Hepatitis C virus NS4B carboxy terminal domain is a membrane binding domain

<p>Abstract</p> <p>Background</p> <p>Hepatitis C virus (HCV) induces membrane rearrangements during replication. All HCV proteins are associated to membranes, pointing out the importance of membranes for HCV. Non structural protein 4B (NS4B) has been reported to induce cellular membrane alterations like the membranous web. Four transmembrane segments in the middle of the protein anchor NS4B to membranes. An amphipatic helix at the amino-terminus attaches to membranes as well. The carboxy-terminal domain (CTD) of NS4B is highly conserved in Hepaciviruses, though its function remains unknown.</p> <p>Results</p> <p>A cytosolic localization is predicted for the NS4B-CTD. However, using membrane floatation assays and immunofluorescence, we now show targeting of the NS4B-CTD to membranes. Furthermore, a profile-profile search, with an HCV NS4B-CTD multiple sequence alignment, indicates sequence similarity to the membrane binding domain of prokaryotic D-lactate dehydrogenase (d-LDH). The crystal structure of E. coli d-LDH suggests that the region similar to NS4B-CTD is located in the membrane binding domain (MBD) of d-LDH, implying analogy in membrane association. Targeting of d-LDH to membranes occurs via electrostatic interactions of positive residues on the outside of the protein with negative head groups of lipids. To verify that anchorage of d-LDH MBD and NS4B-CTD is analogous, NS4B-CTD mutants were designed to disrupt these electrostatic interactions. Membrane association was confirmed by swopping the membrane contacting helix of d-LDH with the corresponding domain of the 4B-CTD. Furthermore, the functionality of these residues was tested in the HCV replicon system.</p> <p>Conclusion</p> <p>Together these data show that NS4B-CTD is associated to membranes, similar to the prokaryotic d-LDH MBD, and is important for replication.</p

How much of the intraaortic balloon volume is displaced toward the coronary circulation?

This is a post-print version of the published article. Copyright @ 2010 The American Association for Thoracic Surgery.This article has been made available through the Brunel Open Access Publishing Fund.Objective: During intraaortic balloon inflation, blood volume is displaced toward the heart (Vtip), traveling retrograde in the descending aorta, passing by the arch vessels, reaching the aortic root (Vroot), and eventually perfusing the coronary circulation (Vcor). Vcor leads to coronary flow augmentation, one of the main benefits of the intraaortic balloon pump. The aim of this study was to assess Vroot and Vcor in vivo and in vitro, respectively. Methods: During intraaortic balloon inflation, Vroot was obtained by integrating over time the aortic root flow signals measured in 10 patients with intraaortic balloon assistance frequencies of 1:1 and 1:2. In a mock circulation system, flow measurements were recorded simultaneously upstream of the intraaortic balloon tip and at each of the arch and coronary branches of a silicone aorta during 1:1 and 1:2 intraaortic balloon support. Integration over time of the flow signals during inflation yielded Vcor and the distribution of Vtip. Results: In patients, Vroot was 6.4% ± 4.8% of the intraaortic balloon volume during 1:1 assistance and 10.0% ± 5.0% during 1:2 assistance. In vitro and with an artificial heart simulating the native heart, Vcor was smaller, 3.7% and 3.8%, respectively. The distribution of Vtip in vitro varied, with less volume displaced toward the arch and coronary branches and more volume stored in the compliant aortic wall when the artificial heart was not operating. Conclusion: The blood volume displaced toward the coronary circulation as the result of intraaortic balloon inflation is a small percentage of the nominal intraaortic balloon volume. Although small, this percentage is still a significant fraction of baseline coronary flow.This article is available through the Open Access Publishing Fund

Cancer risk in children, adolescents, and young adults conceived by ART in 1983-2011

