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Comprehensive in scope, Aesthetic Orthognathic Surgery and Rhinoplasty presents orthognathic surgery from an aesthetic perspective, encompassing analysis, diagnosis, treatment, 3D virtual planning, and adjunctive procedures. * Easily accessible clinical information presented in a concise and approachable format * Well-illustrated throughout with more than1, 000 clinical photographs * Includes access to a companion website with videos of surgical procedures

Anthropogenic nitrogen inputs cause major negative environmental impacts, including emissions of the important greenhouse gas N₂O. Despite their importance, shifts in terrestrial N loss pathways driven by global change are highly uncertain. Here we present a coupled soil-atmosphere isotope model (IsoTONE) to quantify terrestrial N losses and N₂O emission factors from 1850-2020. We find that N inputs from atmospheric deposition caused 51% of anthropogenic N₂O emissions from soils in 2020. The mean effective global emission factor for N₂O was 4.3 ± 0.3% in 2020 (weighted by N inputs), much higher than the surface area-weighted mean (1.1 ± 0.1%). Climate change and spatial redistribution of fertilisation N inputs have driven an increase in global emission factor over the past century, which accounts for 18% of the anthropogenic soil flux in 2020. Predicted increases in fertilisation in emerging economies will accelerate N₂O-driven climate warming in coming decades, unless targeted mitigation measures are introduced.

Changes in baseline (here understood as representative of continental to hemispheric scales) tropospheric O3 concentrations that have occurred at northern mid-latitudes over the past six decades are quantified from available measurement records with the goal of providing benchmarks to which retrospective model calculations of the global O3 distribution can be compared. Eleven data sets (ten ground-based and one airborne) including six European (beginning in the 1950's and before), three North American (beginning in 1984) and two Asian (beginning in 1991) are analyzed. When the full time periods of the data records are considered a consistent picture emerges; O3 has increased at all sites in all seasons at approximately 1% yr−1 relative to the site's 2000 yr mixing ratio in each season. For perspective, this rate of increase sustained from 1950 to 2000 corresponds to an approximate doubling. There is little if any evidence for statistically significant differences in average rates of increase among the sites, regardless of varying length of data records. At most sites (most definitively at the European sites) the rate of increase has slowed over the last decade (possibly longer), to the extent that at present O3 is decreasing at some sites in some seasons, particularly in summer. The average rate of increase before 2000 shows significant seasonal differences (1.08 ± 0.09, 0.89 ± 0.10, 0.85 ± 0.11 and 1.21 ± 0.12% yr−1 in spring, summer, autumn and winter, respectively, over North America and Europe).

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent–offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10−11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

Premature fusion of the cranial sutures (craniosynostosis), affecting 1 in 2000 newborns, is treated surgically in infancy to prevent adverse neurologic outcomes. To identify mutations contributing to common non-syndromic midline (sagittal and metopic) craniosynostosis, we performed exome sequencing of 132 parent-offspring trios and 59 additional probands. Thirteen probands (7%) had damaging de novo or rare transmitted mutations in SMAD6, an inhibitor of BMP – induced osteoblast differentiation (p<10−20). SMAD6 mutations nonetheless showed striking incomplete penetrance (<60%). Genotypes of a common variant near BMP2 that is strongly associated with midline craniosynostosis explained nearly all the phenotypic variation in these kindreds, with highly significant evidence of genetic interaction between these loci via both association and analysis of linkage. This epistatic interaction of rare and common variants defines the most frequent cause of midline craniosynostosis and has implications for the genetic basis of other diseases. The bones in the front, back and sides of the human skull are not fused to one another at birth in order to allow the brain to double in size during the first year of life and continue growing into adulthood. However, one in 2,000 infants is born with a condition called craniosynostosis in which some of these bones have already fused. This fusion prevents the skull from growing properly, and can lead to the brain becoming compressed. As such, surgeons routinely undo the fusion in these infants to allow the brain and skull to grow normally. Eighty-five percent of craniosynostosis cases occur in infants with no other abnormalities, (called non-syndromic cases) and most have no other affected family member. It has therefore been unclear whether these infants have craniosynostosis due to a genetic or non-genetic cause. If the cause is genetic, it is also not clear whether a mutation in a single gene, the combined effects of many genes, or something in between is responsible. Now, by focusing on a group of 191 infants with premature fusion of bones joined at the midline of the skull, Timberlake et al. asked if any of the approximately 20,000 genes in the human genome were altered more frequently in these infants than would be expected by chance. This search revealed that rare mutations that disable one copy of a gene called SMAD6 in combination with a common DNA variant near another gene called BMP2 account for about 7% of infants with midline forms of craniosynostosis. These genes are both known to regulate how bones form, which explains how the mutation of these genes could lead to craniosynostosis. In all cases, the parents of these children were unaffected. This was typically because one parent had only the SMAD6 mutation while the other had only the common BMP2 variant; the transmission of both to their offspring resulted in craniosynostosis. The finding that a rare mutation’s effect is strongly modified by a common variant from another site in the genome is unprecedented. These findings will allow doctors to counsel families about the risk of having additional children with craniosynostosis. Timberlake et al. next plan to study more patients with craniosynostosis to identify additional genes that contribute to this disease. They will also look at other diseases to see whether the combination of rare mutation and common DNA variant could be behind other unexplained disorders.

We use ozone observations from sondes, regular aircraft, and alpine surface sites in a self‐consistent analysis to determine robust changes in the time evolution of ozone over Europe. The data are most coherent since 1998, with similar interannual variability and trends. Ozone has decreased slowly since 1998, with an annual mean trend of −0.15 ppb yr−1 at ∼3 km and the largest decrease in summer. There are some substantial differences between the sondes and other data, particularly in the early 1990s. The alpine and aircraft data show that ozone increased from late 1994 until 1998, but the sonde data do not. Time series of differences in ozone between pairs of locations reveal inconsistencies in various data sets. Differences as small as few ppb for 2–3 years lead to different trends for 1995–2008, when all data sets overlap. Sonde data from Hohenpeissenberg and in situ data from nearby Zugspitze show ozone increased by ∼1 ppb yr−1 during 1978–1989. We construct a mean alpine time series using data for Jungfraujoch, Zugspitze, and Sonnblick. Using Zugspitze data for 1978–1989, and the mean time series since 1990, we find that the ozone increased by 6.5–10 ppb in 1978–1989 and 2.5–4.5 ppb in the 1990s and decreased by 4 ppb in the 2000s in summer with no significant changes in other seasons. It is hard to reconcile all these changes with trends in emissions of ozone precursors, and in ozone in the lowermost stratosphere. We recommend data sets that are suitable for evaluation of model hindcasts. Key Points Small decrease or zero trend in tropospheric ozone over Europe since late 1990s Increases in ozone prior to late 1990s, but inconsistencies among data sets Difficult to reconcile trends before late 1990s with known influences on ozone

The identification of atmospheric trace species measurements that are representative of well-mixed background air masses is required for monitoring atmospheric composition change at background sites. We present a statistical method based on robust local regression that is well suited for the selection of background measurements and the estimation of associated baseline curves. The bootstrap technique is applied to calculate the uncertainty in the resulting baseline curve. The non-parametric nature of the proposed approach makes it a very flexible data filtering method. Application to carbon monoxide (CO) measured from 1996 to 2009 at the high-alpine site Jungfraujoch (Switzerland, 3580 m a.s.l.), and to measurements of 1,1-difluoroethane (HFC-152a) from Jungfraujoch (2000 to 2009) and Mace Head (Ireland, 1995 to 2009) demonstrates the feasibility and usefulness of the proposed approach. The determined average annual change of CO at Jungfraujoch for the 1996 to 2009 period as estimated from filtered annual mean CO concentrations is −2.2 ± 1.1 ppb yr−1. For comparison, the linear trend of unfiltered CO measurements at Jungfraujoch for this time period is −2.9 ± 1.3 ppb yr−1.

