An engineering optimization method for distributed spaceborne InSAR formation configuration based on multiple constraints

The formation configuration design of the distributed spaceborne interferometric SAR is the key issue affects the DEM system performance. Combined with the practical engineering of TH-2 satellite, an optimal method of InSAR formation determination based on multi-engineering constraints is proposed. The relative movement of formation is introduced firstly, and the mathematical description of the engineering bounds is modeled; then by using an improved ant colony algorithm, the parameters of formation are finally achieved with safety function maximization. Through the simulation, it is proved that the formation obtained can not only meets all the constraints, but also has the passive safety. Moreover, the correctness and validity of this method has already been verified in the on-orbit experiments

Pharmacological inhibition of AKT activity in human CD34+ cells enhances their ability to engraft immunodeficient mice

Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplantation remains limited by the inability to expand functional HSCs ex vivo. To determine the role of phosphoinositide 3-kinase (PI3K)/AKT signaling in human hematopoietic stem and progenitor cell (HSPC) maintenance, we examined the effect of genetic and pharmacological inhibition of AKT on human umbilical cord blood (UCB) CD34+ cells. We found that knock-down of AKT1 in human UCB CD34+ cells using short interfering RNAs targeting AKT1 enhances their quiescence and colony formation potential in vitro. We treated human UCB CD34+ cells with an AKT-specific inhibitor (AKTi) and performed both in vitro and in vivo stem and progenitor cell assays. We found that ex vivo treatment of human HSPCs maintains CD34 expression and enhances colony formation in serial replating assays. Moreover, pharmacological inhibition of AKT enhances the short-term repopulating potential of human UCB CD34+ cells in immunodeficient mice. Mechanistically, genetic and pharmacological inhibition of AKT activity promotes human HSPC quiescence. These preclinical results suggest a positive role for AKTi during ex vivo culture of human UCB HSPCs

Exploration of the methods of establishing the minimum clinical important difference based on anchors and their applications in the quality of life measurement scale QLICP-BR (V2.0) for breast cancer

ObjectiveThe measurement of the quality of life (QOL) in patients with breast cancer can evaluate the therapeutic effects of medical treatments and help to provide reference for clinical decisions. The minimum clinically important difference (MCID) can be better used in clinical interpretation than the traditional statistical significance. Based on the anchors, a variety of ways including traditional and updated anchor-based methods were used to explore most suitable MCID, so that to find better interpretation on scores of the scale QLICP-BR(V2.0) (Quality of Life Instruments for Cancer Patients-Breast cancer).MethodsAccording to the investigation data of breast cancer patients before and after treatment, the most relevant indicators in various domains of QLICP-BR (V2.0) was found as an anchor to statistically analyze the value of MCID, and three analysis methods of anchors were used: Traditional anchor-based method, ROC curve method, multiple linear regression model analysis. Anchors are divided into four standards according to the degree of change in the treatment effect: one grade difference (Standard A), at least one grade difference (Standard B), one grade better (Standard C), better (Standard D). The final MCID value is selected from different statistical methods and classification standards that are most suitable for clinicians to use.ResultsUsing Q29 of the EORTC QLQ-C30 as an anchor has the highest correlation with each domain of QLICP. The order of magnitude of MCID values among the four standard groups is: standard A< Standard C< Standard B< Standard D. The MCID value obtained by the ROC curve method is the most stable and is least affected by the sample size, and the MCID value obtained by the multiple linear regression model is the least. After comparisons and discussions, Standard C in the multiple linear regression model is used to determine the final MCID, which is the closest to other methods. After integer the MCID values of Physical domain (PHD), Psychological domain (PSD), Social domain (SOD), Common symptoms and side effect domain (SSD), Core/general module (CGD), Specific domain (SPD), Total score(TOT) can be taken as 15,10, 10, 11, 10, 9 and 9, respectively.ConclusionIn the evaluation of the QOL of breast cancer patients, although the results of MCID values produced by different methods are different, the results are relatively close. The anchor-based methods make the results of MCID more clinically interpretable by introducing clinical variables, and clinicians and researchers can choose the appropriate method according to the research purpose

