P. Gong et al. land-cover classification system as well as the International Geosphere-Biosphere Programme (IGBP) system. Using the four classification algorithms, we obtained the initial set of global land-cover maps. The SVM produced the highest overall classification accuracy (OCA) of 64.9% assessed with our test samples, with RF (59.8%), J4.8 (57.9%), and MLC (53.9%) ranked from the second to the fourth. We also estimated the OCAs using a subset of our test samples (8629) each of which represented a homogeneous area greater than 500 m × 500 m. Using this subset, we found the OCA for the SVM to be 71.5%. As a consistent source for estimating the coverage of global land-cover types in the world, estimation from the test samples shows that only 6.90% of the world is planted for agricultural production. The total area of cropland is 11.51% if unplanted croplands are included. The forests, grasslands, and shrublands cover 28.35%, 13.37%, and 11.49% of the world, respectively. The impervious surface covers only 0.66% of the world. Inland waterbodies, barren lands, and snow and ice cover 3.56%, 16.51%, and 12.81% of the world, respectively.
Abstract-Phenotypic modulation of vascular smooth muscle cells (VSMCs) plays a critical role in the pathogenesis of a variety of proliferative vascular diseases. Recently, we have found that microRNA (miRNA) miR-145 is the most abundant miRNA in normal vascular walls and in freshly isolated VSMCs; however, the role of miR-145 in VSMC phenotypic modulation and vascular diseases is currently unknown. Here we find that miR-145 is selectively expressed in VSMCs of the vascular wall and its expression is significantly downregulated in the vascular walls with neointimal lesion formation and in cultured dedifferentiated VSMCs.
Recently reported metamaterial analogues of electromagnetically induced transparency enable a unique route to endow classical optical structures with aspects of quantum optical systems. This method opens up many fascinating prospects on novel optical components, such as slow light units, highly sensitive sensors and nonlinear devices. In particular, optical control of electromagnetically induced transparency in metamaterials promises essential application opportunities in optical networks and terahertz communications. Here we present active optical control of metamaterial-induced transparency through active tuning of the dark mode. By integrating photoconductive silicon into the metamaterial unit cell, a giant switching of the transparency window occurs under excitation of ultrafast optical pulses, allowing for an optically tunable group delay of the terahertz light. This work opens up the possibility for designing novel chip-scale ultrafast devices that would find utility in optical buffering and terahertz active filtering.
Purpose Using gene-disrupted allogeneic T cells as universal effector cells provides an alternative to and potentially improves current chimeric antigen receptor (CAR) T cell therapy against cancers and infectious diseases. Experimental Design The CRISPR/Cas9 system has recently emerged as a simple and efficient way for multiplex genome engineering. By combining the lentiviral delivery of CAR and CRISPR RNA electroporation to co-introduce RNA encoding the Cas9 and gRNAs targeting endogenous TCR, beta-2 microglobulin (B2M) and PD1 simultaneously, to generate gene-disrupted allogeneic CAR T cells deficient of TCR, HLA class I molecule and PD1. Results The CRISPR gene-edited CAR T cells showed potent anti-tumor activities, both in vitro and in animal models and were as potent as non-gene edited CAR T cells. In addition the TCR and HLA class I double deficient T cells had reduced alloreactivity and did not cause graft-versus-host disease. Finally, simultaneous triple genome editing by adding the disruption of PD1 led to enhanced in vivo anti-tumor activity of the gene-disrupted CART cells. Conclusions Gene-disrupted allogeneic CAR and TCR T cells could provide an alternative as a universal donor to autologous T cells, which carry difficulties and high production costs. Gene-disrupted CAR and TCR T cells with disabled checkpoint molecules may be potent effector cells against cancers and infectious diseases.