Vascularization of engineered bone tissue is critical for ensuring its survival after implantation. In vitro pre-vascularization of bone grafts with endothelial cells is a promising strategy to improve implant survival. In this study, we pre-cultured human smooth muscle cells (hSMCs) on bone scaffolds for 3 weeks followed by seeding of human umbilical vein endothelial cells (HUVECs), which produced a desirable environment for microvasculature formation. The sequential cell-seeding protocol was successfully applied to both natural (decellularized native bone, or DB) and synthetic (3D-printed Hyperelastic “Bone” scaffolds, or HB) scaffolds, demonstrating a comprehensive platform for developing natural and synthetic-based in vitro vascularized bone grafts. Using this sequential cell-seeding process, the HUVECs formed lumen structures throughout the DB scaffolds as well as vascular tissue bridging 3D-printed fibers within the HB. The pre-cultured hSMCs were essential for endothelial cell (EC) lumen formation within DB scaffolds, as well as for upregulating EC-specific gene expression of HUVECs grown on HB scaffolds. We further applied this co-culture protocol to DB scaffolds using a perfusion bioreactor, to overcome the limitations of diffusive mass transport into the interiors of the scaffolds. Compared with static culture, panoramic histological sections of DB scaffolds cultured in bioreactors showed improved cellular density, as well as a nominal increase in the number of lumen structures formed by ECs in the interior regions of the scaffolds. In conclusion, we have demonstrated that the sequential seeding of hSMCs and HUVECs can serve to generate early microvascular networks that could further support the in vitro tissue engineering of naturally or synthetically derived bone grafts and in both random (DB) and ordered (HB) pore networks. Combined with the preliminary bioreactor study, this process also shows potential to generate clinically sized, vascularized bone scaffolds for tissue and regenerative engineering.

Results from photooxidation of aromatic compounds in a reaction chamber show that a substantial fraction of the organic aerosol mass is composed of polymers. This polymerization results from reactions of carbonyls and their hydrates. After aging for more than 20 hours, about 50% of the particle mass consists of polymers with a molecular mass up to 1000 daltons. This results in a lower volatility of this secondary organic aerosol and a higher aerosol yield than a model using vapor pressures of individual organic species would predict.

Atmospheric carbon dioxide (CO 2) mole fractions were continuously measured from January 2009 to Decem-ber 2011 at four atmospheric observatories in China using cavity ring-down spectroscopy instruments. The stations are Lin'an (LAN), Longfengshan (LFS), Shangdianzi (SDZ), and Waliguan (WLG), which are regional (LAN, LFS, SDZ) or global (WLG) measurement stations of the World Meteorological Organization's Global Atmosphere Watch program (WMO/GAW). LAN is located near the megacity of Shang-hai, in China's economically most developed region. LFS is in a forest and rice production area, close to the city of Harbin in northeastern China. SDZ is located 150 km northeast of Beijing. WLG, hosting the longest record of measured CO 2 mole fractions in China, is a high-altitude site in northwestern China recording background CO 2 concentration. The CO 2 growth rates are 3.7 ± 1.2 ppm yr −1 for LAN, 2.7 ± 0.8 ppm yr −1 for LFS, 3.5 ± 1.6 ppm yr −1 for SDZ, and 2.2 ± 0.8 ppm yr −1 (1σ) for WLG during the period of 2009 to 2011. The highest annual mean CO 2 mole fraction of 404.2 ± 3.9 ppm was observed at LAN in 2011. A comprehensive analysis of CO 2 variations, their diurnal and seasonal cycles as well as the analysis of the influence of local sources on the CO 2 mole fractions allows a characterization of the sampling sites and of the key processes driving the CO 2 mole fractions. These data form a basis to improve our understanding of atmospheric CO 2 variations in China and the underlying fluxes using atmospheric inversion models.