Assessing functional novelty of PSI structures via structure-function analysis of large and diverse superfamilies

The structural genomics initiatives have had as one of their aims to improve our understanding of protein function by providing representative structures for many structurally uncharacterised protein families. As suggested by the recent assessment of the Protein Structure Initiative (Structural Genomics Initiative, funded by the NIH), doubts have arisen as to whether Structural Genomics as initially planned were really beneficial to our understanding of biological issues, and in particular of protein function.
A few protein domain superfamilies have been shown to account for unexpectedly large numbers of proteins encoded in fully sequenced genomes. These large superfamilies are generally very diverse, spanning a wide range of functions, both in terms of molecular activities and biological processes. Some of these superfamilies, such as the Rossmann-fold P-loop nucleotide hydrolases or the TIM-barrel glycosidases, have been the subject of extensive structural studies which in turn have shed light on how evolution of the sequence and structure properties produce functional diversity amongst homologues. Recently, the Structure-Function Linkage Database (SFLD) has been setup with the aim of helping the study of structure-function correlations in such superfamilies. Since the evolutionary success of these large superfamilies suggests biological importance, several Structural Genomics Centers have focused on providing full structural coverage for representatives of all sequence families in these superfamilies.
In this work we evaluate structure/function diversity in a set of these large superfamilies and attempt to assess the quality and quantity of biological information gained from Structural Genomics.
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Vegetation analysis in the Laramie Basin, Wyoming from ERTS-1 imagery

The author has identified the following significant results. The application of ERTS-1 imagery to vegetation mapping and identification was tested and confirmed by field checking. ERTS-1 imagery interpretation and density contour mapping allows definition of minute vegetation features and estimation of vegetative biomass and species composition. Large- and small-scale vegetation maps were constructed for test areas in the Laramie Basin and Laramie mountains of Wyoming. Vegetative features reflecting grazing intensity, moisture availability, changes within the growing season, cutting of hay crops, and plant community constituents in forest and grassland are discussed and illustrated. Theoretical considerations of scattering, sun angle, slope, and instrument aperture upon image and map resolution were investigated. Future suggestions for applications of ERTS-1 data to vegetative analysis are included

High Speed Phase-Resolved 2-d UBV Photometry of the Crab pulsar

We report a phase-resolved photometric and morphological analysis of UBV data of the Crab pulsar obtained with the 2-d TRIFFID high speed optical photometer mounted on the Russian 6m telescope. By being able to accurately isolate the pulsar from the nebular background at an unprecedented temporal resolution (1 \mu s), the various light curve components were accurately fluxed via phase-resolved photometry. Within the $UBV$ range, our datasets are consistent with the existing trends reported elsewhere in the literature. In terms of flux and phase duration, both the peak Full Width Half Maxima and Half Width Half Maxima decrease as a function of photon energy. This is similarly the case for the flux associated with the bridge of emission. Power-law fits to the various light curve components are as follows; \alpha = 0.07 \pm 0.19 (peak 1), \alpha = -0.06 \pm 0.19 (peak 2) and \alpha = -0.44 \pm 0.19 (bridge) - the uncertainty here being dominated by the integrated CCD photometry used to independently reference the TRIFFID data. Temporally, the main peaks are coincident to \le 10 \mu s although an accurate phase lag with respect to the radio main peak is compromised by radio timing uncertainties. The plateau on the Crab's main peak was definitively determined to be \leq 55 \mu s in extent and may decrease as a function of photon energy. There is no evidence for non-stochastic activity over the light curves or within various phase regions, nor is there evidence of anything akin to the giant pulses noted in the radio. Finally, there is no evidence to support the existence of a reported 60 second modulation suggested to be as a consequence of free precession.Comment: 13 pages, 12 figures, accepted for publication in Astronomy & Astrophysic

Synchrotron X-ray microscopy of marine calcifiers: how plankton record past climate change

We have used STXM and PEEM to reveal the underpinning chemistry and nanoscale structure behind palaeo-climate geochemical signatures, such as trace Mg in shells- proposed proxies for palaeo-ocean temperature. This has allowed us to test the chemical assumptions and mechanisms underpinning the use of such empirical proxies. We have determined the control on driving chemical variations in biogenic carbonates using STXM at the absorption edge of Mg, B, and Na in the shells of modern plankton. The power of these observations lies in their ability to link changes in chemistry, microstructure, and growth process in biogenic carbonate to environmental influences. We have seen that such changes occur at length scales of tens of nanometres and demonstrated that STXM provides an invaluable route to understanding chemical environment and key heterogeneity at the appropriate length scale. This new understanding provides new routes for future measurements of past climate variation in the sea floor fossil record

Mechanical suppression of osteolytic bone metastases in advanced breast cancer patients: A randomised controlled study protocol evaluating safety, feasibility and preliminary efficacy of exercise as a targeted medicine

