Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass. 相似文献
Female Genital mutilation/cutting (FGM/C) is associated with enduring psychiatric complications. In this study, we investigate the rates of co-morbid abuses and polyvictimization experienced by survivors of FGM/C. This is a sub-analysis of a cohort study examining the patient population at the EMPOWER Center for Survivors of Sex Trafficking and Sexual Violence in New York City. A retrospective chart-review of electronic medical records was conducted for all consenting adult patients who had FGM/C and had an intake visit between January 16, 2014 and March 6, 2020. Of the 80 participants, ages ranged from 20 to 62 years with a mean of 37.4 (SD?=?9.1) years. In addition to FGM/C, participants were victims of physical abuse (43; 53.8%), emotional abuse (35; 43.8%), sexual abuse (35; 43.8%), forced marriage (20; 25%), child marriage (13; 16.3%), and sex trafficking (1; 1.4%). There was a high degree of polyvictimization, with 41 (51.2%) experiencing 3 or more of the aforementioned abuses. Having FGM/C on or after age 13 or having a higher total abuse score was also found to be strong predictors of depression and PTSD. The high rates of polyvictimization among survivors of FGM/C are associated with development of depression and PTSD. Despite co-morbid abuses, patients still attribute substantial psychiatric symptoms to their FGM/C. Health care providers should understand the high risk of polyvictimization when caring for this patient population.
A priori subcell limiting approach is developed for high-order flux reconstruction/correction procedure via reconstruction (FR/CPR) methods on two-dimensional unstructured quadrilateral meshes. Firstly, a modified indicator based on
modal energy coefficients is proposed to detect troubled cells, where discontinuities
exist. Then, troubled cells are decomposed into nonuniform subcells and each subcell has one solution point. A second-order finite difference shock-capturing scheme
based on nonuniform nonlinear weighted (NNW) interpolation is constructed to perform the calculation on troubled cells while smooth cells are calculated by the CPR
method. Numerical investigations show that the proposed subcell limiting strategy on
unstructured quadrilateral meshes is robust in shock-capturing. 相似文献
BACKGROUND Postoperative liver failure is the most severe complication in cirrhotic patients with hepatocellular carcinoma(HCC) after major hepatectomy. Current available clinical indexes predicting postoperative residual liver function are not sufficiently accurate.AIM To determine a radiomics model based on preoperative gadoxetic acid-enhanced magnetic resonance imaging for predicting liver failure in cirrhotic patients with HCC after major hepatectomy.METHODS For this retrospective study, a radiomics-based model was developed based on preoperative hepatobiliary phase gadoxetic acid-enhanced magnetic resonance images in 101 patients with HCC between June 2012 and June 2018. Sixty-one radiomic features were extracted from hepatobiliary phase images and selected by the least absolute shrinkage and selection operator method to construct a radiomics signature. A clinical prediction model, and radiomics-based model incorporating significant clinical indexes and radiomics signature were built using multivariable logistic regression analysis. The integrated radiomics-based model was presented as a radiomics nomogram. The performances of clinical prediction model, radiomics signature, and radiomics-based model for predicting post-operative liver failure were determined using receiver operating characteristics curve, calibration curve, and decision curve analyses.RESULTS Five radiomics features from hepatobiliary phase images were selected to construct the radiomics signature. The clinical prediction model, radiomics signature, and radiomics-based model incorporating indocyanine green clearance rate at 15 min and radiomics signature showed favorable performance for predicting postoperative liver failure(area under the curve: 0.809-0.894). The radiomics-based model achieved the highest performance for predicting liver failure(area under the curve: 0.894; 95%CI: 0.823-0.964). The integrated discrimination improvement analysis showed a significant improvement in the accuracy of liver failure prediction when radiomics signature was added to the clinical prediction model(integrated discrimination improvement = 0.117, P =0.002). The calibration curve and an insignificant Hosmer-Lemeshow test statistic(P = 0.841) demonstrated good calibration of the radiomics-based model. The decision curve analysis showed that patients would benefit more from a radiomics-based prediction model than from a clinical prediction model and radiomics signature alone.CONCLUSION A radiomics-based model of preoperative gadoxetic acid–enhanced MRI can be used to predict liver failure in cirrhotic patients with HCC after major hepatectomy. 相似文献