Native electrospray mass spectrometry approaches to probe the interaction between zinc and an anti-angiogenic peptide from histidine-rich glycoprotein

This work was supported by the BBSRC (grant ref. BB/J006467/1 and CASE studentship to E.M.M.) and the British Heart Foundation (grant ref. PG/15/9/31270 and FS/15/42/31556).Zinc modulates the biological function of histidine-rich glycoprotein (HRG) through binding to its His-rich region (HRR). The Zn2+-binding properties of a 35 amino-acid biologically-active peptide mimic of the HRR, HRGP330, were investigated using dissociative mass spectrometry approaches in addition to travelling-wave ion mobility mass spectrometry (TWIM-MS). Native mass spectrometry confirmed zinc binding to HRGP330; however, broadening of the 1H NMR resonances upon addition of Zn2+ ions precluded the attainment of structural information. A complementary approach employing TWIM-MS indicated that HRGP330 has a more compact structure in the presence of Zn2+ ions. Top-down MS/MS data supported a metal-binding-induced conformational change, as fewer fragments were observed for Zn2+-bound HRGP330. Zn2+-bound fragments of both N-terminal and C-terminal ends of the peptide were identified from collision-induced dissociation (CID) and electron transfer dissociation/proton transfer reaction (ETD/PTR) experiments, suggesting that multiple binding sites exist within this region of HRG. The combination of mass spectrometry and NMR approaches provides new insight into the highly dynamic interaction between zinc and this His-rich peptide.Publisher PDFPeer reviewe

Are they ‘worth their weight in gold’? Sport for older adults: benefits and barriers of their participation for sporting organisations

The ageing global population has led to an increased focus on health for older adults. However, older adults have not been a specific priority for some sporting organisations (SOs). Thus, there is an emerging opportunity for this age group to be considered within international sport policy. The aim of this study was to understand the benefits and barriers that SOs encounter when engaging older adults. Eight focus group interviews (n = 49) were held with representatives of Australian national sporting organisations (NSOs), and older adults who were either sport club or non-sport club members. The socioecological model domains, interpersonal, organisational and policy, were used as a framework for thematic analysis, and organisational capacity building concepts were utilised to explain the findings. Common perceived benefits included interpersonal benefits (intergenerational opportunities and role models) and organisational benefits (volunteering, financial contributions and maximised facility usage) for engaging older adults. Common perceived barriers included interpersonal barriers (competing priorities and perceived societal expectations), organisational barriers (lack of appropriate playing opportunities, lack of facility access and lack of club capacity) and policy barriers (strategic organisational focus on children and elite sport and risk management). Whilst participation in sport is not common for older adults, their involvement can be invaluable for sport clubs. It is not anticipated that any policy focus on older adults will significantly increase active participation for this age group. However, any increase in older adults’ sport participation either through actively playing, supporting family and friends and/or volunteering will contribute to the positive health of individuals, sport clubs and the community.Peer reviewedFinal Accepted Versio

Modern clinician-initiated clinical trials to determine optimal therapy for multidrug-resistant gram-negative infections

Treatment options for multidrug-resistant (MDR) gram-negative infection are growing. However, postregistration, pragmatic, and clinician-led clinical trials in this field are few, recruit small sample sizes, and experience deficiencies in design and operations. MDR gram-negative therapeutic trials are often inefficient, only evaluating a single antibiotic or strategy at a time. Novel clinical trial designs offer potential solutions by attempting to obtain clinically meaningful conclusions at the end or during a trial, for many treatment strategies, simultaneously. An integrated, consensus approach to MDR gram-negative infection trial design is crucial

Age-specific diastolic dysfunction improves prediction of symptomatic heart failure by Stage B heart failure

Aims: We investigated whether addition of diastolic dysfunction (DD) and longitudinal strain (LS) to Stage B heart failure (SBHF) criteria (structural or systolic abnormality) improves prediction of symptomatic HF in participants of the SCReening Evaluation of the Evolution of New Heart Failure study, a self-selected population at increased cardiovascular disease risk recruited from members of a health insurance fund in Melbourne and Shepparton, Australia. Both American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACVI) criteria and age-specific Atherosclerosis Risk in Communities (ARIC) study criteria, for SBHF and DD, and ARIC criteria for abnormal LS, were examined. Methods and results: Inclusion criteria were age ≥60 years with one or more of self-reported ischaemic or other heart disease, irregular or rapid heart rhythm, cerebrovascular disease, renal impairment, or treatment for hypertension or diabetes for ≥2 years. Exclusion criteria were known HF, or ejection fraction mild valve abnormality detected on previous echocardiography or other imaging. Echocardiography was performed in 3190 participants who were followed for a median of 3.9 (interquartile range: 3.4, 4.5) years after echocardiography. Symptomatic HF was diagnosed in 139 participants at a median of 3.1 (interquartile range: 2.1, 3.9) years after echocardiography. ARIC structural, systolic, and diastolic abnormalities predicted HF in univariate and multivariable proportional hazards analyses, whereas ASE/EACVI structural and systolic, but not diastolic, abnormalities predicted HF. ARIC and ASE/EACVI SBHF criteria predicted HF with sensitivities of 81% and 55%, specificities of 39% and 76%, and C statistics of 0.60 (95% confidence interval: 0.57, 0.64) and 0.66 (0.61, 0.71), respectively. Adding ARIC DD to SBHF increased sensitivity to 94% with specificity of 24% and C statistic of 0.59 (0.57, 0.61), whereas addition of ASE/EACVI DD to SBHF increased sensitivity to 97% but reduced specificity to 9% and the C statistic to 0.52 (0.50, 0.54, P < 0.0001). Addition of LS to ARIC or ASE/EACVI SBHF criteria had minimal impact on prediction of HF. Conclusions: Age-specific ARIC DD criteria, but not ASE/EACVI DD criteria, predicted symptomatic HF, and addition of age-specific ARIC DD criteria to ARIC SBHF criteria improved prediction of symptomatic HF in asymptomatic individuals with cardiovascular disease risk factors. Addition of LS to ASE/EACVI or ARIC SBHF criteria did not improve prediction of symptomatic HF

