Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption.

Osteoclasts are large multinucleated bone-resorbing cells formed by the fusion of monocyte/macrophage-derived precursors that are thought to undergo apoptosis once resorption is complete. Here, by intravital imaging, we reveal that RANKL-stimulated osteoclasts have an alternative cell fate in which they fission into daughter cells called osteomorphs. Inhibiting RANKL blocked this cellular recycling and resulted in osteomorph accumulation. Single-cell RNA sequencing showed that osteomorphs are transcriptionally distinct from osteoclasts and macrophages and express a number of non-canonical osteoclast genes that are associated with structural and functional bone phenotypes when deleted in mice. Furthermore, genetic variation in human orthologs of osteomorph genes causes monogenic skeletal disorders and associates with bone mineral density, a polygenetic skeletal trait. Thus, osteoclasts recycle via osteomorphs, a cell type involved in the regulation of bone resorption that may be targeted for the treatment of skeletal diseases.

Quantized Majorana conductance.

Majorana zero-modes-a type of localized quasiparticle-hold great promise for topological quantum computing. Tunnelling spectroscopy in electrical transport is the primary tool for identifying the presence of Majorana zero-modes, for instance as a zero-bias peak in differential conductance. The height of the Majorana zero-bias peak is predicted to be quantized at the universal conductance value of 2e2/h at zero temperature (where e is the charge of an electron and h is the Planck constant), as a direct consequence of the famous Majorana symmetry in which a particle is its own antiparticle. The Majorana symmetry protects the quantization against disorder, interactions and variations in the tunnel coupling. Previous experiments, however, have mostly shown zero-bias peaks much smaller than 2e2/h, with a recent observation of a peak height close to 2e2/h. Here we report a quantized conductance plateau at 2e2/h in the zero-bias conductance measured in indium antimonide semiconductor nanowires covered with an aluminium superconducting shell. The height of our zero-bias peak remains constant despite changing parameters such as the magnetic field and tunnel coupling, indicating that it is a quantized conductance plateau. We distinguish this quantized Majorana peak from possible non-Majorana origins by investigating its robustness to electric and magnetic fields as well as its temperature dependence. The observation of a quantized conductance plateau strongly supports the existence of Majorana zero-modes in the system, consequently paving the way for future braiding experiments that could lead to topological quantum computing.

Epitaxy of advanced nanowire quantum devices.

Semiconductor nanowires are ideal for realizing various low-dimensional quantum devices. In particular, topological phases of matter hosting non-Abelian quasiparticles (such as anyons) can emerge when a semiconductor nanowire with strong spin-orbit coupling is brought into contact with a superconductor. To exploit the potential of non-Abelian anyons-which are key elements of topological quantum computing-fully, they need to be exchanged in a well-controlled braiding operation. Essential hardware for braiding is a network of crystalline nanowires coupled to superconducting islands. Here we demonstrate a technique for generic bottom-up synthesis of complex quantum devices with a special focus on nanowire networks with a predefined number of superconducting islands. Structural analysis confirms the high crystalline quality of the nanowire junctions, as well as an epitaxial superconductor-semiconductor interface. Quantum transport measurements of nanowire 'hashtags' reveal Aharonov-Bohm and weak-antilocalization effects, indicating a phase-coherent system with strong spin-orbit coupling. In addition, a proximity-induced hard superconducting gap (with vanishing sub-gap conductance) is demonstrated in these hybrid superconductor-semiconductor nanowires, highlighting the successful materials development necessary for a first braiding experiment. Our approach opens up new avenues for the realization of epitaxial three-dimensional quantum architectures which have the potential to become key components of various quantum devices.

The Role of Suburbanization in Metropolitan Segregation After 1940.

The three decades from 1940 through 1970 mark a turning point in the spatial scale of Black-White residential segregation in the United States compared with earlier years. We decompose metropolitan segregation into three components: segregation within the city, within the suburbs, and between the city and its suburbs. We then show that extreme levels of segregation were well established in most cities by 1940, and they changed only modestly by 1970. In this period, changes in segregation were greater at the metropolitan scale, driven by racially selective population growth in the suburbs. We also examine major sources of rising segregation, including region, metropolitan total, and Black population sizes, and indicators of redlining in the central cities based on risk maps prepared by the Home Owners Loan Corporation (HOLC) in the late 1930s. In addition to overall regional differences, segregation between the city and suburbs and within suburbia increased more in metropolitan areas with larger Black populations, but this relationship was found only in the North. In contrast to some recent theorizing, there is no association between preparation of an HOLC risk map or the share of city neighborhoods that were redlined and subsequent change in any component of segregation.

Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

Movement and population dispersal of dolphinfish (Coryphaena hippurus) across the Eastern Tropical Pacific inferred from carbon and nitrogen stable isotope analyses.

The dolphinfish (Coryphaena hippurus) is a globally distributed marine predator that supports one of the most important coastal fisheries along the Eastern Tropical Pacific (ETP), but its spatial movements in this area are poorly understood. Stable isotope values (δ13 C and δ15 N) of white muscle from dolphinfish (n = 220) captured at different locations across the ETP (i.e., Mexico, Costa Rica, Ecuador, Peru and oceanic areas) were normalized to copepod baseline stable isotope values to estimate dolphinfish trophic position, movements and population dispersal. Movement or residence patterns were inferred from the difference in δ15 N values (Δ15 Ndolphinfish-copepod ‰) between copepods and dolphinfish muscle. Baseline corrected isotope values (δ13 Cdolphinfish-copepod and δ15 Ndolphinfish-copepod ) of dolphinfish muscle were used to estimate isotopic niche metrics and infer population dispersal across isoscapes. Values of δ13 C and δ15 N differed between juvenile and adult dolphinfish and across the ETP. Trophic position estimates ranged from 3.1 to 6.0 with a mean of 4.6. Adults and juveniles had similar trophic position estimates, whereas isotopic niche areas (SEA ‰2 ) of adults were greater relative to juveniles in every location. Adult dolphinfish showed "moderate movement by some individuals" in all locations based on Δ15 Ndolphinfish-copepod values, except for Costa Rica where adults were classified with "high degree of movement by some individuals" whereas juveniles showed "limited movement" in all areas except Mexico. Population dispersal based on Δ15 Ndolphinfish-copepod values showed "moderate" and "high" dispersal for adults and "no dispersal" for most juveniles, except for Mexico. This study provides insight into potential dolphinfish spatial mobility across an area of interest for multiple nations, which can help to improve stock assessments and management of the species.

The Clinical and Economic Burden of Tardive Dyskinesia in Israel: Real-World Data Analysis.

PURPOSE/BACKGROUND: Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by exposure to dopamine-receptor blockers. Data on TD burden in Israel are scarce. This analysis assesses the clinical and economic burden of TD in Israeli patients. METHODS/PROCEDURES: This retrospective analysis used a national health plan database (Maccabi Healthcare Services), representing 25% of the Israeli population. The study included adults alive at index date with an International Classification of Diseases, Ninth Revision, Clinical Modification TD diagnosis before 2018 and more than or equal to 1-year enrollment before diagnosis. Tardive dyskinesia patients were matched to non-TD patients (1:3) by underlying psychiatric condition, birth year, and sex. Treatment patterns and 2018 annual health care resource utilization and costs were assessed. FINDINGS/RESULTS: Of 454 TD patients alive between 2013 and 2018, 333 alive on January 1, 2018, were matched to 999 non-TD patients. At baseline, TD patients had lower socioeconomic status and higher proportion of chronic kidney disease and antipsychotic medication use; all analyses were adjusted accordingly. Tardive dyskinesia patients had significantly more visits to general physicians, neurologists, psychiatrists, physiotherapists, and emergency departments versus non-TD patients (all P < 0.05). Tardive dyskinesia patients also had significantly longer hospital stays than non-TD patients ( P = 0.003). Total healthcare and medication costs per patient were significantly higher in the TD versus non-TD population (US $11,079 vs US $7145, P = 0.018). IMPLICATIONS/CONCLUSIONS: Israeli TD patients have higher clinical and economic burden than non-TD patients. Understanding real-world health care resource utilization and costs allows clinicians and decision makers to quantify TD burden and prioritize resources for TD patients' treatment.

Broadbill swordfish (Xiphias gladius) foraging and vertical movements in the north-west Atlantic.

