Human Bocavirus NS1 and NS1-70 Proteins Inhibit TNF-α-Mediated Activation of NF-κB by targeting p65.

Human bocavirus (HBoV), a parvovirus, is a single-stranded DNA etiologic agent causing lower respiratory tract infections in young children worldwide. Nuclear factor kappa B (NF-κB) transcription factors play crucial roles in clearance of invading viruses through activation of many physiological processes. Previous investigation showed that HBoV infection could significantly upregulate the level of TNF-α which is a strong NF-κB stimulator. Here we investigated whether HBoV proteins modulate TNF-α-mediated activation of the NF-κB signaling pathway. We showed that HBoV NS1 and NS1-70 proteins blocked NF-κB activation in response to TNF-α. Overexpression of TNF receptor-associated factor 2 (TRAF2)-, IκB kinase alpha (IKKα)-, IκB kinase beta (IKKβ)-, constitutively active mutant of IKKβ (IKKβ SS/EE)-, or p65-induced NF-κB activation was inhibited by NS1 and NS1-70. Furthermore, NS1 and NS1-70 didn't interfere with TNF-α-mediated IκBα phosphorylation and degradation, nor p65 nuclear translocation. Coimmunoprecipitation assays confirmed the interaction of both NS1 and NS1-70 with p65. Of note, NS1 but not NS1-70 inhibited TNF-α-mediated p65 phosphorylation at ser536. Our findings together indicate that HBoV NS1 and NS1-70 inhibit NF-κB activation. This is the first time that HBoV has been shown to inhibit NF-κB activation, revealing a potential immune-evasion mechanism that is likely important for HBoV pathogenesis

Building professional discourse in emerging markets: Language, context and the challenge of sensemaking

Using ethnographic evidence from the former Soviet republics, this article examines a relatively new and mainly unobserved in the International Business (IB) literature phenomenon of communication disengagement that manifests itself in many emerging markets. We link it to the deficiencies of the local professional business discourse rooted in language limitations reflecting lack of experience with the market economy. This hampers cognitive coherence between foreign and local business entities, adding to the liability of foreignness as certain instances of professional experience fail to find adequate linguistic expression, and complicates cross-cultural adjustments causing multi-national companies (MNCs) financial losses. We contribute to the IB literature by examining cross-border semantic sensemaking through a retrospectively constructed observational study. We argue that a relative inadequacy of the national professional idiom is likely to remain a feature of business environment in post-communist economies for some time and therefore should be factored into business strategies of MNCs. Consequently, we recommend including discursive hazards in the risk evaluation of international projects

The PolyA tail length of yeast histone mRNAs varies during the cell cycle and is influenced by Sen1p and Rrp6p

Yeast histone mRNAs are polyadenylated, yet factors such as Rrp6p and Trf4p, required for the 3′-end processing of non-polyadenylated RNAs, contribute to the cell cycle regulation of these transcripts. Here, we investigated the role of other known 3′-end processing/transcription termination factors of non-polyadenylated RNA in the biogenesis of histone mRNAs, specifically the Nab3p/Nrd1p/Sen1p complex. We also re-evaluated the polyadenylation status of these mRNAs during the cell cycle. Our analysis reveals that yeast histone mRNAs have shorter than average PolyA tails and the length of the PolyA tail varies during the cell cycle; S-phase histone mRNAs possess very short PolyA tails while in G1, the tail length is relatively longer. Inactivation of either Sen1p or Rrp6p leads to a decrease in the PolyA tail length of histone mRNAs. Our data also show that Sen1p contributes to 3′-end processing of histone primary transcripts. Thus, histone mRNAs are distinct from the general pool of yeast mRNAs and 3′-end processing and polyadenylation contribute to the cell cycle regulation of these transcripts

The conserved C-terminus of the PcrA/UvrD helicase interacts directly with RNA polymerase

Copyright: © 2013 Gwynn et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by a Wellcome Trust project grant to MD (Reference: 077368), an ERC starting grant to MD (Acronym: SM-DNA-REPAIR) and a BBSRC project grant to PM, NS and MD (Reference: BB/I003142/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Trypanosoma cruzi Immune Response Modulation Decreases Microbiota in Rhodnius prolixus Gut and Is Crucial for Parasite Survival and Development

