The Abnormal Phenotypes of Cartilage and Bone in Calcium-Sensing Receptor Deficient Mice Are Dependent on the Actions of Calcium, Phosphorus, and PTH

Patients with neonatal severe hyperparathyroidism (NSHPT) are homozygous for the calcium-sensing receptor (CaR) mutation and have very high circulating PTH, abundant parathyroid hyperplasia, and severe life-threatening hypercalcemia. Mice with homozygous deletion of CaR mimic the syndrome of NSHPT. To determine effects of CaR deficiency on skeletal development and interactions between CaR and 1,25(OH)2D3 or PTH on calcium and skeletal homeostasis, we compared the skeletal phenotypes of homozygous CaR–deficient (CaR−/−) mice to those of double homozygous CaR– and 1α(OH)ase–deficient [CaR−/−1α(OH)ase−/−] mice or those of double homozygous CaR– and PTH–deficient [CaR−/−PTH−/−] mice at 2 weeks of age. Compared to wild-type littermates, CaR−/− mice had hypercalcemia, hypophosphatemia, hyperparathyroidism, and severe skeletal growth retardation. Chondrocyte proliferation and PTHrP expression in growth plates were reduced significantly, whereas trabecular volume, osteoblast number, osteocalcin-positive areas, expression of the ALP, type I collagen, osteocalcin genes, and serum ALP levels were increased significantly. Deletion of 1α(OH)ase in CaR−/− mice resulted in a longer lifespan, normocalcemia, lower serum phosphorus, greater elevation in PTH, slight improvement in skeletal growth with increased chondrocyte proliferation and PTHrP expression, and further increases in indices of osteoblastic bone formation. Deletion of PTH in CaR−/− mice resulted in rescue of early lethality, normocalcemia, increased serum phosphorus, undetectable serum PTH, normalization in skeletal growth with normal chondrocyte proliferation and enhanced PTHrP expression, and dramatic decreases in indices of osteoblastic bone formation. Our results indicate that reductions in hypercalcemia play a critical role in preventing the early lethality of CaR−/− mice and that defects in endochondral bone formation in CaR−/− mice result from effects of the marked elevation in serum calcium concentration and the decreases in serum phosphorus concentration and skeletal PTHrP levels, whereas the increased osteoblastic bone formation results from direct effects of PTH

Deep learning with wearable based heart rate variability for prediction of mental and general health

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordData Availability: The data collected in this study resides in a secure network and access to data for further analysis would require further ethics approval due to the data containing sensitive participant information, but may be available upon request.The ubiquity and commoditisation of wearable biosensors (fitness bands) has led to a deluge of personal healthcare data, but with limited analytics typically fed back to the user. The feasibility of feeding back more complex, seemingly unrelated measures to users was investigated, by assessing whether increased levels of stress, anxiety and depression (factors known to affect cardiac function) and general health measures could be accurately predicted using heart rate variability (HRV) data from wrist wearables alone. Levels of stress, anxiety, depression and general health were evaluated from subjective questionnaires completed on a weekly or twice-weekly basis by 652 participants. These scores were then converted into binary levels (either above or below a set threshold) for each health measure and used as tags to train Deep Neural Networks (LSTMs) to classify each health measure using HRV data alone. Three data input types were investigated: time domain, frequency domain and typical HRV measures. For mental health measures, classification accuracies of up to 83% and 73% were achieved, with five and two minute HRV data streams respectively, showing improved predictive capability and potential future wearable use for tracking stress and well-being.Engineering and Physical Sciences Research Council (EPSRC

Bis(N-phenyl­ethane-1,2-diamine)dithio­cyanato­nickel(II)

The asymmetric unit of the title mononuclear NiII compound, [Ni(NCS)2(C8H12N2)2], contains two independent half-mol­ecules, the Ni atoms of which lie on crystallographic inversion centres. Each NiII ion is chelated by two N atoms from two N-phenyl­ethane-1,2-diamine ligands and is also coordinated by two N atoms from two thio­cyanate ligands, giving a distorted octa­hedral geometry. In the crystal, mol­ecules are linked into a two-dimensional network parallel to (100) by N—H⋯S inter­actions

Proteomic analysis of Artemisia annua – towards elucidating the biosynthetic pathways of the antimalarial pro-drug artemisinin

Background: MS-based proteomics was applied to the analysis of the medicinal plant Artemisia annua, exploiting a recently published contig sequence database (Graham et al. (2010) Science 327, 328–331) and other genomic and proteomic sequence databases for comparison. A. annua is the predominant natural source of artemisinin, the precursor for artemisinin-based combination therapies (ACTs), which are the WHO-recommended treatment for P. falciparum malaria. Results: The comparison of various databases containing A. annua sequences (NCBInr/viridiplantae, UniProt/ viridiplantae, UniProt/A. annua, an A. annua trichome Trinity contig database, the above contig database and another A. annua EST database) revealed significant differences in respect of their suitability for proteomic analysis, showing that an organism-specific database that has undergone extensive curation, leading to longer contig sequences, can greatly increase the number of true positive protein identifications, while reducing the number of false positives. Compared to previously published data an order-of-magnitude more proteins have been identified from trichome-enriched A. annua samples, including proteins which are known to be involved in the biosynthesis of artemisinin, as well as other highly abundant proteins, which suggest additional enzymatic processes occurring within the trichomes that are important for the biosynthesis of artemisinin. Conclusions: The newly gained information allows for the possibility of an enzymatic pathway, utilizing peroxidases, for the less well understood final stages of artemisinin’s biosynthesis, as an alternative to the known non-enzymatic in vitro conversion of dihydroartemisinic acid to artemisinin. Data are available via ProteomeXchange with identifier PXD000703

The Shear TEsting Programme 1: Weak lensing analysis of simulated ground-based observations

The Shear TEsting Programme, STEP, is a collaborative project to improve the accuracy and reliability of all weak lensing measurements in preparation for the next generation of wide-field surveys. In this first STEP paper we present the results of a blind analysis of simulated ground-based observations of relatively simple galaxy morphologies. The most successful methods are shown to achieve percent level accuracy. From the cosmic shear pipelines that have been used to constrain cosmology, we find weak lensing shear measured to an accuracy that is within the statistical errors of current weak lensing analyses, with shear measurements accurate to better than 7%. The dominant source of measurement error is shown to arise from calibration uncertainties where the measured shear is over or under-estimated by a constant multiplicative factor. This is of concern as calibration errors cannot be detected through standard diagnostic tests. The measured calibration errors appear to result from stellar contamination, false object detection, the shear measurement method itself, selection bias and/or the use of biased weights. Additive systematics (false detections of shear) resulting from residual point-spread function anisotropy are, in most cases, reduced to below an equivalent shear of 0.001, an order of magnitude below cosmic shear distortions on the scales probed by current surveys. Our results provide a snapshot view of the accuracy of current ground-based weak lensing methods and a benchmark upon which we can improve. To this end we provide descriptions of each method tested and include details of the eight different implementations of the commonly used Kaiser, Squires and Broadhurst (1995) method (KSB+) to aid the improvement of future KSB+ analyses

Measuring the impact and costs of a universal group based parenting programme : protocol and implementation of a trial

Background Sub-optimal parenting is a common risk factor for a wide range of negative health, social and educational outcomes. Most parenting programmes have been developed in the USA in the context of delinquency prevention for targeted or indicated groups and the main theoretical underpinning for these programmes is behaviour management. The Family Links Nurturing Programme (FLNP) focuses on family relationships as well as behaviour management and is offered on a universal basis. As a result it may be better placed to improve health and educational outcomes. Developed in the UK voluntary sector, FLNP is popular with practitioners, has impressed policy makers throughout the UK, has been found to be effective in before/after and qualitative studies, but lacks a randomised controlled trial (RCT) evidence base. Methods/Design A multi-centre, investigator blind, randomised controlled trial of the FLNP with a target sample of 288 south Wales families who have a child aged 2-4 yrs living in or near to Flying Start/Sure Start areas. Changes in parenting, parent child relations and parent and child wellbeing are assessed with validated measures immediately and at 6 months post intervention. Economic components include cost consequences and cost utility analyses based on parental ranking of states of quality of life. Attendance and completion rates and fidelity to the FLNP course delivery are assessed. A nested qualitative study will assess reasons for participation and non-participation and the perceived value of the programme to families. By the end of May 2010, 287 families have been recruited into the trial across four areas of south Wales. Recruitment has not met the planned timescales with barriers including professional anxiety about families entering the control arm of the trial, family concern about video and audio recording, programme facilitator concern about the recording of FLNP sessions for fidelity purposes and delays due to the new UK research governance procedures. Discussion Whilst there are strong theoretical arguments to support universal provision of parenting programmes, few universal programmes have been subjected to randomised controlled trials. In this paper we describe a RCT protocol with quantitative and qualitative outcome measures and an economic evaluation designed to provide clear evidence with regard to effectiveness and costs. We describe challenges implementing the protocol and how we are addressing these

Controlling the Electromagnetic Field Confinement with Metamaterials

The definition of a precise illumination region is essential in many applications where the electromagnetic field should be confined in some specific volume. By using conventional structures, it is difficult to achieve an adequate confinement distance (or volume) with negligible levels of radiation leakage beyond it. Although metamaterial structures and metasurfaces are well-known to provide high controllability of their electromagnetic properties, this feature has not yet been applied to solve this problem. We present a method of electromagnetic field confinement based on the generation of evanescent waves by means of metamaterial structures. With this method, the confinement volume can be controlled, namely, it is possible to define a large area with an intense field without radiation leakage. A prototype working in the microwave region has been implemented, and very good agreement between the measurements and the theoretical prediction of field distribution has been obtained