[1] We present here a fully coupled global aerosol and chemistry model for the troposphere. The model is used to assess the interactions between aerosols and chemical oxidants in the troposphere, including (1) the conversion from gas-phase oxidants into the condensed phase during the formation of aerosols, (2) the heterogeneous reactions occurring on the surface of aerosols, and (3) the effect of aerosols on ultraviolet radiation and photolysis rates. The present study uses the global three-dimensional chemical/ transport model, Model for Ozone and Related Chemical Tracers, version 2 (MOZART-2), in which aerosols are coupled with the model. The model accounts for the presence of sulfate, soot, primary organic carbon, ammonium nitrate, secondary organic carbon, sea salt, and mineral dust particles. The simulated global distributions of the aerosols are analyzed and evaluated using satellite measurements (Moderate-Resolution Imaging Spectroradiometer (MODIS)) and surface measurements. The results suggest that in northern continental regions the tropospheric aerosol loading is highest in Europe, North America, and east Asia. Sulfate, organic carbon, black carbon, and ammonium nitrate are major contributions for the high aerosol loading in these regions. Aerosol loading is also high in the Amazon and in Africa. In these areas the aerosols consist primarily of organic carbon and black carbon. Over the southern high-latitude ocean (around 60°S), high concentrations of sea-salt aerosol are predicted. The concentration of mineral dust is highest over the Sahara and, as a result of transport, spread out into adjacent regions. The model and MODIS show similar geographical distributions of aerosol particles. However, the model overestimates the sulfate and carbonaceous aerosol in the eastern United States, Europe, and east Asia. In the region where aerosol loading is high, aerosols have important impacts on tropospheric ozone and other oxidants. The model suggests that heterogeneous reactions of HO 2 and CH 2 O on sulfate have an important impact on HO x (OH + HO 2 ) concentrations, while the heterogeneous reaction of O 3 on soot has a minor effect on O 3 concentrations in the lower troposphere. The heterogeneous reactions on dust have very important impacts on HO x and O 3 in the region of dust mobilization, where the reduction of HO x and O 3 concentrations can reach a maximum of 30% and 20%, respectively, over the Sahara desert. Dust, organic carbon, black carbon, and sulfate aerosols have important impacts on photolysis rates. For example, the photodissociation frequencies of ozone and nitrogen dioxide are reduced by 20% at the surface in the Sahara, in the Amazon, and in eastern Asia, leading to 5-20% reduction in the concentration of HO x and to a few percent change in the O 3 abundance in these regions.

Background Due to post-cleavage residence of the Cas9-sgRNA complex at its target, Cas9-induced DNA double-strand breaks (DSBs) have to be exposed to engage DSB repair pathways. Target interaction of Cas9-sgRNA determines its target binding affinity and modulates its post-cleavage target residence duration and exposure of Cas9-induced DSBs. This exposure, via different mechanisms, may initiate variable DNA damage responses, influencing DSB repair pathway choices and contributing to mutational heterogeneity in genome editing. However, this regulation of DSB repair pathway choices is poorly understood. Results In repair of Cas9-induced DSBs, repair pathway choices vary widely at different target sites and classical nonhomologous end joining (c-NHEJ) is not even engaged at some sites. In mouse embryonic stem cells, weakening the target interaction of Cas9-sgRNA promotes bias towards c-NHEJ and increases target dissociation and reduces target residence of Cas9-sgRNAs in vitro. As an important strategy for enhancing homology-directed repair, inactivation of c-NHEJ aggravates off-target activities of Cas9-sgRNA due to its weak interaction with off-target sites. By dislodging Cas9-sgRNA from its cleaved targets, DNA replication alters DSB end configurations and suppresses c-NHEJ in favor of other repair pathways, whereas transcription has little effect on c-NHEJ engagement. Dissociation of Cas9-sgRNA from its cleaved target by DNA replication may generate three-ended DSBs, resulting in palindromic fusion of sister chromatids, a potential source for CRISPR/Cas9-induced on-target chromosomal rearrangements. Conclusions Target residence of Cas9-sgRNA modulates DSB repair pathway choices likely through varying dissociation of Cas9-sgRNA from cleaved DNA, thus widening on-target and off-target mutational spectra in CRISPR/Cas9 genome editing.

OBJECT The aim of the present study was to retrospectively evaluate progressive correction of coronal and sagittal alignment and pelvic parameters in patients treated with a Chêneau brace. METHODS Thirty-two patients with adolescent idiopathic scoliosis (AIS) were assessed before initiation of bracing treatment and at the final follow-up. Each patient underwent radiological examinations, and coronal, sagittal, and pelvic parameters were measured. RESULTS No statistically significant modification of the Cobb angle was noted. The pelvic incidence remained unchanged in 59% of the cases and increased in 28% of the cases. The sacral slope decreased in 34% of the cases but remained unchanged in 50%. Thoracic kyphosis and lumbar lordosis were significantly decreased, whereas the sagittal vertical axis was significantly increased from a mean of -44.0 to -30.2 mm (p = 0.02). The mean pelvic tilt increased significantly from 4.5° to 8.3° (p = 0.002). CONCLUSIONS The Chêneau brace can be useful for preventing curvature progression in patients with AIS. However, the results of this study reveal high variability in the effect of brace treatment on sagittal and pelvic alignment. Treatment with the Chêneau brace may also influence sagittal global balance.

