Estimating bone mass in children: can bone health index replace dual energy x-ray absorptiometry?

BACKGROUND: Bisphosphonates have been shown to increase metacarpal cortical width. Bone health index is computed from hand radiographs by measuring cortical thickness, width and length of the three middle metacarpals, and may potentially help predict fracture risk in children. OBJECTIVE: To compare bone health index with bone mineral density as measured from dual energy X-ray absorptiometry scans in patients with and without bisphosphonate treatment. MATERIALS AND METHODS: Two hundred ninety-three Caucasian patients (mean age: 11.5±3.7 years) were included. We documented absolute values and z-scores for whole-body less head and lumbar spine bone mineral density then correlated these with the bone health index, which were acquired on the same day, in different patient groups, depending on their ethnicity and diagnosis. RESULTS: Bone health index showed moderate to strong correlation with absolute values for whole-body (r=0.52) and lumbar spine (r=0.70) bone mineral density in those not treated with bisphosphonates and moderate correlation absolute values for whole-body (r=0.54) and lumber spine (r=0.51) bone mineral density for those treated with bisphosphonates. There was weak correlation of z-scores, ranging from r=0.11 to r=0.35 in both groups. CONCLUSION: The lack of a strong correlation between dual energy X-ray absorptiometry and bone health index suggests that they may be assessing different parameters

Decentralizing Inner-Product Functional Encryption

International audienceMulti-client functional encryption (MCFE) is a more flexible variant of functional encryption whose functional decryption involves multiple ciphertexts from different parties. Each party holds a different secret key and can independently and adaptively be corrupted by the adversary. We present two compilers for MCFE schemes for the inner-product functionality, both of which support encryption labels. Our first compiler transforms any scheme with a special key-derivation property into a decentralized scheme, as defined by Chotard et al. (ASIACRYPT 2018), thus allowing for a simple distributed way of generating functional decryption keys without a trusted party. Our second compiler allows to lift an unnatural restriction present in existing (decentralized) MCFE schemes, which requires the adversary to ask for a ciphertext from each party. We apply our compilers to the works of Abdalla et al. (CRYPTO 2018) and Chotard et al. (ASIACRYPT 2018) to obtain schemes with hitherto unachieved properties. From Abdalla et al., we obtain instantiations of DMCFE schemes in the standard model (from DDH, Paillier, or LWE) but without labels. From Chotard et al., we obtain a DMCFE scheme with labels still in the random oracle model, but without pairings

Evolutionary distances in the twilight zone -- a rational kernel approach

Phylogenetic tree reconstruction is traditionally based on multiple sequence alignments (MSAs) and heavily depends on the validity of this information bottleneck. With increasing sequence divergence, the quality of MSAs decays quickly. Alignment-free methods, on the other hand, are based on abstract string comparisons and avoid potential alignment problems. However, in general they are not biologically motivated and ignore our knowledge about the evolution of sequences. Thus, it is still a major open question how to define an evolutionary distance metric between divergent sequences that makes use of indel information and known substitution models without the need for a multiple alignment. Here we propose a new evolutionary distance metric to close this gap. It uses finite-state transducers to create a biologically motivated similarity score which models substitutions and indels, and does not depend on a multiple sequence alignment. The sequence similarity score is defined in analogy to pairwise alignments and additionally has the positive semi-definite property. We describe its derivation and show in simulation studies and real-world examples that it is more accurate in reconstructing phylogenies than competing methods. The result is a new and accurate way of determining evolutionary distances in and beyond the twilight zone of sequence alignments that is suitable for large datasets.Comment: to appear in PLoS ON

A Genome-Wide Analysis of Promoter-Mediated Phenotypic Noise in Escherichia coli

Gene expression is subject to random perturbations that lead to fluctuations in the rate of protein production. As a consequence, for any given protein, genetically identical organisms living in a constant environment will contain different amounts of that particular protein, resulting in different phenotypes. This phenomenon is known as “phenotypic noise.” In bacterial systems, previous studies have shown that, for specific genes, both transcriptional and translational processes affect phenotypic noise. Here, we focus on how the promoter regions of genes affect noise and ask whether levels of promoter-mediated noise are correlated with genes' functional attributes, using data for over 60% of all promoters in Escherichia coli. We find that essential genes and genes with a high degree of evolutionary conservation have promoters that confer low levels of noise. We also find that the level of noise cannot be attributed to the evolutionary time that different genes have spent in the genome of E. coli. In contrast to previous results in eukaryotes, we find no association between promoter-mediated noise and gene expression plasticity. These results are consistent with the hypothesis that, in bacteria, natural selection can act to reduce gene expression noise and that some of this noise is controlled through the sequence of the promoter region alon

Reconstructing the three-dimensional GABAergic microcircuit of the striatum

A system's wiring constrains its dynamics, yet modelling of neural structures often overlooks the specific networks formed by their neurons. We developed an approach for constructing anatomically realistic networks and reconstructed the GABAergic microcircuit formed by the medium spiny neurons (MSNs) and fast-spiking interneurons (FSIs) of the adult rat striatum. We grew dendrite and axon models for these neurons and extracted probabilities for the presence of these neurites as a function of distance from the soma. From these, we found the probabilities of intersection between the neurites of two neurons given their inter-somatic distance, and used these to construct three-dimensional striatal networks. The MSN dendrite models predicted that half of all dendritic spines are within 100 mu m of the soma. The constructed networks predict distributions of gap junctions between FSI dendrites, synaptic contacts between MSNs, and synaptic inputs from FSIs to MSNs that are consistent with current estimates. The models predict that to achieve this, FSIs should be at most 1% of the striatal population. They also show that the striatum is sparsely connected: FSI-MSN and MSN-MSN contacts respectively form 7% and 1.7% of all possible connections. The models predict two striking network properties: the dominant GABAergic input to a MSN arises from neurons with somas at the edge of its dendritic field; and FSIs are interconnected on two different spatial scales: locally by gap junctions and distally by synapses. We show that both properties influence striatal dynamics: the most potent inhibition of a MSN arises from a region of striatum at the edge of its dendritic field; and the combination of local gap junction and distal synaptic networks between FSIs sets a robust input-output regime for the MSN population. Our models thus intimately link striatal micro-anatomy to its dynamics, providing a biologically grounded platform for further study

Novel mutations in the VKORC1 gene of wild rats and mice – a response to 50 years of selection pressure by warfarin?

<p>Abstract</p> <p>Background</p> <p>Coumarin derivatives have been in world-wide use for rodent pest control for more than 50 years. Due to their retarded action as inhibitors of blood coagulation by repression of the vitamin K reductase (VKOR) activity, they are the rodenticides of choice against several species. Resistance to these compounds has been reported for rodent populations from many countries around the world and poses a considerable problem for efficacy of pest control.</p> <p>Results</p> <p>In the present study, we have sequenced the <it>VKORC1 </it>genes of more than 250 rats and mice trapped in anticoagulant-exposed areas from four continents, and identified 18 novel and five published missense mutations, as well as eight neutral sequence variants, in a total of 178 animals. Mutagenesis in <it>VKORC1 </it>cDNA constructs and their recombinant expression revealed that these mutations reduced VKOR activities as compared to the wild-type protein. However, the <it>in vitro </it>enzyme assay used was not suited to convincingly demonstrate the warfarin resistance of all mutant proteins</p> <p>Conclusion</p> <p>Our results corroborate the <it>VKORC1 </it>gene as the main target for spontaneous mutations conferring warfarin resistance. The mechanism(s) of how mutations in the <it>VKORC1 </it>gene mediate insensitivity to coumarins <it>in vivo </it>has still to be elucidated.</p

The Exhibition as an Experiment: An Analogy and its Implications

The analogy of the exhibition as an experiment suggests innovative curatorial approaches that challenge institutional practices. This analogy has however a historical precedence in modernism when itbecame paradigmatic of the exhibitions at the Museum of ModernArt in New York in the 1940s, defining the curatorial approach of its founding director Alfred J Barr. This article considers this early useof the analogy of the exhibition as an experiment and further reflects on its redefinition at the turn of the 20th century by examining how both the notions of the exhibition and of the experiment havechanged over time. In particular, the article examines the different meanings and practices inferred by the concepts of the exhibition and the experiment in the first decades of the 20th century and in the present. It outlines how correspondences between cultural and scientific paradigms can be deployed to tease unacknowledged synergies between two modes of knowledge production (i.e. the art exhibition and the experiment) and address questions of presentness, authority and legitimacy that they imply

Genome-wide pleiotropy and shared biological pathways for resistance to bovine pathogens

<div><p>Host genetic architecture is a major factor in resistance to pathogens and parasites. The collection and analysis of sufficient data on both disease resistance and host genetics has, however, been a major obstacle to dissection the genetics of resistance to single or multiple pathogens. A severe challenge in the estimation of heritabilities and genetic correlations from pedigree-based studies has been the confounding effects of the common environment shared among relatives which are difficult to model in pedigree analyses, especially for health traits with low incidence rates. To circumvent this problem we used genome-wide single-nucleotide polymorphism data and implemented the Genomic-Restricted Maximum Likelihood (G-REML) method to estimate the heritabilities and genetic correlations for resistance to 23 different infectious pathogens in calves and cows in populations undergoing natural pathogen challenge. Furthermore, we conducted gene-based analysis and generalized gene-set analysis to understand the biological background of resistance to infectious diseases. The results showed relatively higher heritabilities of resistance in calves than in cows and significant pleiotropy (both positive and negative) among some calf and cow resistance traits. We also found significant pleiotropy between resistance and performance in both calves and cows. Finally, we confirmed the role of the B-lymphocyte pathway as one of the most important biological pathways associated with resistance to all pathogens. These results both illustrate the potential power of these approaches to illuminate the genetics of pathogen resistance in cattle and provide foundational information for future genomic selection aimed at improving the overall production fitness of cattle.</p></div

The antioxidant enzyme peroxiredoxin-2 is depleted in lymphocytes seven days after ultra-endurance exercise

Purpose: Peroxiredoxin-2 (PRDX-2) is an antioxidant and chaperone-like protein critical for cell function. This study examined whether the levels of lymphocyte PRDX-2 are altered over one month following ultra-endurance exercise. Methods: Nine middle-aged men undertook a single-stage, multi-day 233 km (145 mile) ultra-endurance running race. Blood was collected immediately before (PRE), upon completion/retirement (POST), and following the race at DAY 1, DAY 7 and DAY 28. Lymphocyte lysates were examined for PRDX-2 by reducing SDS-PAGE and western blotting. In a sub-group of men who completed the race (n = 4) PRDX-2 oligomeric state (indicative of redox status) was investigated. Results: Ultra-endurance exercise caused significant changes in lymphocyte PRDX-2 (F (4,32) 3.409, p=0.020, ?(2) =0.299): seven-days after the race, PRDX-2 levels in lymphocytes had fallen to 30% of pre-race values (p=0.013) and returned to near-normal levels at DAY 28. Non-reducing gels demonstrated that dimeric PRDX-2 (intracellular reduced PRDX-2 monomers) was increased in 3 of 4 race completers immediately post-race, indicative of an "antioxidant response". Moreover, monomeric PRDX-2 was also increased immediately post-race in 2 of 4 race-completing subjects, indicative of oxidative damage, which was not detectable by DAY 7. Conclusions: Lymphocyte PRDX-2 was decreased below normal levels 7 days after ultra-endurance exercise. Excessive accumulation of reactive oxygen species induced by ultra-endurance exercise may underlie depletion of lymphocyte PRDX-2 by triggering its turnover after oxidation. Low levels of lymphocyte PRDX-2 could influence cell function and might, in part, explain reports of dysregulated immunity following ultra-endurance exercise