An autoinhibitory control element defines calcium-regulated isoforms of nitric oxide synthase

Nitric oxide synthases (NOSs) are classified functionally, based on whether calmodulin binding is Ca2+-dependent (cNOS) or Ca2+-independent (iNOS). This key dichotomy has not been defined at the molecular level. Here we show that cNOS isoforms contain a unique polypeptide insert in their FMN binding domains which is not shared with iNOS or other related flavoproteins. Previously identified autoinhibitory domains in calmodulin-regulated enzymes raise the possibility that the polypeptide insert is the autoinhibitory domain of cNOSs. Consistent with this possibility, three-dimensional molecular modeling suggested that the insert originates from a site immediately adjacent to the calmodulin binding sequence. Synthetic peptides derived from the 45-amino acid insert of endothelial NOS were found to potently inhibit binding of calmodulin and activation of cNOS isoforms. This inhibition was associated with peptide binding to NOS, rather than free calmodulin, and inhibition could be reversed by increasing calmodulin concentration. In contrast, insert-derived peptides did not interfere with the arginine site of cNOS, as assessed from [3H]NG-nitro-L-arginine binding, nor did they potently effect iNOS activity. Limited proteolysis studies showed that calmodulin's ability to gate electron flow through cNOSs is associated with displacement of the insert polypeptide; this is the first specific calmodulin-induced change in NOS conformation to be identified. Together, our findings strongly suggest that the insert is an autoinhibitory control element, docking with a site on cNOSs which impedes calmodulin binding and enzymatic activation. The autoinhibitory control element molecularly defines cNOSs and offers a unique target for developing novel NOS activators and inhibitors

DXA-derived hip shape is related to osteoarthritis:findings from in the MrOS cohort

BF conducted this research whilst on a clinical research primer fellowship awarded by the Elizabeth Blackwell Institute, University of Bristol, UK. This study was funded by Arthritis Research UK project grant ref 20244. CG is funded by Arthritis Research UK grant ref 20000. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: the National Institute on Aging (NIA), the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Center for Advancing Translational Sciences (NCATS), and NIH Roadmap for Medical Research under the following grant numbers: R01 AR052000, K24 AR048841, U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, and UL1 TR000128.Peer reviewedPostprin

Learning from COVID-19 related trial adaptations to inform efficient trial design—a sequential mixed methods study

Background Many clinical trial procedures were often undertaken in-person prior to the COVID-19 pandemic, which has resulted in adaptations to these procedures to enable trials to continue. The aim of this study was to understand whether the adaptations made to clinical trials by UK Clinical Trials Units (CTUs) during the pandemic have the potential to improve the efficiency of trials post-pandemic. Methods This was a mixed methods study, initially involving an online survey administered to all registered UK CTUs to identify studies that had made adaptations due to the pandemic. Representatives from selected studies were qualitatively interviewed to explore the adaptations made and their potential to improve the efficiency of future trials. A literature review was undertaken to locate published evidence concerning the investigated adaptations. The findings from the interviews were reviewed by a group of CTU and patient representatives within a workshop, where discussions focused on the potential of the adaptations to improve the efficiency of future trials. Results Forty studies were identified by the survey. Fourteen studies were selected and fifteen CTU staff were interviewed about the adaptations. The workshop included 15 CTU and 3 patient representatives. Adaptations were not seen as leading to direct efficiency savings for CTUs. However, three adaptations may have the potential to directly improve efficiencies for trial sites and participants beyond the pandemic: a split remote-first eligibility assessment, recruitment outside the NHS via a charity, and remote consent. There was a lack of published evidence to support the former two adaptations, however, remote consent is widely supported in the literature. Other identified adaptations may benefit by improving flexibility for the participant. Barriers to using these adaptations include the impact on scientific validity, limitations in the role of the CTU, and participant’s access to technology. Conclusions Three adaptations (a split remote-first eligibility assessment, recruitment outside the NHS via a charity, and remote consent) have the potential to improve clinical trials but only one (remote consent) is supported by evidence. These adaptations could be tested in future co-ordinated ‘studies within a trial’ (SWAT)

From Quantum Systems to L-Functions: Pair Correlation Statistics and Beyond

The discovery of connections between the distribution of energy levels of heavy nuclei and spacings between prime numbers has been one of the most surprising and fruitful observations in the twentieth century. The connection between the two areas was first observed through Montgomery's work on the pair correlation of zeros of the Riemann zeta function. As its generalizations and consequences have motivated much of the following work, and to this day remains one of the most important outstanding conjectures in the field, it occupies a central role in our discussion below. We describe some of the many techniques and results from the past sixty years, especially the important roles played by numerical and experimental investigations, that led to the discovery of the connections and progress towards understanding the behaviors. In our survey of these two areas, we describe the common mathematics that explains the remarkable universality. We conclude with some thoughts on what might lie ahead in the pair correlation of zeros of the zeta function, and other similar quantities.Comment: Version 1.1, 50 pages, 6 figures. To appear in "Open Problems in Mathematics", Editors John Nash and Michael Th. Rassias. arXiv admin note: text overlap with arXiv:0909.491

