Mesenchymal stem cells (MSCs), a non-hematopoietic stem cell population first discovered in bone marrow, are multipotent cells capable of differentiating into mature cells of several mesenchymal ...tissues, such as fat and bone. As common progenitor cells of adipocytes and osteoblasts, MSCs are delicately balanced for their differentiation commitment. Numerous in vitro investigations have demonstrated that fat-induction factors inhibit osteogenesis, and, conversely, bone-induction factors hinder adipogenesis. In fact, a variety of external cues contribute to the delicate balance of adipo-osteogenic differentiation of MSCs, including chemical, physical, and biological factors. These factors trigger different signaling pathways and activate various transcription factors that guide MSCs to commit to either lineage. The dysregulation of the adipo-osteogenic balance has been linked to several pathophysiologic processes, such as aging, obesity, osteopenia, osteopetrosis, and osteoporosis. Thus, the regulation of MSC differentiation has increasingly attracted great attention in recent years. Here, we review external factors and their signaling processes dictating the reciprocal regulation between adipocytes and osteoblasts during MSC differentiation and the ultimate control of the adipo-osteogenic balance.
ABSTRACT
WRKY‐type transcription factors are involved in multiple aspects of plant growth, development and stress response. WRKY genes have been found to be responsive to abiotic stresses; however, ...their roles in abiotic stress tolerance are largely unknown especially in crops. Here, we identified stress‐responsive WRKY genes from wheat (Triticum aestivum L.) and studied their functions in stress tolerance. Forty‐three putative TaWRKY genes were identified and two multiple stress‐induced genes, TaWRKY2 and TaWRKY19, were further characterized. TaWRKY2 and TaWRKY19 are nuclear proteins, and displayed specific binding to typical cis‐element W box. Transgenic Arabidopsis plants overexpressing TaWRKY2 exhibited salt and drought tolerance compared with controls. Overexpression of TaWRKY19 conferred tolerance to salt, drought and freezing stresses in transgenic plants. TaWRKY2 enhanced expressions of STZ and RD29B, and bound to their promoters. TaWRKY19 activated expressions of DREB2A, RD29A, RD29B and Cor6.6, and bound to DREB2A and Cor6.6 promoters. The two TaWRKY proteins may regulate the downstream genes through direct binding to the gene promoter or via indirect mechanism. Manipulation of TaWRKY2 and TaWRKY19 in wheat or other crops should improve their performance under various abiotic stress conditions.
WRKY‐type transcription factors are involved in multiple aspects of plant growth and development. Their roles in abiotic stress tolerance are largely unknown especially in crops. Here, we find that TaWRKY2 and TaWRKY19 from wheat play differential roles in abiotic stress tolerance through activation of different downstream genes.
Multivariate failure time data are frequently analyzed using the marginal proportional hazards models and the frailty models. When the sample size is extraordinarily large, using either approach ...could face computational challenges. In this paper, we focus on the marginal model approach and propose a divide‐and‐combine method to analyze large‐scale multivariate failure time data. Our method is motivated by the Myocardial Infarction Data Acquisition System (MIDAS), a New Jersey statewide database that includes 73,725,160 admissions to nonfederal hospitals and emergency rooms (ERs) from 1995 to 2017. We propose to randomly divide the full data into multiple subsets and propose a weighted method to combine these estimators obtained from individual subsets using three weights. Under mild conditions, we show that the combined estimator is asymptotically equivalent to the estimator obtained from the full data as if the data were analyzed all at once. In addition, to screen out risk factors with weak signals, we propose to perform the regularized estimation on the combined estimator using its combined confidence distribution. Theoretical properties, such as consistency, oracle properties, and asymptotic equivalence between the divide‐and‐combine approach and the full data approach are studied. Performance of the proposed method is investigated using simulation studies. Our method is applied to the MIDAS data to identify risk factors related to multivariate cardiovascular‐related health outcomes.
CTCF and the associated cohesin complex play a central role in insulator function and higher-order chromatin organization of mammalian genomes. Recent studies identified a correlation between the ...orientation of CTCF-binding sites (CBSs) and chromatin loops. To test the functional significance of this observation, we combined CRISPR/Cas9-based genomic-DNA-fragment editing with chromosome-conformation-capture experiments to show that the location and relative orientations of CBSs determine the specificity of long-range chromatin looping in mammalian genomes, using protocadherin (Pcdh) and β-globin as model genes. Inversion of CBS elements within the Pcdh enhancer reconfigures the topology of chromatin loops between the distal enhancer and target promoters and alters gene-expression patterns. Thus, although enhancers can function in an orientation-independent manner in reporter assays, in the native chromosome context, the orientation of at least some enhancers carrying CBSs can determine both the architecture of topological chromatin domains and enhancer/promoter specificity. These findings reveal how 3D chromosome architecture can be encoded by linear genome sequences.
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•The orientation of Pcdh CBSs determines the direction of topological DNA looping•Directional CTCF binding to CBSs is crucial for loop topology and gene expression•The CTCF binding orientation functions similarly in β-globin and the whole genome•CTCF/cohesin-mediated directional DNA-looping determines chromosome architecture
The relative orientations of CTCF binding sites in enhancers and promoters determine the directionality of DNA looping and regulation of gene expression. The findings reveal how chromosome architecture is encoded by genome sequence and provoke thinking about how sequence orientation is functionally translated into a 3D genome.
Air pollution is a risk factor for cardiovascular diseases (CVD), but the underlying biological mechanisms are not well understood.
To determine whether markers related to CVD pathophysiological ...pathways (biomarkers for systemic inflammation and thrombosis, heart rate, and blood pressure) are sensitive to changes in air pollution.
Using a quasi-experimental opportunity offered by greatly restricted air pollution emissions during the Beijing Olympics, we measured pollutants daily and the outcomes listed below in 125 healthy young adults before, during, and after the 2008 Olympics (June 2-October 30). We used linear mixed-effects models to estimate the improvement in outcome levels during the Olympics and the anticipated reversal of outcome levels after pollution controls ended to determine whether changes in outcome levels were associated with changes in pollutant concentrations.
C-reactive protein (CRP), fibrinogen, von Willebrand factor, soluble CD40 ligand (sCD40L), soluble P-selectin (sCD62P) concentrations; white blood cell count (WBC); heart rate; and blood pressure.
Concentrations of particulate and gaseous pollutants decreased substantially (-13% to -60%) from the pre-Olympic period to the during-Olympic period. Using 2-sided tests conducted at the .003 level, we observed statistically significant improvements in sCD62P levels by -34.0% (95% CI, -38.4% to -29.2%; P < .001) from a pre-Olympic mean of 6.29 ng/mL to a during-Olympic mean of 4.16 ng/mL and von Willebrand factor by -13.1% (95% CI, -18.6% to -7.5%; P < .001) from 106.4% to 92.6%. After adjustments for multiple comparisons, changes in the other outcomes were not statistically significant. In the post-Olympic period when pollutant concentrations increased, most outcomes approximated pre-Olympic levels, but only sCD62P and systolic blood pressure were significantly worsened from the during-Olympic period. The fraction of above-detection-limit values for CRP (percentage ≥ 0.3 mg/L) was reduced from 55% in the pre-Olympic period to 46% in the during-Olympic period and reduced further to 36% in the post-Olympic period. Interquartile range increases in pollutant concentrations were consistently associated with statistically significant increases in fibrinogen, von Willebrand factor, heart rate, sCD62P, and sCD40L concentrations.
Changes in air pollution levels during the Beijing Olympics were associated with acute changes in biomarkers of inflammation and thrombosis and measures of cardiovascular physiology in healthy young persons. These findings are of uncertain clinical significance.
Background
This study evaluated the clinical characteristics, surgical procedures and prognosis of duodenal gastrointestinal stromal tumours (GISTs).
Methods
Patients with a diagnosis of primary ...duodenal GIST treated between January 2000 and December 2012 were analysed. Patients with gastric and small intestinal GISTs were chosen as control groups according to the following parameters: age, tumour size, mitotic index and adjuvant imatinib therapy. Operative procedures for patients with duodenal GIST included pancreaticoduodenectomy or limited resection. Disease‐free survival (DFS) was calculated using Kaplan–Meier analysis.
Results
Some 71 patients with duodenal, 71 with gastric and 70 with small intestinal GISTs were included in the study. DFS of patients with duodenal GIST was shorter than that of patients with gastric GIST (3‐year DFS 84 versus 94 per cent; hazard ratio (HR) 3.67, 95 per cent c.i. 1.21 to 11.16; P = 0.014), but was similar to that of patients with small intestinal GIST (3‐year DFS 84 versus 81 per cent; HR 0.75, 0.37 to 1.51; P = 0.491). Patients who underwent pancreaticoduodenectomy were older, and had larger tumours and a higher mitotic index than patients who had limited resection. The 3‐year DFS was 93 per cent among patients who had limited resection compared with 64 per cent for those who underwent PD (HR 0.18, 0.06 to 0.59; P = 0.001).
Conclusion
The prognosis of duodenal GISTs is similar to that of small intestinal GISTs.
Prognosis no different than for small bowel gastrointestinal stromal tumours
In order to implement radiotherapy based on a laser accelerator, it is necessary to precisely control the spatial distribution and energy spectrum of the proton beams to meet the requirements of the ...radiation dose distribution in the three-dimensional biological target. A compact laser plasma accelerator has been built at Peking University, which can reliably generate and transport MeV-energy protons with a specified energy onto the irradiation platform. In this paper, we discuss several technologies for the accurate control of a laser-accelerated proton beam with large divergence angle and broad energy spread, including the determination of the beam source position with micron accuracy, a tuning algorithm for the transport line which we refer to as “matching-image-point two-dimensional energy analysis” to realize accurate energy selection, and the control of beam distribution uniformity. In the prototype experiment with low energy protons and 0.5-Hz irradiation rate, a tailored energy deposition is demonstrated, which shows the potential feasibility of future irradiation based on laser-accelerated proton beams.
It has been shown that p53 has a critical role in the differentiation and functionality of various multipotent progenitor cells. P53 mutations can lead to genome instability and subsequent functional ...alterations and aberrant transformation of mesenchymal stem cells (MSCs). The significance of p53 in safeguarding our body from developing osteosarcoma (OS) is well recognized. During bone remodeling, p53 has a key role in negatively regulating key factors orchestrating the early stages of osteogenic differentiation of MSCs. Interestingly, changes in the p53 status can compromise bone homeostasis and affect the tumor microenvironment. This review aims to provide a unique opportunity to study the p53 function in MSCs and OS. In the context of loss of function of p53, we provide a model for two sources of OS: MSCs as progenitor cells of osteoblasts and bone tumor microenvironment components. Standing at the bone remodeling point of view, in this review we will first explain the determinant function of p53 in OS development. We will then summarize the role of p53 in monitoring MSC fidelity and in regulating MSC differentiation programs during osteogenesis. Finally, we will discuss the importance of loss of p53 function in tissue microenvironment. We expect that the information provided herein could lead to better understanding and treatment of OS.
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