The northern edge of Georges Bank is an important seasonal foraging habitat for swordfish (Xiphias gladius) in the North Atlantic, where aggregations support commercial pelagic longline and harpoon fisheries. Following a period of overfishing during the 1990s, the North Atlantic X. gladius stock underwent a period of recovery during the early 2000s and was considered rebuilt in 2009. We analysed stomach contents from X. gladius (n = 39) harvested by the Canadian harpoon fishery on Georges Bank in 2007 to characterize diet in this important foraging habitat. We used electronic tagging data from X. gladius (n = 6) on Georges Bank in 2005-2007 to assess vertical habitat preferences and associated prey composition within those zones. We also used stable isotope analysis (δ13 C and δ15 N) of X. gladius liver (n = 2) and common prey types (Paralepididae, Myctophidae, Merluccidae, Ommastrephidae) as a longer-term record of feeding. Stomach contents were co-dominated by Paralepididae [31.9% weight (W)] and Ommastrephidae (36.8%W) with secondary contributions from hake (Merluccidae, 6.5%W), Myctophidae (2.9%W) and Sebastidae (2.1%W). X. gladius displayed diel vertical migrations, descending to depths of 300-400 m during daytime followed by residence in surface waters at night. X. gladius liver δ15 N values were similar to or lower than values of primary stomach contents, likely due to bias of diet consumed in southerly waters with lower nitrogen isotope baselines prior to arrival on Georges Bank. Diet data are similar to results from historical studies from the late 1950s to the early 1980s. This apparent temporal stability to the underlying food web in this region may explain the high X. gladius site fidelity observed in electronic tagging studies and the consistent aggregation of these fish to this region.

Improving Estimates of Neighborhood Change with Constant Tract Boundaries.

Social scientists routinely rely on methods of interpolation to adjust available data to their research needs. Spatial data from different sources often are based on different geographies that need to be reconciled, and some boundaries (e.g., administrative or political boundaries) change frequently. This study calls attention to the potential for substantial error in efforts to harmonize data to constant boundaries using standard approaches to areal and population interpolation. The case in point is census tract boundaries in the United States, which are redefined before every decennial census. Research on neighborhood effects and neighborhood change rely heavily on estimates of local area characteristics for a consistent area of time, for which they now routinely use estimates based on interpolation offered by sources such as the Neighborhood Change Data Base (NCDB) and Longitudinal Tract Data Base (LTDB). We identify a fundamental problem with how these estimates are created, and we reveal an alarming level of error in estimates of population characteristics in 2000 within 2010 boundaries. We do this by comparing estimates from one of these sources (the LTDB) to true values calculated by re-aggregating original 2000 census microdata to 2010 tract areas. We then demonstrate an alternative approach that allows the re-aggregated values to be publicly disclosed, using "differential privacy" (DP) methods to inject random noise that meets Census Bureau standards for protecting confidentiality of the raw data. We show that the DP estimates are considerably more accurate than the LTDB estimates based on interpolation, and we examine conditions under which interpolation is more susceptible to error. This study reveals cause for greater caution in the use of interpolated estimates from any source. Until and unless DP estimates can be publicly disclosed for a wide range of variables and years, research on neighborhood change should routinely examine data for signs of estimation error that may be substantial in a large share of tracts that experienced complex boundary changes.

Trends in tuna carbon isotopes suggest global changes in pelagic phytoplankton communities.

Considerable uncertainty remains over how increasing atmospheric CO2 and anthropogenic climate changes are affecting open-ocean marine ecosystems from phytoplankton to top predators. Biological time series data are thus urgently needed for the world's oceans. Here, we use the carbon stable isotope composition of tuna to provide a first insight into the existence of global trends in complex ecosystem dynamics and changes in the oceanic carbon cycle. From 2000 to 2015, considerable declines in δ13 C values of 0.8‰-2.5‰ were observed across three tuna species sampled globally, with more substantial changes in the Pacific Ocean compared to the Atlantic and Indian Oceans. Tuna recorded not only the Suess effect, that is, fossil fuel-derived and isotopically light carbon being incorporated into marine ecosystems, but also recorded profound changes at the base of marine food webs. We suggest a global shift in phytoplankton community structure, for example, a reduction in 13 C-rich phytoplankton such as diatoms, and/or a change in phytoplankton physiology during this period, although this does not rule out other concomitant changes at higher levels in the food webs. Our study establishes tuna δ13 C values as a candidate essential ocean variable to assess complex ecosystem responses to climate change at regional to global scales and over decadal timescales. Finally, this time series will be invaluable in calibrating and validating global earth system models to project changes in marine biota.

