Future health implications of prenatal and early-life vitamin D status

Current or recent low vitamin D status (or proxy measures such as dietary intake or ambient ultraviolet radiation) is linked to several chronic diseases, including osteoporosis, cancers, and cardiovascular and autoimmune diseases. Low prenatal vitamin D status may also increase susceptibility to such diseases in later life via specific target organ effects and/or through changes to the developing immune system. Maternal vitamin D supplementation during pregnancy could be an important public health measure to decrease risk of a range of chronic diseases, but further research is required to clarify beneficial and adverse effects of high prenatal vitamin D.

PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate

The use of copper radioisotopes in cancer diagnosis and radionuclide therapy is possible using chelators that are capable of binding Cu(II) with sufficient stability in vivo to provide high tumour-to-background contrast. Here we report the design and synthesis of a new bifunctional chelator, 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar), that forms copper complexes of exceptional stability by virtue of a cage amine (sarcophagine) ligand and a new conjugate referred to as SarTATE, obtained by the conjugation of MeCOSar to the tumour-targeting peptide Tyr(3)-octreotate. Radiolabeling of SarTATE with (64)Cu(II), a radioisotope suitable for positron emission tomography (PET), was fast (~20 min), easily performed at room temperature and consistently resulted in high radiochemical purity (>99%). In vitro and in vivo evaluation of (64)CuSarTATE demonstrated its high selectivity for tumour cells expressing somatostatin receptor 2 (sstr2). Biodistribution and PET imaging comparisons were made between (64)CuSarTATE and (64)Cu-labeled DOTA-Tyr(3)-octreotate ((64)CuDOTATATE). Both radiopharmaceuticals showed excellent uptake in sstr2-positive tumours at 2 h post-injection. While tumour uptake of (64)CuDOTATATE decreased significantly at 24 h, (64)CuSarTATE activity was retained, improving contrast at later time points. (64)CuSarTATE accumulated less than (64)CuDOTATATE in the non-target organs, liver and lungs. The uptake of (64)CuSarTATE in the kidneys was high at 2 h but showed significant clearance by 24 h. The new chemistry and pre-clinical evaluation presented here demonstrates that MeCOSar is a promising bifunctional chelator for Tyr(3)-octreotate that could be applied to a combined imaging and therapeutic regimen using a combination of (64)Cu- and (67)CuSarTATE complexes, owing to improved tumour-to-non-target organ ratios compared to (64)CuDOTATATE at longer time points.

Drug bioactivation, covalent binding to target proteins and toxicity relevance

A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by nucleophilic substitution and/or Schiff's base mechanism. These drugs include analgesics (e.g., acetaminophen), antibacterial agents (e.g., sulfonamides and macrolide antibiotics), anticancer drugs (e.g., irinotecan), antiepileptic drugs (e.g., carbamazepine), anti-HIV agents (e.g., ritonavir), antipsychotics (e.g., clozapine), cardiovascular drugs (e.g., procainamide and hydralazine), immunosupressants (e.g., cyclosporine A), inhalational anesthetics (e.g., halothane), nonsteroidal anti-inflammatory drugs (NSAIDSs) (e.g., diclofenac), and steroids and their receptor modulators (e.g., estrogens and tamoxifen). Some herbal and dietary constituents are also bioactivated to reactive metabolites capable of binding covalently and inactivating cytochrome P450s (CYPs). A number of important target proteins of drugs have been identified by mass spectrometric techniques and proteomic approaches. The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity, and selective protein covalent binding by drug metabolites may lead to selective organ toxicity. However, the mechanisms involved in the protein adduct-induced toxicity are largely undefined, although it has been suggested that drug-protein adducts may cause toxicity either through impairing physiological functions of the modified proteins or through immune-mediated mechanisms. In addition, mechanism-based inhibition of CYPs may result in toxic drug-drug interactions. The clinical consequences of drug bioactivation and covalent binding to proteins are unpredictable, depending on many factors that are associated with the administered drugs and patients. Further studies using proteomic and genomic approaches with high throughput capacity are needed to identify the protein targetsof reactive drug metabolites, and to elucidate the structure-activity relationships of drug's covalent binding to proteins and their clinical outcomes.

Effects of approach velocity and foot-target characteristics on the visual regulation of step length

Two questions emerge from the literature concerning the perceptual-motor processes underlying the visual regulation of step length. The first concerns the effects of velocity on the onset of visual control (VCO), when visual regulation of step length begins during goal-directed locomotion. The second concerns the effects of different obstacles such as a target or raised surface on step length regulation. In two separate experiments, participants (Experiment 1 & 2: n=12, 6 female, 6 male) walked, jogged, or sprinted towards an obstacle along a 10 m walkway, consisting of two marker-strips with alternating black and white 0.50 m markings. Each experiment consisted of three targeting or obstacle tasks with the requirement to both negotiate and continue moving (run-through) through the target. Five trials were conducted for each task and approach speed, with trials block randomised between the six participants of each gender. One 50 Hz video camera panned and filmed each trial from an elevated position, adjacent to the walkway. Video footage was digitized to deduce the gait characteristics. Results for the targeting tasks indicate a linear relationship between approach velocity and accuracy of final foot placement (r=0.89). When foot placement was highly constrained by the obstacle step length shortened during the entire approach. VCO was found to occur at an earlier tau-margin for lower approach velocities for both experiments, indicating that the optical variable ‘tau' is affected by approach velocity. A three-phase kinematic profile was found for all tasks, except for the take-off board condition when sprinting. Further research is needed to determine whether this velocity affect on VCO is due to ‘whole-body' approach velocity or whether it is a function of the differences between gait modes.

Blaming the target of sexual harrassment: impact of gender role, sexist attitudes and work role.