A pain science education and walking program to increase physical activity in people with symptomatic knee osteoarthritis: A feasibility study

Introduction: Nine of 10 people with knee osteoarthritis are inactive. Unhelpful pain beliefs may negatively influence physical activity levels. Targeting these unhelpful pain beliefs, through contemporary pain science education (PSE), may provide benefit. Objectives: To evaluate the feasibility of conducting a clinical trial to determine the effect of adding PSE (vs adding sham ultrasound) to an individualised, physiotherapist-led education and walking program in people with painful knee osteoarthritis. Methods: Twenty participants were randomised (1:1) into the PSE group or Control group, each receiving 4 in-person weekly treatments, then 4 weeks of at-home activities (weekly telephone check-in). Clinical outcomes and physical activity (7 days of wristworn accelerometry) were assessed at baseline, 4 (clinical outcomes only), 8, and 26 weeks. A priori feasibility criteria for recruitment, intervention adherence, viability of wrist-based accelerometry, and follow-up retention were set. Perceived intervention credibility, acceptability, and usefulness from participants and clinicians were assessed (ratings, written/verbal feedback). Results: Most feasibility criteria were met. On average, 7 adults/wk were eligible, with 70% recruited. Treatment compliance was high (in-person: 80% PSE; 100% Control; at-home: 78% PSE; 75% Control). Wrist-based accelerometry had .75% valid weartime. Sufficient follow-up rates were not achieved (26 weeks: 65%). Participant and clinician feedback highlighted that PSE was too complex and did not match patient expectations of “physiotherapy”, that sham ultrasound was problematic (clinician), but that both treatments had high credibility, acceptability, and usefulness. Conclusions: Progression to a full trial is warranted. Strategies to increase participant retention, refine the PSE content/delivery, and replace/remove the sham intervention are required.Tasha R. Stanton, Emma L. Karran, David S. Butler, Melissa J. Hull, Sarah N. Schwetlik, Felicity A. Braithwaite, Hannah G. Jones, G. Lorimer Moseley, Catherine L. Hill, Christy Tomkins-Lane, Carol Maher, Kim Bennel

D* Production in Deep Inelastic Scattering at HERA

This paper presents measurements of D^{*\pm} production in deep inelastic scattering from collisions between 27.5 GeV positrons and 820 GeV protons. The data have been taken with the ZEUS detector at HERA. The decay channel $D^{*+}\to (D^0 \to K^- \pi^+) \pi^+$ (+ c.c.) has been used in the study. The $e^+p$ cross section for inclusive D^{*\pm} production with $5<Q^2<100 GeV^2$ and $y<0.7$ is 5.3 \pms 1.0 \pms 0.8 nb in the kinematic region {$1.3<p_T(D^{*\pm})<9.0$ GeV and $| \eta(D^{*\pm}) |<1.5$}. Differential cross sections as functions of p_T(D^{*\pm}), $\eta(D^{*\pm}), W$ and $Q^2$ are compared with next-to-leading order QCD calculations based on the photon-gluon fusion production mechanism. After an extrapolation of the cross section to the full kinematic region in p_T(D^{*\pm}) and $\eta$(D^{*\pm}), the charm contribution $F_2^{c\bar{c}}(x,Q^2)$ to the proton structure function is determined for Bjorken $x$ between 2 $\cdot$ 10$^{-4}$ and 5 $\cdot$ 10$^{-3}$.Comment: 17 pages including 4 figure

Observation of Scaling Violations in Scaled Momentum Distributions at HERA

Charged particle production has been measured in deep inelastic scattering (DIS) events over a large range of $x$ and $Q^2$ using the ZEUS detector. The evolution of the scaled momentum, $x_p$, with $Q^2,$ in the range 10 to 1280 $GeV^2$, has been investigated in the current fragmentation region of the Breit frame. The results show clear evidence, in a single experiment, for scaling violations in scaled momenta as a function of $Q^2$.Comment: 21 pages including 4 figures, to be published in Physics Letters B. Two references adde

Measurement of the dijet invariant mass cross section in proton anti-proton collisions at sqrt{s} = 1.96 TeV

The inclusive dijet production double differential cross section as a function of the dijet invariant mass and of the largest absolute rapidity of the two jets with the largest transverse momentum in an event is measured in proton anti-proton collisions at sqrt{s} = 1.96 TeV using 0.7 fb^{-1} integrated luminosity collected with the D0 detector at the Fermilab Tevatron Collider. The measurement is performed in six rapidity regions up to a maximum rapidity of 2.4. Next-to-leading order perturbative QCD predictions are found to be in agreement with the data.Comment: Published in Phys. Lett. B, 693, (2010), 531-538, 8 pages, 2 figures, 6 table

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters