Enhanced conformational space sampling improves the prediction of chemical shifts in proteins.

A biased-potential molecular dynamics simulation method, accelerated molecular dynamics (AMD), was combined with the chemical shift prediction algorithm SHIFTX to calculate (1)H(N), (15)N, (13)Calpha, (13)Cbeta, and (13)C' chemical shifts of the ankyrin repeat protein IkappaBalpha (residues 67-206), the primary inhibitor of nuclear factor kappa-B (NF-kappaB). Free-energy-weighted molecular ensembles were generated over a range of acceleration levels, affording systematic enhancement of the conformational space sampling of the protein. We have found that the predicted chemical shifts, particularly for the (15)N, (13)Calpha, and (13)Cbeta nuclei, improve substantially with enhanced conformational space sampling up to an optimal acceleration level. Significant improvement in the predicted chemical shift data coincides with those regions of the protein that exhibit backbone dynamics on longer time scales. Interestingly, the optimal acceleration level for reproduction of the chemical shift data has previously been shown to best reproduce the experimental residual dipolar coupling (RDC) data for this system, as both chemical shift data and RDCs report on an ensemble and time average in the millisecond range

Contemporary hormone therapy with LHRH agonists for prostate cancer: avoiding osteoporosis and fracture.

© 2015 Polish Urological Association. All Rights Reserved.Introduction Prostate cancer is a large clinical burden across Europe. It is, in fact, the most common cancer in males, accounting for more than 92,300 deaths annually throughout the continent. Prostate cancer is androgen-sensitive; thus an androgen deprivation therapy (ADT) is often used for treatment by reducing androgen to castrate levels. Several ADT agents have achieved benefits with effective palliation, but, unfortunately, severe adverse events are frequent. Contemporary ADT (Luteinising Hormone Releasing Hormone agonist - LHRHa injections) can result in side effects that include osteoporosis and fractures, compromising quality of life and survival.  Methods In this review we analysed the associated bone toxicity consequent upon contemporary ADT and based on the literature and our own experience we present future perspectives that seek to mitigate this associated toxicity both by development of novel therapies and by better identification and prediction of fracture risk. Results Preliminary results indicate that parenteral oestrogen can mitigate associated osteoporotic risk and that CT scans could provide a more accurate indicator of overall bone quality and hence fracture risk.  Conclusions As healthcare costs increase globally, cheap and effective alternatives that achieve ADT, but mitigate or avoid such bone toxicities, will be needed. More so, innovative techniques to improve both the measurement and the extent of this toxicity, by assessing bone health and prediction of fracture risk, are also required

Laser-wakefield accelerators as hard x-ray sources for 3D medical imaging of human bone

A bright μm-sized source of hard synchrotron x-rays (critical energy Ecrit > 30 keV) based on the betatron oscillations of laser wakefield accelerated electrons has been developed. The potential of this source for medical imaging was demonstrated by performing micro-computed tomography of a human femoral trabecular bone sample, allowing full 3D reconstruction to a resolution below 50 μm. The use of a 1 cm long wakefield accelerator means that the length of the beamline (excluding the laser) is dominated by the x-ray imaging distances rather than the electron acceleration distances. The source possesses high peak brightness, which allows each image to be recorded with a single exposure and reduces the time required for a full tomographic scan. These properties make this an interesting laboratory source for many tomographic imaging applications

Synchrotron imaging assessment of bone quality

Bone is a complex hierarchical structure and its principal function is to resist mechanical forces and fracture. Bone strength depends not only on the quantity of bone tissue but also on the shape and hierarchical structure. The hierarchical levels are interrelated, especially the micro-architecture, collagen and mineral components; hence analysis of their specific roles in bone strength and stiffness is difficult. Synchrotron imaging technologies including micro-CT and small/wide angle X-Ray scattering/diffraction are becoming increasingly popular for studying bone because the images can resolve deformations in the micro-architecture and collagen-mineral matrix under in situ mechanical loading. Synchrotron cannot be directly applied in-vivo due to the high radiation dose but will allow researchers to carry out systematic multifaceted studies of bone ex-vivo. Identifying characteristics of aging and disease will underpin future efforts to generate novel devices and interventional therapies for assessing and promoting healthy aging. With our own research work as examples, this paper introduces how synchrotron imaging technology can be used with in-situ testing in bone research

A new species of Dermopristis Kearn, Whittington & Evans-Gowing, 2010 (Monogenea: Microbothriidae), with observations on associations between the gut diverticula and reproductive system and on the presence of denticles in the nasal fossae of the host Glaucostegus typus (Bennett) (Elasmobranchii: Rhinobatidae)

Dermopristis cairae n. sp. (Microbothriidae) is described from the skin and possibly from the nasal fossae of the giant shovelnosed ray Glaucostegus typus (Bennett). The new species is distinguished from D. paradoxus Kearn, Whittington & Evans-Gowing, 2010 by its larger size, body shape, lack of transverse ridges on the ventral surface and absence of a seminal receptacle. Extensive short gut branches lie dorsal to the testes and adjacent to the coiled region of the vas deferens and the oo¨type, possibly reflecting high metabolic demand in these areas. Denticles are present in the lining of the nasal fossae of G. typus, providing a firm substrate for the cement-based attachment of a microbothriid. However, confirmation that D. cairae inhabits the nasal fossae of G. typus is required

A randomised comparison evaluating changes in bone mineral density in advanced prostate cancer: luteinising hormone-releasing hormone agonists versus transdermal oestradiol.

BACKGROUND: Luteinising hormone-releasing hormone agonists (LHRHa), used as androgen deprivation therapy (ADT) in prostate cancer (PCa) management, reduce serum oestradiol as well as testosterone, causing bone mineral density (BMD) loss. Transdermal oestradiol is a potential alternative to LHRHa. OBJECTIVE: To compare BMD change in men receiving either LHRHa or oestradiol patches (OP). DESIGN, SETTING, AND PARTICIPANTS: Men with locally advanced or metastatic PCa participating in the randomised UK Prostate Adenocarcinoma TransCutaneous Hormones (PATCH) trial (allocation ratio of 1:2 for LHRHa:OP, 2006-2011; 1:1, thereafter) were recruited into a BMD study (2006-2012). Dual-energy x-ray absorptiometry scans were performed at baseline, 1 yr, and 2 yr. INTERVENTIONS: LHRHa as per local practice, OP (FemSeven 100μg/24h patches). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 1-yr change in lumbar spine (LS) BMD from baseline compared between randomised arms using analysis of covariance. RESULTS AND LIMITATIONS: A total of 74 eligible men (LHRHa 28, OP 46) participated from seven centres. Baseline clinical characteristics and 3-mo castration rates (testosterone ≤1.7 nmol/l, LHRHa 96% [26 of 27], OP 96% [43 of 45]) were similar between arms. Mean 1-yr change in LS BMD was -0.021g/cm(3) for patients randomised to the LHRHa arm (mean percentage change -1.4%) and +0.069g/cm(3) for the OP arm (+6.0%; p<0.001). Similar patterns were seen in hip and total body measurements. The largest difference between arms was at 2 yr for those remaining on allocated treatment only: LS BMD mean percentage change LHRHa -3.0% and OP +7.9% (p<0.001). CONCLUSIONS: Transdermal oestradiol as a single agent produces castration levels of testosterone while mitigating BMD loss. These early data provide further supporting evidence for the ongoing phase 3 trial. PATIENT SUMMARY: This study found that prostate cancer patients treated with transdermal oestradiol for hormonal therapy did not experience the loss in bone mineral density seen with luteinising hormone-releasing hormone agonists. Other clinical outcomes for this treatment approach are being evaluated in the ongoing PATCH trial. TRIAL REGISTRATION: ISRCTN70406718, PATCH trial (ClinicalTrials.gov NCT00303784)

Discovering the constrained NMSSM with tau leptons at the LHC

The constrained Next-to-Minimal Supersymmetric Standard Model (cNMSSM) with mSugra-like boundary conditions at the GUT scale implies a singlino-like LSP with a mass just a few GeV below a stau NLSP. Hence, most of the squark/gluino decay cascades contain two tau leptons. The gluino mass >~ 1.2 TeV is somewhat larger than the squark masses of >~ 1 TeV. We simulate signal and background events for such a scenario at the LHC, and propose cuts on the transverse momenta of two jets, the missing transverse energy and the transverse momentum of a hadronically decaying tau lepton. This dedicated analysis allows to improve on the results of generic supersymmetry searches for a large part of the parameter space of the cNMSSM. The distribution of the effective mass and the signal rate provide sensitivity to distinguish the cNMSSM from the constrained Minimal Supersymmetric Standard Model in the stau-coannihilation region.Comment: 18 pages, 3 Figure

Neutron Electric Dipole Moment Constraint on Scale of Minimal Left-Right Symmetric Model

Using an effective theory approach, we calculate the neutron electric dipole moment (nEDM) in the minimal left-right symmetric model with both explicit and spontaneous CP violations. We integrate out heavy particles to obtain flavor-neutral CP-violating effective Lagrangian. We run the Wilson coefficients from the electroweak scale to the hadronic scale using one-loop renormalization group equations. Using the state-of-the-art hadronic matrix elements, we obtain the nEDM as a function of right-handed W-boson mass and CP-violating parameters. We use the current limit on nEDM combined with the kaon-decay parameter $\epsilon$ to provide the most stringent constraint yet on the left-right symmetric scale $M_{W_R} > (10 \pm 3)$ TeV.Comment: 20 pages and 8 figure

Brief Report: AIP Mutation in Pituitary Adenomas in the 18th Century and Today

From New England Journal of Medicine, Volume 364, issue 1, p.43-50. Copyright © (2011) Massachusetts Medical Society. Reprinted with permission.Gigantism results when a growth hormone–secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783,1-3 he noted an enlarged pituitary fossa. We extracted DNA from the patient’s teeth and identified a germline mutation in the aryl hydrocarbon–interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier