard Model, these decays have branching fractions that are below the current experimental sensitivity, but various models of physics beyond the Standard Model predict significant contributions for these channels. Using 471 million BB pairs collected at the Y(4S) resonance by the BABAR experiment at the PEP-II e+e- storage ring at the SLAC National Accelerator Laboratory, we establish upper limits at the 90% confidence level of 2.4x10^-5 for the branching fraction of B0-->Invisible and 1.7x10^-5 for the branching fraction of B0-->Invisible+gammaComment: 8 pages, 3 postscript figures, submitted to Phys. Rev. D (Rapid Communications

Microglia and the urokinase plasminogen activator receptor/uPA system in innate brain inflammation

The urokinase plasminogen activator (uPA) receptor (uPAR) is a GPI-linked cell surface protein that facilitates focused plasmin proteolytic activity at the cell surface. uPAR has been detected in macrophages infiltrating the central nervous system (CNS) and soluble uPAR has been detected in the cerebrospinal fluid during a number of CNS pathologies. However, its expression by resident microglial cells in vivo remains uncertain. In this work, we aimed to elucidate the murine CNS expression of uPAR and uPA as well as that of tissue plasminogen activator and plasminogen activator inhibitor 1 (PAI-1) during insults generating distinct and well-characterized inflammatory responses; acute intracerebral lipopolysaccharide (LPS), acute kainate-induced neurodegeneration, and chronic neurodegeneration induced by prion disease inoculation. All three insults induced marked expression of uPAR at both mRNA and protein level compared to controls (naïve, saline, or control inoculum-injected). uPAR expression was microglial in all cases. Conversely, uPA transcription and activity was only markedly increased during chronic neurodegeneration. Dissociation of uPA and uPAR levels in acute challenges is suggestive of additional proteolysis-independent roles for uPAR. PAI-1 was most highly expressed upon LPS challenge, whereas tissue plasminogen activator mRNA was constitutively present and less responsive to all insults studied. These data are novel and suggest much wider involvement of the uPAR/uPA system in CNS function and pathology than previously supposed. © 2009 Wiley-Liss, Inc

Measurement of B(B-->X_s {\gamma}), the B-->X_s {\gamma} photon energy spectrum, and the direct CP asymmetry in B-->X_{s+d} {\gamma} decays

The photon spectrum in B --> X_s {\gamma} decay, where X_s is any strange hadronic state, is studied using a data sample of (382.8\pm 4.2) \times 10^6 e^+ e^- --> \Upsilon(4S) --> BBbar events collected by the BABAR experiment at the PEP-II collider. The spectrum is used to measure the branching fraction B(B --> X_s \gamma) = (3.21 \pm 0.15 \pm 0.29 \pm 0.08)\times 10^{-4} and the first, second, and third moments = 2.267 \pm 0.019 \pm 0.032 \pm 0.003 GeV,, )^2> = 0.0484 \pm 0.0053 \pm 0.0077 \pm 0.0005 GeV^2, and )^3> = -0.0048 \pm 0.0011 \pm 0.0011 \pm 0.0004 GeV^3, for the range E_\gamma > 1.8 GeV, where E_{\gamma} is the photon energy in the B-meson rest frame. Results are also presented for narrower E_{\gamma} ranges. In addition, the direct CP asymmetry A_{CP}(B --> X_{s+d} \gamma) is measured to be 0.057 \pm 0.063. The spectrum itself is also unfolded to the B-meson rest frame; that is the frame in which theoretical predictions for its shape are made.Comment: 37 pages, 19 postscript figures, submitted to Phys. Rev. D. No analysis or results have changed from previous version. Some changes to improve clarity based on interactions with Phys. Rev. D referees, including one new Figure (Fig. 13), and some minor wording/punctuation/spelling mistakes fixe

Evidence for an excess of B -> D(*) Tau Nu decays

Based on the full BaBar data sample, we report improved measurements of the ratios R(D(*)) = B(B -> D(*) Tau Nu)/B(B -> D(*) l Nu), where l is either e or mu. These ratios are sensitive to new physics contributions in the form of a charged Higgs boson. We measure R(D) = 0.440 +- 0.058 +- 0.042 and R(D*) = 0.332 +- 0.024 +- 0.018, which exceed the Standard Model expectations by 2.0 sigma and 2.7 sigma, respectively. Taken together, our results disagree with these expectations at the 3.4 sigma level. This excess cannot be explained by a charged Higgs boson in the type II two-Higgs-doublet model. We also report the observation of the decay B -> D Tau Nu, with a significance of 6.8 sigma.Comment: Expanded section on systematics, text corrections, improved the format of Figure 2 and included the effect of the change of the Tau polarization due to the charged Higg

Search for the decay modes D^0 → e^+e^-, D^0 → μ^+μ^-, and D^0 → e^±μ∓

We present searches for the rare decay modes D^0→e^+e^-, D^0→μ^+μ^-, and D^0→e^±μ^∓ in continuum e^+e^-→cc events recorded by the BABAR detector in a data sample that corresponds to an integrated luminosity of 468  fb^(-1). These decays are highly Glashow–Iliopoulos–Maiani suppressed but may be enhanced in several extensions of the standard model. Our observed event yields are consistent with the expected backgrounds. An excess is seen in the D^0→μ^+μ^- channel, although the observed yield is consistent with an upward background fluctuation at the 5% level. Using the Feldman–Cousins method, we set the following 90% confidence level intervals on the branching fractions: B(D^0→e^+e^-)<1.7×10^(-7), B(D^0→μ^+μ^-) within [0.6,8.1]×10^(-7), and B(D^0→e^±μ^∓)<3.3×10^(-7)