Comparing healthcare cost associated with the use of enzyme-inducing and non-enzyme active antiepileptic drugs in elderly patients with epilepsy in the UK: a long-term retrospective, matched cohort study.

BACKGROUND: In elderly patients (≥65 years of age) with epilepsy who take medications for comorbid conditions, some antiepileptic drugs (AEDs) may alter the metabolism of other treatments and increase the risk of adverse consequences and healthcare utilisation. This analysis compares healthcare costs associated with enzyme-inducing AEDs (EIAEDs) and non-enzyme active AEDs (nEAAEDs) use in elderly patients with epilepsy. METHODS: This retrospective matched cohort study used the Clinical Practice Research Datalink (CPRD) of UK primary care medical records, linked to the Hospital Episode Statistics (HES) database. Selected patients with epilepsy were ≥ 65 years and prescribed an EIAED or nEAAED between 2001 and 2010 (index) after ≥1 year without AEDs (baseline) and followed until the first occurrence of the following: end of HES data coverage, end of GP registration, or death; practice's up-to-standard status or addition of an AED belonging to another cohort or discontinuation of the last AED of that cohort. Propensity score matching reduced confounding factor effects between cohorts. Key outcomes included time to cohort treatment failure, time to index AED treatment failure, and direct healthcare costs in 2014 Pound Sterling (£) values. RESULTS: Overall, 1425 elderly patients were included: 964 with EIAEDs and 461 with nEAAEDs. At baseline, the EIAED cohort was older (mean age, 76.2 vs. 75.1 years) and a higher proportion were male. Baseline direct healthcare costs were similar. After matching (n = 210 each), and over the entire follow-up period, median monthly direct healthcare costs were higher for patients taking EIAEDs than nEAAEDs (£403 vs. £317; p = 0.0150, Mann-Whitney U). Costs were higher for patients remaining in the EIAED cohort after 3 follow-up years. The median time to cohort treatment failure for the EIAED cohort was 1110 days vs. 1175 days for the nEAAED cohort. CONCLUSION: Newly treated elderly patients with epilepsy were more likely to be prescribed EIAEDs than nEAAEDs. In matched cohorts, elderly patients with epilepsy treated with EIAEDs had higher average total direct and epilepsy-related healthcare costs than nEAAED-treated patients; this difference was greater than previously reported in the overall adult population. Changing treatment practices could improve patient care and reduce costs.

Income Segregation: Up or Down, and for Whom?

Reports of rising income segregation in the United States have been brought into question by the observation that post-2000 estimates are upwardly biased because of a reduction in the sample sizes on which they are based. Recent studies have offered estimates of this sample-count bias using public data. We show here that there are two substantial sources of systematic bias in estimating segregation levels: bias associated with sample size and bias associated with using weighted sample data. We rely on new correction methods using the original census sample data for individual households to provide more accurate estimates. Family income segregation rose markedly in the 1980s but only selectively after 1990. For some categories of families, segregation declined after 1990. There has been an upward trend for families with children but not specifically for families with children in the upper or lower 10% of the income distribution. Separate analyses by race/ethnicity show that income segregation was not generally higher among Blacks and Hispanics than among White families, and evidence of income segregation trends for these separate groups is mixed. Income segregation increased for all three racial groups for families with children, particularly for Hispanics (but not Whites or Blacks) in the upper 10% of the income distribution. Trends vary for specific combinations of race/ethnicity, presence of children, and location in the income distribution, offering new challenges for understanding the underlying processes of change.

Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo.

Thyroid hormone (TH) and TH receptors (TRs) α and ß act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRα and TRß, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding-defective TRß leads to disruption of the hypothalamic-pituitary-thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level.

Pharmacological Inhibition of NFκB Reduces Prostate Cancer Related Osteoclastogenesis In Vitro and Osteolysis Ex Vivo.

NFκB is implicated in cancer and bone remodelling, and we have recently reported that the verified NFκB inhibitor Parthenolide (PTN) reduced osteolysis and skeletal tumour growth in models of metastatic breast cancer. Here, we took advantage of in vitro and ex vivo bone cell and organ cultures to study the effects of PTN on the ability of prostate cancer cells and their derived factors to regulate bone cell activity and osteolysis. PTN inhibited the in vitro growth of a panel of human, mouse and rat prostate cancer cells in a concentration-dependent manner with a varying degree of potency. In prostate cancer cell-osteoclast co-cultures, the rat Mat-Ly-Lu, but not human PC3 or mouse RM1-BT, enhanced RANKL stimulated osteoclast formation and PTN reduced these effects without affecting prostate cancer cell viability. In the absence of cancer cells, PTN reduced the support of Mat-Ly-Lu conditioned medium for the adhesion and spreading of osteoclast precursors, and survival of mature osteoclasts. Pre-exposure of osteoblasts to PTN prior to the addition of conditioned medium from Mat-Ly-Lu cells suppressed their ability to support the formation of osteoclasts by inhibition of RANKL/OPG ratio. PTN enhanced the ability of Mat-Ly-Lu derived factors to increase calvarial osteoblast differentiation and growth. Ex vivo, PTN enhanced bone volume in calvaria organ-Mat-Ly-Lu cell co-culture, without affecting Mat-Ly-Lu viability or apoptosis. Mechanistic studies in osteoclasts and osteoblasts confirmed that PTN inhibit NFκB activation related to derived factors from Mat-Ly-Lu cells. Collectively, these findings suggest that pharmacological inhibition of the skeletal NFκB signalling pathway reduces prostate cancer related osteolysis, but further studies in the therapeutic implications of NFκB inhibition in cells of the osteoblastic lineage are needed.

Health care cost associated with the use of enzyme-inducing and non-enzyme-active antiepileptic drugs in the UK: a long-term retrospective matched cohort study.

BACKGROUND: Some antiepileptic drugs (AEDs) induce expression of hepatic enzymes. This can contribute to comorbidities via interference with metabolic pathways and concomitant drug metabolization, thereby increasing the likelihood of health care interventions. Using medical records, we compared the direct health care cost in patients initiating epilepsy therapy with enzyme-inducing AEDs (EIAEDs) vs non-enzyme-active AEDs (nEAAEDs) over up to 12 years. METHODS: Patients with untreated epilepsy were indexed in the UK Clinical Practice Research Datalink and Hospital Episode Statistics database when prescribed a new EIAED or nEAAED between January 2001 and December 2010. Propensity score matching reduced confounding factors between cohorts. Patients were followed until cohort treatment failure or data cut-off. The primary outcome was the median standardized monthly direct health care cost during follow-up in 2014 £GBP, calculated using published reference costs and compared using a Mann-Whitney U test. RESULTS: The unmatched EIAED cohort (n = 2752) was older (54 vs 46 years), more likely to be male, had more comorbidities, and higher health care resource use/cost during the 1-year pre-index period (median £3014 vs £2516) than the nEAAED cohort (n = 2,137). The most common index EIAED and nEAAED were carbamazepine (63.3%) and lamotrigine (58.0%), respectively. After matching, cohorts had similar features (n = 951 each). Over up to 12 years of follow-up, the median standardized monthly direct health care cost was £229 for the EIAED and £188 for the nEAAED cohorts (p = 0.0091). The median cost was higher for the EIAED cohort in every year of follow-up. In the two cohorts, 25.1% and 20.1% of total mean cost during follow-up was epilepsy-related, with approximately 4.6% and 3.0% for AED acquisition, respectively. The median time to cohort treatment failure was shorter in the matched EIAED cohort (468 vs 1194 days). CONCLUSIONS: Patients in the UK who initiated epilepsy therapy with an EIAED appeared to be at higher risk of complications associated with enzyme induction. In long-term matched cohort analyses, the median total direct health care cost associated with EIAED therapy was higher than with nEAAEDs. Changing current treatment practices could potentially improve patient outcomes and reduce costs.

Schools at the Rural-Urban Boundary - Blurring the Divide?

Schools mirror the communities in which they are located. Research on school inequality across the rural-urban spectrum tends to focus on the contrast between urban, suburban, and rural schools and glosses over the variation within these areas as well as the similarities between them. To address this gap and provide a richer description of the spatial distribution of educational inequality, we examine the school composition, achievement, and resources of all U.S. elementary schools in 2010-2011. We apply standard census definitions of what areas fall within central cities, the remainder of metropolitan regions, and in rural America. We then apply spatially explicit methods to reveal blurred boundaries and gradual gradients rather than sharp breaks at the edges of these zones. The results show high levels of variation within the suburbs and substantial commonality between rural and urban areas.