Insuring Against Losses from Transgenic Contamination: The Case of Pharmaceutical Maize

Concerns about the risk of food supply contamination and the resulting financial losses have limited the development and commercialization of certain pharmaceutical plants. This article develops an insurance pricing model that helps translate these concerns into a cost-benefit analysis. The model first estimates the physical dispersal of maize pollen subject to a number of weather parameters. This distribution is then validated with the limited amount of currently available field trial data. The physical distribution is then used to calculate the premium for a fair-valued insurance policy that would fund the destruction of possibly contaminated fields. The flexible framework can be readily adapted to other crops, management practices, and regions

Exotic Heavy Fermion State in the Filled Skutterudite PrFe4_4P12_{12} Uncovered by the de Haas-van Alphen Effect

We report the de Haas-van Alphen (dHvA) experiment on the filled skutterudite PrFe$_4$P$_{12}$ exhibiting apparent Kondo-like behaviors in the transport and thermal properties. We have found enormously enhanced cyclotron effective mass $m^{\rm \ast}_{\rm c}=81 m_{\rm 0}$ in the high field phase (HFP), which indicates that PrFe$_4$P$_{12}$ is the first Pr-compound in which really heavy mass has been unambiguously confirmed. Also in the low field non-magnetic ordered phase (LOP), we observed the dHvA branch with $m^{\rm \ast}_{\rm c}=10 m_{0}$ that is quite heavy taking into account its small Fermi surface volume (0.15% of the Brillouin zone size). The insensitivity of mass in LOP against the magnetic field suggests that the quadrupolar interaction plays a main role both in the mass renormalization and the LOP formation.Comment: 5 pages, 5 figures, Phys. Rev. B (01 October 2002) in pres

Further analysis of the quantum critical point of Ce1−x_{1-x}Lax_{x}Ru2_{2}Si2_{2}

New data on the spin dynamics and the magnetic order of Ce$_{1-x}$La$_{x}$Ru$_{2}$Si$_{2}$ are presented. The importance of the Kondo effect at the quantum critical point of this system is emphasized from the behaviour of the relaxation rate at high temperature and from the variation of the ordered moment with respect to the one of the N\'eel temperature for various $x$.Comment: Contribution for the Festschrift on the occasion of Hilbert von Loehneysen 60 th birthday. To be published as a special issue in the Journal of Low Temperature Physic

Crystal field effects in the zig zag chain compound SrTm2O4

The single ion properties of the zig zag chain compound SrTm2O4 have been investigated using heat capacity, magnetic susceptibility, magnetization, inelastic neutron scattering, and polarized muon spectroscopy. Two crystal field models are employed to estimate the single ion properties; a Density Function Theory based model and an effective charge model based on the Hutchings point charge model. The latter describes our experimental results well. This model estimates an easy axis anisotropy for one of the Tm3 sites and an easyplane anisotropy for the second site. It also predicts a mixed ground state with dominating amp; 119869; 0 characteristics for both sites. Additionally, muon spin rotation relaxation amp; 120583; SR spectra reveal oscillations, typically a sign of long range magnetic order. However, the temperature dependence of the precession frequency and the relaxation rates indicate that the system is in an extended critical regime and the observed relaxation is actually dynami

Transport properties of strongly correlated metals:a dynamical mean-field approach

The temperature dependence of the transport properties of the metallic phase of a frustrated Hubbard model on the hypercubic lattice at half-filling are calculated. Dynamical mean-field theory, which maps the Hubbard model onto a single impurity Anderson model that is solved self-consistently, and becomes exact in the limit of large dimensionality, is used. As the temperature increases there is a smooth crossover from coherent Fermi liquid excitations at low temperatures to incoherent excitations at high temperatures. This crossover leads to a non-monotonic temperature dependence for the resistance, thermopower, and Hall coefficient, unlike in conventional metals. The resistance smoothly increases from a quadratic temperature dependence at low temperatures to large values which can exceed the Mott-Ioffe-Regel value, hbar a/e^2 (where "a" is a lattice constant) associated with mean-free paths less than a lattice constant. Further signatures of the thermal destruction of quasiparticle excitations are a peak in the thermopower and the absence of a Drude peak in the optical conductivity. The results presented here are relevant to a wide range of strongly correlated metals, including transition metal oxides, strontium ruthenates, and organic metals.Comment: 19 pages, 9 eps figure