STUDY QUESTION: Do children, adolescents, and young adults born after ART, including IVF, ICSI and frozen-thawed embryo transfer (FET), have an increased risk of cancer compared with children born to subfertile couples not conceived by ART and children from the general population? SUMMARY ANSWER: After a median follow-up of 18 years, the overall cancer risk was not increased in children conceived by ART, but a slight risk increase was observed in children conceived after ICSI. WHAT IS KNOWN ALREADY: There is growing evidence that ART procedures could perturb epigenetic processes during the pre-implantation period and influence long-term health. Recent studies showed (non-)significantly increased cancer risks after ICSI and FET, but not after IVF. STUDY DESIGN, SIZE, DURATION: A nationwide historical cohort study with prospective follow-up was carried out, including all live-born offspring from women treated with ART between 1983 and 2011 and subfertile women not treated with ART in one of the 13 Dutch IVF clinics and two fertility centers. PARTICIPANTS/MATERIALS, SETTING, METHODS: Children were identified through the mothers' records in the Personal Records Database. Information on the conception method of each child was collected through the mother's medical record. In total, the cohort comprises 89 249 live-born children of subfertile couples, of whom 51 417 were conceived using ART and 37 832 were not (i.e. conceived naturally, through ovulation induction, or after IUI). Cancer incidence was ascertained through linkage with the Netherlands Cancer Registry for the period 1989-2019. Cancer risk in children conceived using ART was compared with risk in children born to subfertile couples but not conceived by ART (hazard ratio (HR)) and children from the general population (standardized incidence ratios (SIRs)). MAIN RESULTS AND THE ROLE OF CHANCE: In total, 358 cancers were observed after a median follow-up of 18 years. Overall cancer risk was not increased in children conceived using ART, when compared with the general population (SIR = 0.96, 95% CI = 0.81-1.12) or with children from subfertile couples not conceived by ART (HR = 1.06, 95% CI = 0.84-1.33). Compared with children from subfertile couples not conceived by ART, the use of IVF or FET was not associated with increased cancer risk, but ICSI was associated with a slight risk increase (HR = 1.58, 95% CI = 1.08-2.31). Risk of cancer after ART did not increase at older ages (≥18 years, HR = 1.26, 95% CI = 0.88-1.81) compared to cancer risk in children not conceived by ART. LIMITATIONS, REASONS FOR CAUTION: The observed increased risk among children conceived using ICSI must be interpreted with caution owing to the small number of cases. WIDER IMPLICATIONS OF THE FINDINGS: After a median follow-up of 18 years, children conceived using ART do not have an increased overall cancer risk. Many large studies with prolonged follow-up are needed to investigate cancer risk in (young) adults conceived by different types of ART. In addition, international pooling of studies is recommended to provide sufficient power to study risk of specific cancer sites after ART. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by The Dutch Cancer Society (NKI 2006-3631) that funded the OMEGA-women's cohort, Children Cancer Free (KIKA; 147) that funded the OMEGA-I-II offspring cohort. The OMEGA-III offspring cohort was supported by a Postdoc Stipend of Amsterdam Reproduction &amp; Development, and the Eunice Kennedy Shriver National Institute of Child Health &amp; Human Development of the National Institutes of Health under Award Number R01HD088393. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare no competing interests. TRIAL REGISTRATION NUMBER:N/A.</p

Improved performance of the LHCb Outer Tracker in LHC Run 2

The LHCb Outer Tracker is a gaseous detector covering an area of $5\times 6 m^2$ with 12 double layers of straw tubes. The performance of the detector is presented based on data of the LHC Run 2 running period from 2015 and 2016. Occupancies and operational experience for data collected in $p p$, pPb and PbPb collisions are described. An updated study of the ageing effects is presented showing no signs of gain deterioration or other radiation damage effects. In addition several improvements with respect to LHC Run 1 data taking are introduced. A novel real-time calibration of the time-alignment of the detector and the alignment of the single monolayers composing detector modules are presented, improving the drift-time and position resolution of the detector by 20\%. Finally, a potential use of the improved resolution for the timing of charged tracks is described, showing the possibility to identify low-momentum hadrons with their time-of-flight.Comment: 29 pages, 20 figures, minor changes to match the published versio

Caveats for using statistical significance tests in research assessments

This paper raises concerns about the advantages of using statistical significance tests in research assessments as has recently been suggested in the debate about proper normalization procedures for citation indicators. Statistical significance tests are highly controversial and numerous criticisms have been leveled against their use. Based on examples from articles by proponents of the use statistical significance tests in research assessments, we address some of the numerous problems with such tests. The issues specifically discussed are the ritual practice of such tests, their dichotomous application in decision making, the difference between statistical and substantive significance, the implausibility of most null hypotheses, the crucial assumption of randomness, as well as the utility of standard errors and confidence intervals for inferential purposes. We argue that applying statistical significance tests and mechanically adhering to their results is highly problematic and detrimental to critical thinking. We claim that the use of such tests do not provide any advantages in relation to citation indicators, interpretations of them, or the decision making processes based upon them. On the contrary their use may be harmful. Like many other critics, we generally believe that statistical significance tests are over- and misused in the social sciences including scientometrics and we encourage a reform on these matters.Comment: Accepted version for Journal of Informetric

Temporal and Spatial Patterns of Ambient Endotoxin Concentrations in Fresno, California

BackgroundEndotoxins are found in indoor dust generated by human activity and pets, in soil, and adsorbed onto the surfaces of ambient combustion particles. Endotoxin concentrations have been associated with respiratory symptoms and the risk of atopy and asthma in children.ObjectiveWe characterized the temporal and spatial variability of ambient endotoxin in Fresno/Clovis, California, located in California's Central Valley, to identify correlates and potential predictors of ambient endotoxin concentrations in a cohort of children with asthma [Fresno Asthmatic Children's Environment Study (FACES)].MethodsBetween May 2001 and October 2004, daily ambient endotoxin and air pollutants were collected at the central ambient monitoring site of the California Air Resources Board in Fresno and, for shorter time periods, at 10 schools and indoors and outdoors at 84 residences in the community. Analyses were restricted to May-October, the dry months during which endotoxin concentrations are highest.ResultsDaily endotoxin concentration patterns were determined mainly by meteorologic factors, particularly the degree of air stagnation. Overall concentrations were lowest in areas distant from agricultural activities. Highest concentrations were found in areas immediately downwind from agricultural/pasture land. Among three other measured air pollutants [fine particulate matter, elemental carbon (a marker of traffic in Fresno), and coarse particulate matter (PMc)], PMc was the only pollutant correlated with endotoxin. Endotoxin, however, was the most spatially variable.ConclusionsOur data support the need to evaluate the spatial/temporal variability of endotoxin concentrations, rather than relying on a few measurements made at one location, in studies of exposure and and respiratory health effects, particularly in children with asthma and other chronic respiratory diseases

Determination of the Michel Parameters rho, xi, and delta in tau-Lepton Decays with tau --> rho nu Tags

Using the ARGUS detector at the $e^+ e^-$ storage ring DORIS II, we have measured the Michel parameters $\rho$, $\xi$, and $\xi\delta$ for $\tau^{\pm}\to l^{\pm} \nu\bar\nu$ decays in $\tau$-pair events produced at center of mass energies in the region of the $\Upsilon$ resonances. Using $\tau^\mp \to \rho^\mp \nu$ as spin analyzing tags, we find $\rho_{e}=0.68\pm 0.04 \pm 0.08$, $\xi_{e}= 1.12 \pm 0.20 \pm 0.09$, $\xi\delta_{e}= 0.57 \pm 0.14 \pm 0.07$, $\rho_{\mu}= 0.69 \pm 0.06 \pm 0.08$, $\xi_{\mu}= 1.25 \pm 0.27 \pm 0.14$ and $\xi\delta_{\mu}= 0.72 \pm 0.18 \pm 0.10$. In addition, we report the combined ARGUS results on $\rho$, $\xi$, and $\xi\delta$ using this work und previous measurements.Comment: 10 pages, well formatted postscript can be found at http://pktw06.phy.tu-dresden.de/iktp/pub/desy97-194.p

Measurements of the Ratios B(Ds+→ηℓ+ν)/B(Ds+→ϕℓ+ν){\cal B}(D_s^+\to \eta\ell^+\nu)/{\cal B}(D_s^+\to \phi\ell^+\nu) and B(Ds+→η′ℓ+ν)/B(Ds+→ϕℓ+ν){\cal B}(D_s^+\to \eta'\ell^+\nu)/{\cal B}(D_s^+\to \phi\ell^+\nu)

Using the CLEO~II detector we measure ${\cal B}(D_s^+\to \eta e^+\nu)/{\cal B}(D_s^+\to \phi e^+\nu) =1.24\pm0.12\pm0.15$, ${\cal B}(D_s^+\to \eta' e^+\nu)/{\cal B}(D_s^+\to \phi e^+\nu) =0.43\pm0.11\pm0.07$ and ${\cal B}(D_s^+\to \eta' e^+\nu)/{\cal B}(D_s^+\to \eta e^+\nu) =0.35\pm0.09\pm0.07$. We find the vector to pseudoscalar ratio, ${\cal B}(D_s^+\to \phi e^+\nu)/{\cal B}(D_s^+\to (\eta+\eta') e^+\nu) =0.60\pm0.06\pm0.06$, which is similar to the ratio found in non strange $D$ decays.Comment: 11 page uuencoded postscript file, postscript file also available through http://w4.lns.cornell.edu/public/CLN

Measurement of the Inclusive Semi-electronic D0D^0 Branching Fraction

Using the angular correlation between the $\pi^+$ emitted in a $D^{*+} \rightarrow D^0 \pi^+$ decay and the $e^+$ emitted in the subsequent $D^0 \rightarrow Xe^+\nu$ decay, we have measured the branching fraction for the inclusive semi-electronic decay of the $D^0$ meson to be: {\cal B}(D^0 \rightarrow X e^+ \nu) = [6.64 \pm 0.18 (stat.) \pm 0.29 (syst.)] \%. The result is based on 1.7 fb$^{-1}$ of $e^+e^-$ collisions recorded by the CLEO II detector located at the Cornell Electron Storage Ring (CESR). Combining the analysis presented in this paper with previous CLEO results we find, \frac{{\cal B} (D^0 \rightarrow X e^+ \nu)} {{\cal B} (D^0 \rightarrow K^- \pi^+)} = 1.684 \pm 0.056 (stat.) \pm 0.093(syst.) and \frac{{\cal B}(D\rightarrow K^-e^+\nu)} {{\cal B}(D\rightarrow Xe^+\nu)} = 0.581 \pm 0.023 (stat.) \pm 0.028(syst.). The difference between the inclusive rate and the sum of the measured exclusive branching fractions (measured at CLEO and other experiments) is $(3.3 \pm 7.2) \%$ of the inclusive rate.Comment: Latex file, 33pages, 4 figures Submitted to PR