ObjectiveThis study aimed to conduct a systematic review of literature comparing the clinical effectiveness and safety between anterior reconstruction (AR) and posterior osteotomy (PO) in the treatment of Kümmell's disease with neurological deficits.MethodsWe systematically reviewed the literature in PubMed, EMBASE, Cochrane Database of Systematic Reviews, and the Web of Science for “spin*,” “surg*,” “Kümmell's disease,” “Kummell's disease,” “Kummell disease,” “vertebral osteonecrosis,” “vertebral pseudarthrosis,” “intravertebral vacuum cleft,” “delayed vertebral collapse,” and “compression fracture nonunion”. Quality was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation method.ResultsA total of 10 publications involving 268 Kümmell's disease patients with neurological deficits were included in this review, with 7 studies of low- or very low-quality. There were 37.7% and 62.3% of patients receiving AR and PO, respectively. For clinical outcomes, AR group showed no significant differences in pain, neurological dysfunction, and imaging outcome improvements compared with patients who underwent PO. However, the incidence of implant-related complications including loose screw, screw fracture, screw disconnection, and plate dislodgment, was higher in AR group compared with PO group (21.6% vs. 14.3%). As another major complication, AR group more often required a second surgery.ConclusionThis systematic review demonstrated that both AR and PO could improve pain, neurological dysfunction and imaging outcomes. However, serious comorbidities, multilevel corpectomies and/or severe osteoporosis highly required PO. Design discrepancies were found in the current studies, further higher-quality studies are warranted.Level of evidenceLevel III, therapeutic study.

Current pharmacological intervention for the treatment of osteolytic bone diseases such as osteoporosis focuses on the prevention of excessive osteoclastic bone resorption but does not enhance osteoblast‐mediated bone formation. In our study, we have shown that 4‐iodo‐6‐phenylpyrimidine (4‐IPP), an irreversible inhibitor of macrophage migration inhibitory factor (MIF), can inhibit receptor activator of NF‐κB ligand (RANKL)‐induced osteoclastogenesis and potentiate osteoblast‐mediated mineralization and bone nodule formation in vitro. Mechanistically, 4‐IPP inhibited RANKL‐induced p65 phosphorylation and nuclear translocation by preventing the interaction of MIF with thioredoxin‐interacting protein—p65 complexes. This led to the suppression of late osteoclast marker genes such as nuclear factor of activated T cells cytoplasmic 1, resulting in impaired osteoclast formation. In contrast, 4‐IPP potentiated osteoblast differentiation and mineralization also through the inhibition of the p65/NF‐κB signaling cascade. In the murine model of pathologic osteolysis induced by titanium particles, 4‐IPP protected against calvarial bone destruction. Similarly, in the murine model of ovariectomy‐induced osteoporosis, 4‐IPP treatment ameliorated the bone loss associated with estrogen deficiency by reducing osteoclastic activities and enhancing osteoblastic bone formation. Collectively, these findings provide evidence for the pharmacological targeting of MIF for the treatment of osteolytic bone disorders.—Zheng, L., Gao, J., Jin, K., Chen, Z., Yu, W., Zhu, K., Huang, W., Liu, F., Mei, L., Lou, C., He, D. Macrophage migration inhibitory factor (MIF) inhibitor 4‐IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF‐κB signaling pathway. FASEB J. 33, 7667–7683 (2019). http://www.fasebj.org

Menopause is associated with lumbar disc degeneration. The association occurred in the first 15 YSM, suggesting estrogen deficiency might be a risk factor of disc degeneration of the lumbar spine. Further studies need to be carried out for deciding whether age or menopause plays a more important role in the progression of disc degeneration in the lumbar spine.

Objective Identifying patients who meet selection criteria for clinical trials is typically challenging and time-consuming. In this article, we describe our clinical natural language processing (NLP) system to automatically assess patients’ eligibility based on their longitudinal medical records. This work was part of the 2018 National NLP Clinical Challenges (n2c2) Shared-Task and Workshop on Cohort Selection for Clinical Trials. Materials and Methods The authors developed an integrated rule-based clinical NLP system which employs a generic rule-based framework plugged in with lexical-, syntactic- and meta-level, task-specific knowledge inputs. In addition, the authors also implemented and evaluated a general clinical NLP (cNLP) system which is built with the Unified Medical Language System and Unstructured Information Management Architecture. Results and Discussion The systems were evaluated as part of the 2018 n2c2-1 challenge, and authors’ rule-based system obtained an F-measure of 0.9028, ranking fourth at the challenge and had less than 1% difference from the best system. While the general cNLP system didn’t achieve performance as good as the rule-based system, it did establish its own advantages and potential in extracting clinical concepts. Conclusion Our results indicate that a well-designed rule-based clinical NLP system is capable of achieving good performance on cohort selection even with a small training data set. In addition, the investigation of a Unified Medical Language System-based general cNLP system suggests that a hybrid system combining these 2 approaches is promising to surpass the state-of-the-art performance.

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