Necdin modulates leukemia-initiating cell quiescence and chemotherapy response

Acute myeloid leukemia (AML) is a devastating illness which carries a very poor prognosis, with most patients living less than 18 months. Leukemia relapse may occur because current therapies eliminate proliferating leukemia cells but fail to eradicate quiescent leukemia-initiating cells (LICs) that can reinitiate the disease after a period of latency. While we demonstrated that p53 target gene Necdin maintains hematopoietic stem cell (HSC) quiescence, its roles in LIC quiescence and response to chemotherapy are unclear. In this study, we utilized two well-established murine models of human AML induced by MLL-AF9 or AML1-ETO9a to determine the role of Necdin in leukemogenesis. We found that loss of Necdin decreased the number of functional LICs and enhanced myeloid differentiation in vivo, leading to delayed development of leukemia induced by MLL-AF9. Importantly, Necdin null LICs expressing MLL-AF9 were less quiescent than wild-type LICs. Further, loss of Necdin enhanced the response of MLL-AF9+ leukemia cells to chemotherapy treatment, manifested by decreased viability and enhanced apoptosis. We observed decreased expression of Bcl2 and increased expression of p53 and its target gene Bax in Necdin null leukemia cells following chemotherapy treatment, indicating that p53-dependent apoptotic pathways may be activated in the absence of Necdin. In addition, we found that loss of Necdin decreased the engraftment of AML1-ETO9a+ hematopoietic stem and progenitor cells in transplantation assays. However, Necdin-deficiency did not affect the response of AML1-ETO9a+ hematopoietic cells to chemotherapy treatment. Thus, Necdin regulates leukemia-initiating cell quiescence and chemotherapy response in a context-dependent manner. Our findings suggest that pharmacological inhibition of Necdin may hold potential as a novel therapy for leukemia patients with MLL translocations

Formation-maintaining control strategy for InSAR satellite

The control accuracy of distributed interferometric synthetic aperture radar satellite formation configuration maintenance is one of the key factors affecting the baseline length and thus the elevation measurement accuracy. According to the description and analysis of the relative orbital elements of formation dynamics, an unbiased four-pulse formation maintenance control method with independent in-plane and out-of-plane control is optimized and designed based on the traditional pulse control scheme. In particular, the coupling influence between relative orbital roots in the control process is compensated by combining with engineering practice, also the corresponding control strategy is formulated. The method has been applied to TH-2 system, and the correctness of the method has been proved by ground simulation and in-orbit data, so as to effectively ensure the expected distribution of interference baseline and provide guarantee for the smooth development of land elevation survey task

Protein Tyrosine Phosphatase PRL2 Mediates Notch and Kit Signals in Early T Cell Progenitors

The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow hematopoietic stem and progenitor cells (HSPCs) that continuously feed thymic progenitors remain largely unknown. While Notch signal is indispensable for T cell specification and differentiation, the downstream effectors are not well understood. PRL2, a protein tyrosine phosphatase that regulates hematopoietic stem cell proliferation and self-renewal, is highly expressed in murine thymocyte progenitors. Here we demonstrate that protein tyrosine phosphatase PRL2 and receptor tyrosine kinase c-Kit are critical downstream targets and effectors of the canonical Notch/RBPJ pathway in early T cell progenitors. While PRL2 deficiency resulted in moderate defects of thymopoiesis in the steady state, de novo generation of T cells from Prl2 null hematopoietic stem cells was significantly reduced following transplantation. Prl2 null HSPCs also showed impaired T cell differentiation in vitro. We found that Notch/RBPJ signaling upregulated PRL2 as well as c-Kit expression in T cell progenitors. Further, PRL2 sustains Notch-mediated c-Kit expression and enhances stem cell factor/c-Kit signaling in T cell progenitors, promoting effective DN1-DN2 transition. Thus, we have identified a critical role for PRL2 phosphatase in mediating Notch and c-Kit signals in early T cell progenitors

Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations