In vivo axial loading of the mouse tibia

Noninvasive methods to apply controlled, cyclic loads to the living skeleton are used as anabolic procedures to stimulate new bone formation in adults and enhance bone mass accrual in growing animals. These methods are also invaluable for understanding bone signaling pathways. Our focus here is on a particular loading model: in vivo axial compression of the mouse tibia. An advantage of loading the tibia is that changes are present in both the cancellous envelope of the proximal tibia and the cortical bone of the tibial diaphysis. To load the tibia of the mouse axially in vivo, a cyclic compressive load is applied up to five times a week to a single tibia per mouse for a duration lasting from 1 day to 6 weeks. With the contralateral limb as an internal control, the anabolic response of the skeleton to mechanical stimuli can be studied in a pairwise experimental design. Here, we describe the key parameters that must be considered before beginning an in vivo mouse tibial loading experiment, including methods for in vivo strain gauging of the tibial midshaft, and then we describe general methods for loading the mouse tibia for an experiment lasting multiple days

Mice lacking substance P have normal bone modeling but diminished bone formation, increased resorption, and accelerated osteopenia with aging

Substance P (SP) is a sensory neuropeptide that is expressed by the neurons innervating bone. There is considerable evidence that SP can regulate bone cell function in vitro, but it is unclear whether SP modulates bone modeling or remodeling in vivo. To answer this question we characterized the bone phenotype of mice with deletion of the Tac1 gene expressing SP. The phenotypes of 2-month-old and 5-month-old SP deficient mice and their wildtype controls were characterized by using μCT imaging, static and dynamic bone histomorphometry, and urinary deoxypyridinoline cross-links (DPD) measurement. No differences in bone phenotypes were observed between the 2 strains at 2 months of age. By 5 months both the wildtype and SP deficient mice had developed cancellous osteopenia, but relative to the wild-type mice the SP deficient mice had significantly greater cancellous bone loss. The SP deficient mice also exhibited decreased bone formation, increased osteoclast number, and increased urinary DPD levels. Cortical defect early repair was delayed in 5-month-old mice lacking SP. Collectively, these findings indicate that SP signaling is not required for bone modeling, but SP signaling reduces age-related osteopenia and accelerates cortical defect reparation, data supporting the hypothesis that SP is an anabolic physiologic regulator of bone metabolism

Large Fluctuations in Anti-Coordination Games on Scale-Free Graphs

We study the influence of the complex topology of scale-free graphs on the dynamics of anti-coordination games (e.g. snowdrift games). These reference models are characterized by the coexistence (evolutionary stable mixed strategy) of two competing species, say 'cooperators' and 'defectors', and, in finite systems, by metastability and large-fluctuation-driven fixation. In this work, we use extensive computer simulations and an effective diffusion approximation (in the weak selection limit) to determine under which circumstances, depending on the individual-based update rules, the topology drastically affects the long-time behavior of anti-coordination games. In particular, we compute the variance of the number of cooperators in the metastable state and the mean fixation time when the dynamics is implemented according to the voter model (death-first/birth-second process) and the link dynamics (birth/death or death/birth at random). For the voter update rule, we show that the scale-free topology effectively renormalizes the population size and as a result the statistics of observables depend on the network's degree distribution. In contrast, such a renormalization does not occur with the link dynamics update rule and we recover the same behavior as on complete graphs

Novel Genetic Variants are Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SCL1A3 and EPHB2

Genome-wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta-analysis (n=15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta-analyses to determine associations with morphometric vertebral fracture (n=21,701) and clinical vertebral fracture (n=5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD-associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF]=3%) was associated with higher vBMD (β=0.22, p=1.9×10-8) and decreased risk of radiographic vertebral fracture (odds ratio [OR]=0.75; false discovery rate [FDR] p=0.01). In 1p36.12, rs12742784 (MAF=21%) was associated with higher vBMD (β=0.09, p=1.2×10-10) and decreased risk of clinical vertebral fracture (OR=0.82; FDR p=7.4×10-4). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β=0.28, FDR p=0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β=0.12, FDR p=1.7×10-3, functions in bone-related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence

Adventures in idealism; a personal record of the life of Professor Sabsovich,

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Hawking fragmentation and Hawking attenuation in Weyl semimetals

We study black and white hole analogues in Weyl semimetals with inhomogenous nodal tilts. We study how the presence of a microscopic lattice, giving rise to low-energy fermion doubler states at large momenta that are not present for elementary particles, affects the analogy between Weyl Hamiltonians and general relativity. Using a microscopic tight-binding lattice model, we find the doubler states to give rise to Hawking fragmentation and Hawking attenuation of wavepackets by the analogue event horizon. These phenomena depend on an analogue Hawking temperature, and can be measured in metamaterials and solids, as we confirm by numerical simulations.Comment: 12 pages, 6 figure

Propofol Infusion Syndrome: A Case of Increasing Morbidity With Traumatic Brain Injury

A previously healthy 16-year-old boy with a closed, severe traumatic brain injury was admitted to a surgical and trauma intensive care unit. He was given a continuous infusion of propofol for sedation and to control intracranial pressure. About 3 days after the propofol infusion was started, metabolic acidosis and rhabdomyolysis developed. Acute renal failure ensued as a result of the rhabdomyolysis. Tachycardia with wide QRS complexes developed without hyperkalemia. The patient died of refractory cardiac dysrhythmia and circulatory collapse approximately 36 hours after the first signs of propofol infusion syndrome appeared. Propofol infusion syndrome is a rare but frequently fatal complication in critically ill children who are given prolonged high-dose infusions of the drug. The syndrome is characterized by severe metabolic acidosis, rhabdomyolysis, acute renal failure, refractory myocardial failure, and hyperlipidemia. Despite several publications on the subject in the past decade, most cases still seem to remain undetectable.</jats:p