Trypanosoma cruzi in order to complete its development in the digestive tract of Rhodnius prolixus needs to overcome the immune reactions and microbiota trypanolytic activity of the gut. We demonstrate that in R. prolixus following infection with epimastigotes of Trypanosoma cruzi clone Dm28c and, in comparison with uninfected control insects, the midgut contained (i) fewer bacteria, (ii) higher parasite numbers, and (iii) reduced nitrite and nitrate production and increased phenoloxidase and antibacterial activities. In addition, in insects pre-treated with antibiotic and then infected with Dm28c, there were also reduced bacteria numbers and a higher parasite load compared with insects solely infected with parasites. Furthermore, and in contrast to insects infected with Dm28c, infection with T. cruzi Y strain resulted in a slight decreased numbers of gut bacteria but not sufficient to mediate a successful parasite infection. We conclude that infection of R. prolixus with the T. cruzi Dm28c clone modifies the host gut immune responses to decrease the microbiota population and these changes are crucial for the parasite development in the insect gut

Roots and (re)sources of value (in)definiteness versus contextuality. A contribution to the Pitowsky Volume in memory of Itamar Pitowsky (1950--2010)

In Itamar Pitowsky's reading of the Gleason and the Kochen-Specker theorems, in particular, his Logical Indeterminacy Principle, the emphasis is on the value indefiniteness of observables which are not within the preparation context. This is in stark contrast to the prevalent term {\em contextuality} used by many researchers in informal, heuristic yet omni-realistic and potentially misleading ways. This paper discusses both concepts and argues in favor of value indefiniteness in all but a continuum of contexts intertwining in the vector representing a single pure (prepared) state. Even more restrictively, and inspired by operationalism but not justified by Pitowsky's Logical Indeterminacy Principle or similar, one could identify with a "quantum state" a single quantum context -- aka the respective maximal observable, or, in terms of its spectral decomposition, the associated orthonormal basis - from the continuum of intertwining context, as per the associated maximal observable actually or implicitly measured.Comment: 11 pages, revised and polished, discussion on joint probabilities of observables in different contexts adde

Oxide_Oxide Ceramic Matrix Composite (CMC) Exhaust Mixer Development in the NASA Environmentally Responsible Aviation (ERA) Project

Rolls-Royce North American Technologies, Inc. (LibertyWorksLW) began considering the development of CMC exhaust forced mixers in 2008, as a means of obtaining reduced weight and hotter operating temperature capability, while minimizing shape distortion during operation, which would improve mixing efficiency and reduce fuel burn. Increased component durability, enhanced ability to fabricate complex-shaped components, and engine noise reduction are other potential advantages of CMC mixers (compared to metallic mixers). In 2010, NASA was pursuing the reduction of NOx emissions, fuel burn, and noise from turbine engines in Phase I of the Environmentally Responsible Aviation (ERA) Project. ERA subtasks, including those focused on CMC components, were formulated with the goal of maturing technology from proof of concept validation (TRL 3) to a systemsubsystem or prototype demonstration in a relevant environment (TRL 6). In April 2010, the NASA Glenn Research Center (GRC) and LibertyWorks jointly initiated a CMC Exhaust System Validation Program within the ERA Project, teaming on CMC exhaust mixer development for subsonic jet engines capable of operating with increased performance. Our initial focus was on designing, fabricating, and characterizing the thrust and acoustic performance of a roughly quarter-scale 16-lobe oxide oxide CMC mixer and tail cone along with a conventional low bypass exhaust nozzle. Support Services, LLC (Allendale, MI) and ATK COI Ceramics, Inc. (COIC, in San Diego, CA) supported the design of a subscale nozzle assembly that consisted of an oxide oxide CMC mixer and center body, with each component mounted on a metallic attachment ring. That design was based upon the operating conditions a mixer would experience in a turbofan engine. Validation of the aerodynamic and acoustic performance of the subscale mixer via testing and the achievement of TRL 4 encouraged the NASALWCOIC team to move to the next phase where a full scale CMC mixer sized for a RR AE3007 engine and a compatible attachment flange were designed, followed by CMC component fabrication by COIC, and vibration testing at GRC under conditions simulating the structural and dynamic environment encountered during engine operation. AFRL (WPAFB) supported this testing by performing 3D laser vibrometry to identify the mixer mode shapes and modal frequencies. The successful fabrication and testing of such a component has been achieved. The CMC mixer demonstrated good durability during vibration testing at room and elevated temperature (TRL5). This has cleared the article for a ground-based test on a Rolls-Royce AE3007 engine, where the performance and benefits of the component can be further assessed

HbA1c levels in schoolchildren with type 1 diabetes are seasonally variable and dependent on weather conditions

Aims/hypothesis: We evaluated seasonal HbA$_{1c}$ changes in children with type 1 diabetes and its relation with measures of weather conditions. Methods: HbA$_{1c}$ changes over more than 3 years were evaluated in type 1 diabetic patients who were younger than 18 years and had diabetes duration of more than 12 months, and correlated with measures of weather conditions (ambient temperature, hours of sunshine and solar irradiance). After comparison of autocorrelation patterns, patterns of metabolic control and meteorological data were evaluated using Spearman rank correlation. Results: A total of 3,935 HbA$_{1c}$ measurements in 589 school (≥7 years) and 88 preschool (<7 years) children were analysed. Mean (±SD) HbA$_{1c}$ level for the whole study period was 7.65±1.12%. The lowest HbA$_{1c}$ levels were observed in late summer and the highest in winter months, with differences consistently exceeding 0.44%. Autocorrelation analysis of HbA$_{1c}$ levels in schoolchildren showed a sine-wave pattern with a cycle length of roughly 12 months, which mirrored changes in ambient temperature. Strong negative correlations of HbA$_{1c}$ with ambient temperature (R=−0.56; p=0.0002), hours of sunshine (R=−0.52; p=0.0007) and solar irradiance (R=−0.52; p=0.0006) were present in schoolchildren, but not in preschoolers (p≥0.29 for each correlation). Conclusions/interpretation: Seasonal changes of HbA$_{1c}$ levels in schoolchildren with type 1 diabetes are a significant phenomenon and should be considered in patient education and diabetes management. They may potentially affect the results of clinical trials using HbA$_{1c}$ levels as their primary outcome, as well as HbA$_{1c}$-based diagnosis of diabetes

The interaction of Pcf11 and Clp1 is needed for mRNA 3′-end formation and is modulated by amino acids in the ATP-binding site

Polyadenylation of eukaryotic mRNAs contributes to stability, transport and translation, and is catalyzed by a large complex of conserved proteins. The Pcf11 subunit of the yeast CF IA factor functions as a scaffold for the processing machinery during the termination and polyadenylation of transcripts. Its partner, Clp1, is needed for mRNA processing, but its precise molecular role has remained enigmatic. We show that Clp1 interacts with the Cleavage–Polyadenylation Factor (CPF) through its N-terminal and central domains, and thus provides cross-factor connections within the processing complex. Clp1 is known to bind ATP, consistent with the reported RNA kinase activity of human Clp1. However, substitution of conserved amino acids in the ATP-binding site did not affect cell growth, suggesting that the essential function of yeast Clp1 does not involve ATP hydrolysis. Surprisingly, non-viable mutations predicted to displace ATP did not affect ATP binding but disturbed the Clp1–Pcf11 interaction. In support of the importance of this interaction, a mutation in Pcf11 that disrupts the Clp1 contact caused defects in growth, 3′-end processing and transcription termination. These results define Clp1 as a bridge between CF IA and CPF and indicate that the Clp1–Pcf11 interaction is modulated by amino acids in the conserved ATP-binding site of Clp1

Bias in mean velocities and noise in variances and covariances measured using a multistatic acoustic profiler: The Nortek Vectrino Profiler

This paper compiles the technical characteristics and operating principles of the Nortek Vectrino Profiler and reviews previously reported user experiences. A series of experiments are then presented that investigate instrument behaviour and performance, with a particular focus on variations within the profile. First, controlled tests investigate the sensitivity of acoustic amplitude (and Signal-to-Noise Ratio, SNR) and pulse-to-pulse correlation coefficient, R2, to seeding concentration and cell geometry. Second, a novel methodology that systematically shifts profiling cells through a single absolute vertical position investigates the sensitivity of mean velocities, SNR and noise to: (a). emitted sound intensity and the presence (or absence) of acoustic seeding; and (b). varying flow rates under ideal acoustic seeding conditions. A new solution is derived to quantify the noise affecting the two orthogonal tristatic systems of the Vectrino Profiler and its contribution to components of the Reynolds stress tensor. Results suggest that for the Vectrino Profiler: 1. optimum acoustic seeding concentrations are ~3,000 to 6,000 mg L-1; 2. mean velocity magnitudes are biased by variable amounts in proximal cells but are consistently underestimated in distal cells; 3. noise varies parabolically with a minimum around the "sweet spot", 50 mm below the transceiver; 4. the receiver beams only intersect at the sweet spot and diverge nearer to and further from the transceiver. This divergence significantly reduces the size of the sampled area away from the sweet spot, reducing data quality; 5. the most reliable velocity data will normally be collected in the region between approximately 43 and 61 mm below the transceiver