Background: Skeletal metastases present a major challenge for clinicians, representing an advanced and typically incurable stage of cancer. Bone is also the most common location for metastatic breast carcinoma, with skeletal lesions identified in over 80% of patients with advanced breast cancer. Preclinical models have demonstrated the ability of mechanical stimulation to suppress tumour formation and promote skeletal preservation at bone sites with osteolytic lesions, generating modulatory interference of tumour-driven bone remodelling. Preclinical studies have also demonstrated anti-cancer effects through exercise by minimising tumour hypoxia, normalising tumour vasculature and increasing tumoural blood perfusion. This study proposes to explore the promising role of targeted exercise to suppress tumour growth while concomitantly delivering broader health benefits in patients with advanced breast cancer with osteolytic bone metastases. Methods: This single-blinded, two-armed, randomised and controlled pilot study aims to establish the safety, feasibility and efficacy of an individually tailored, modular multi-modal exercise programme incorporating spinal isometric training (targeted muscle contraction) in 40 women with advanced breast cancer and stable osteolytic spinal metastases. Participants will be randomly assigned to exercise or usual medical care. The intervention arm will receive a 3-month clinically supervised exercise programme, which if proven to be safe and efficacious will be offered to the control-arm patients following study completion. Primary endpoints (programme feasibility, safety, tolerance and adherence) and secondary endpoints (tumour morphology, serum tumour biomarkers, bone metabolism, inflammation, anthropometry, body composition, bone pain, physical function and patient-reported outcomes) will be measured at baseline and following the intervention. Discussion: Exercise medicine may positively alter tumour biology through numerous mechanical and nonmechanical mechanisms. This randomised controlled pilot trial will explore the preliminary effects of targeted exercise on tumour morphology and circulating metastatic tumour biomarkers using an osteolytic skeletal metastases model in patients with breast cancer. The study is principally aimed at establishing feasibility and safety. If proven to be safe and feasible, results from this study could have important implications for the delivery of this exercise programme to patients with advanced cancer and sclerotic skeletal metastases or with skeletal lesions present in haematological cancers (such as osteolytic lesions in multiple myeloma), for which future research is recommended. Trial registration: anzctr.org.au, ACTRN-12616001368426. Registered on 4 October 2016

Using Administrative Data to Count Local Populations

There is growing evidence that official population statistics based on the decennial census are inaccurate at the local authority level—the fundamental administrative unit of the UK. This paper investigates the use of locally available administrative data sets for counting populations. The method uses truth tables for combining different data sources with different population coverage according to a defined and therefore replicable set of rules. The result is timelier and geographically more flexible data which is more cost-effective to produce than a survey-based census. Associated techniques for linking diverse data sources at individual and household level are briefly discussed. The methodology is then applied to administrative data from a London borough with about 170,000 people. The results are evaluated and compared with other population sources. The paper concludes by discussing potential improvements including scaling up the work to cover multiple local authorities. The practicalities of using alternative central government data sets are briefly considered. A sequel paper in this journal provides examples of key applications of this approach at local level

CATHEDRAL: A Fast and Effective Algorithm to Predict Folds and Domain Boundaries from Multidomain Protein Structures

We present CATHEDRAL, an iterative protocol for determining the location of previously observed protein folds in novel multidomain protein structures. CATHEDRAL builds on the features of a fast secondary-structure–based method (using graph theory) to locate known folds within a multidomain context and a residue-based, double-dynamic programming algorithm, which is used to align members of the target fold groups against the query protein structure to identify the closest relative and assign domain boundaries. To increase the fidelity of the assignments, a support vector machine is used to provide an optimal scoring scheme. Once a domain is verified, it is excised, and the search protocol is repeated in an iterative fashion until all recognisable domains have been identified. We have performed an initial benchmark of CATHEDRAL against other publicly available structure comparison methods using a consensus dataset of domains derived from the CATH and SCOP domain classifications. CATHEDRAL shows superior performance in fold recognition and alignment accuracy when compared with many equivalent methods. If a novel multidomain structure contains a known fold, CATHEDRAL will locate it in 90% of cases, with <1% false positives. For nearly 80% of assigned domains in a manually validated test set, the boundaries were correctly delineated within a tolerance of ten residues. For the remaining cases, previously classified domains were very remotely related to the query chain so that embellishments to the core of the fold caused significant differences in domain sizes and manual refinement of the boundaries was necessary. To put this performance in context, a well-established sequence method based on hidden Markov models was only able to detect 65% of domains, with 33% of the subsequent boundaries assigned within ten residues. Since, on average, 50% of newly determined protein structures contain more than one domain unit, and typically 90% or more of these domains are already classified in CATH, CATHEDRAL will considerably facilitate the automation of protein structure classification

RESPOND – A patient-centred program to prevent secondary falls in older people presenting to the emergency department with a fall: Protocol for a multi-centre randomised controlled trial

Introduction: Participation in falls prevention activities by older people following presentation to the Emergency Department (ED) with a fall is suboptimal. This randomised controlled trial (RCT) will test the RESPOND program which is designed to improve older persons’ participation in falls prevention activities through delivery of patient-centred education and behaviour change strategies. Design and setting: An RCT at two tertiary referral EDs in Melbourne and Perth, Australia. Participants: Five-hundred and twenty eight community-dwelling people aged 60-90 years presenting to the ED with a fall and discharged home will be recruited. People who: require an interpreter or hands-on assistance to walk; live in residential aged care or >50 kilometres from the trial hospital; have terminal illness, cognitive impairment, documented aggressive behaviour or history of psychosis; are receiving palliative care; or are unable to use a telephone will be excluded. Methods: Participants will be randomly allocated to the RESPOND intervention or standard care control group. RESPOND incorporates: (1) home-based risk factor assessment; (2) education, coaching, goal setting, and follow-up telephone support for management of one or more of four risk factors with evidence of effective intervention; and (3) healthcare provider communication and community linkage delivered over six months. Primary outcomes are falls and fall injuries per-person-year. Discussion: RESPOND builds on prior falls prevention learnings and aims to help individuals make guided decisions about how they will manage their falls risk. Patient-centred models have been successfully trialled in chronic and cardiovascular disease however evidence to support this approach in falls prevention is limited. Trial registration. The protocol for this study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12614000336684)