This study was conducted to examine factors associated with blaming the target of sexual harassment. Participants' experiences of sexual harassment, sexist attitudes, gender, gender role identity, age, worker or student status, and belief in a just world were included as independent variables. Level of blame was evaluated using a series of 12 vignettes that manipulated the gender of the target and harasser as well as the seriousness of the harassing behavior. The sample comprised 30 female and 32 male workers from two workplaces, whose ages ranged from 18 to 65 (M = 35) years, and 102 female and 18 male university students whose ages ranged from 17 to 40 (M = 21) years. Approximately 70% of the sample were from Anglo Australian background, and 30% from European, Middle Eastern or Asian background. Females experienced more sexual harassment than males did, although the male rate was higher than expected. Although the majority of subjects attributed little blame to the target, males blamed the target of sexual harassment more than females did, and workers blamed the target of harassment more than university students did. Worker status, sexist attitudes, and gender significantly predicted blame for the total sample. Gender-typing increased the blame of the target by males but not by females. Attribution of blame was significantly influenced by worker versus student status, which supports the social psychological perspective that gender-related behavior is context dependent. The findings from this study suggest that organisational culture and environment influence respondents' attitudes to sexually harassing behavior.

The effects of target length on the visual control of step length for hard and soft impacts

Adjustments to gait were examined when positioning the foot within a narrow target at the end of an approach for two impact conditions, hard and soft. Participants (6 M, 6 F) ran toward a target of three lengths along a 10-m walkway consisting of two marker strips with alternating black and white 0.5-m markings. Five trials were conducted for each target length and impact task, with trials block randomized between the 6 participants of each gender. A 50-Hz digital video camera panned and filmed each trial from an elevated position adjacent to the walkway. Video footage was digitized to deduce the gait characteristics. A linear speed/accuracy tradeoff between target length and approach time was found for both impact tasks (hard, r = 0.99, p < 0.01; soft, r = 0.96, p < 0.05). For the hard-impact task, visual control time increased linearly (r = 0.99, p < 0.05) when whole-body approach velocity decreased. Visual control time was unaffected by whole-body approach velocity in the soft-impact task. A constant tau-margin of 1.08 describes the onset of visual control when approaching a target while running, with the control of braking during visual control described by a tau-dot of –0.85. Further research is needed to examine the control of braking in different targeting tasks.

Radar target tracking via robust linear filtering

In this letter, we provide a robust version of a linear Kalman filter for target tracking based on a measurement conversion technique on the nonlinear radar measurements. We prove that the state estimation error is bounded in a probabilistic sense. We compare our approach with the current state of the art in converted radar measurement-based linear filtering.

Optimality analysis of sensor-target geometries in Passive localization: Part 1 - bearing-only localization

In this paper we characterize the relative sensor-target geometry for bearing-only localization in R2. We analyze the geometry in terms of the Cramer-Rao inequality and the corresponding Fisher information matrix, aiming to characterize and state explicit results in terms of the potential localization performance. In particular, a number of interesting results are rigorously derived which highlight erroneous assumptions often made in the existing literature.

Optimality analysis of sensor-target geometries in passive localization: Part 2 - time-of-arrival based localization

In this paper we characterize the relative sensor-target geometry in R2 in terms of potential localization performance for time-of-arrival based localization. Our aim is to characterize those relative sensor-target geometries which minimize the relative Cramer-Rao lower bound.

Target tracking with range and bearing measurements via robust linear filtering

In this paper we provide a robust version of a linear Kalman filter for target tracking with nonlinear range and bearing measurements. Moreover, we prove that the state estimation error is bounded in a probabilistic sense. We compare our approach with the current state of the art in converted radar measurement based linear filtering.

Vision based target tracking using robust linear filtering

The use of perspective projection in tracking a target from a video stream involves nonlinear observations. The target dynamics, however, are modeled in Cartesian coordinates and result in a linear system. In this paper we provide a robust version of a linear Kalman filter and perform a measurement conversion technique on the nonlinear optical measurements. We show that our linear robust filter significantly outperforms the Extended Kalman Filter. Moreover, we prove that the state estimation error is bounded in a probabilistic sense.

A novel application of a microaccelerometer for target classification

This paper presents a novel method of target classification by means of a microaccelerometer. Its principle is that the seismic signals from moving vehicle targets are detected by a microaccelerometer, and targets are automatically recognized by the advanced signal processing method. The detection system based on the microaccelerometer is small in size, light in weight, has low power consumption and low cost, and can work under severe circumstances for many different applications, such as battlefield surveillance, traffic monitoring, etc. In order to extract features of seismic signals stimulated by different vehicle targets and to recognize targets, seismic properties of typical vehicle targets are researched in this paper. A technique of artificial neural networks (ANNs) is applied to the recognition of seismic signals for vehicle targets. An improved back propagation (BP) algorithm and ANN architecture have been presented to improve learning speed and avoid local minimum points in error curve. The improved BP algorithm has been used for classification and recognition of seismic signals of vehicle targets in the outdoor environment. Through experiments, it can be proven that target seismic properties acquired are correct, ANN is effective to solve the problem of classification and recognition of moving vehicle targets, and the microaccelerometer can be used in vehicle target recognition.

Minimising risks in IT outsourcing: choosing target services

This paper provides a risk-based framework for deciding on which IT services to outsource and which to keep in-house. This framework considers the probabilities both of negative outcomes, and of failing to achieve positive outcomes. The authors examine the major components of outsourcing risk and their drivers, and from this derive a series of questions decision-makers can ask when deciding what sourcing options to adopt for different services. The framework was developed on the basis of five years of qualitative and quantitative research into the experiences of organizations involved in outsourcing IT.