BackgroundSirtuin 3 (SIRT3) is one of the seven mammalian sirtuins, which are homologs of the yeast Sir2 gene. SIRT3 is the only sirtuin with a reported association with the human life span. Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) plays important roles in adaptive thermogenesis, gluconeogenesis, mitochondrial biogenesis and respiration. PGC-1α induces several key reactive oxygen species (ROS)-detoxifying enzymes, but the molecular mechanism underlying this is not well understood.ResultsHere we show that PGC-1α strongly stimulated mouse Sirt3 gene expression in muscle cells and hepatocytes. Knockdown of PGC-1α led to decreased Sirt3 gene expression. PGC-1α activated the mouse SIRT3 promoter, which was mediated by an estrogen-related receptor (ERR) binding element (ERRE) (−407/−399) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that ERRα bound to the identified ERRE and PGC-1α co-localized with ERRα in the mSirt3 promoter. Knockdown of ERRα reduced the induction of Sirt3 by PGC-1α in C2C12 myotubes. Furthermore, Sirt3 was essential for PGC-1α-dependent induction of ROS-detoxifying enzymes and several components of the respiratory chain, including glutathione peroxidase-1, superoxide dismutase 2, ATP synthase 5c, and cytochrome c. Overexpression of SIRT3 or PGC-1α in C2C12 myotubes decreased basal ROS level. In contrast, knockdown of mSIRT3 increased basal ROS level and blocked the inhibitory effect of PGC-1α on cellular ROS production. Finally, SIRT3 stimulated mitochondrial biogenesis, and SIRT3 knockdown decreased the stimulatory effect of PGC-1α on mitochondrial biogenesis in C2C12 myotubes.ConclusionOur results indicate that Sirt3 functions as a downstream target gene of PGC-1α and mediates the PGC-1α effects on cellular ROS production and mitochondrial biogenesis. Thus, SIRT3 integrates cellular energy metabolism and ROS generation. The elucidation of the molecular mechanisms of SIRT3 regulation and its physiological functions may provide a novel target for treating ROS-related disease.
-MicroRNAs (miRNAs) comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate gene expression. Functionally, an individual miRNA is as important as a transcription factor because it is able to regulate the expression of its multiple target genes. Recently, miR-221 and miR-222 have been found to play a critical role in cancer cell proliferation. However, their roles in vascular smooth muscle cell (VSMC) biology are currently unknown.In the present study, the time course changes and cellular distribution of miR-221 and miR-222 expression were identified in rat carotid arteries after angioplasty, in which their expression was upregulated and localized in VSMCs in the injured vascular walls. In cultured VSMCs, miR-221 and miR-222 expression was increased by growth stimulators. Knockdown of miR-221 and miR-222 resulted in decreased VSMC proliferation in vitro. Using both gain-of-function and loss-of-function approaches, we found that p27(Kip1) and p57(Kip2) were 2 target genes that were involved in miR-221-and miR-222-mediated effect on VSMC growth. Finally, knockdown of miR-221 and miR-222 in rat carotid arteries suppressed VSMC proliferation in vivo and neointimal lesion formation after angioplasty. The results indicate that miR-221 and miR-222 are novel regulators for VSMC proliferation and neointimal hyperplasia. These findings may also represent promising therapeutic targets in proliferative vascular diseases. Key Words: microRNAs Ⅲ vascular smooth muscle cells Ⅲ gene regulation Ⅲ proliferation Ⅲ vascular disease R ecently, the most significant breakthrough regarding gene expression regulation has been the discovery of microRNAs (miRNAs). 1 miRNAs comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate gene expression via degradation or translational inhibition of their target mRNAs. [1][2][3][4][5] More importantly, one miRNA is able to regulate the expression of multiple genes because it can bind to its mRNA targets as either an imperfect or perfect complementarity. Thus, one miRNA is as functionally important as a transcription factor. 6 More than 700 miRNAs have been identified and sequenced in humans, 7 and the estimated number of miRNA genes is as high as 1000 in the human genome. 8 As a group, miRNAs may directly regulate at least 30% of the genes in the human genome. 9 It is not surprising that miRNAs are involved in the regulation of almost all major cellular functions, such as cell differentiation, proliferation/growth, mobility, and apoptosis. 1 For that reason, miRNAs could be the pivotal regulators in normal development and physiology and disease development, including cancer and cardiovascular disease. 10 -13 The biological function of an individual miRNA is cell specific. One miRNA may have different cellular effects on different cells. For example, miR-21 has an antiapoptotic effect on glioblastoma cells but increases Hela cell apoptosis. 14,15 Recent studies have revealed that miR-221 and miR-222 are upregulated in cancer cells....
Modern embedded computing systems tend to be heterogeneous in the sense of being composed of subsystems with very different characteristics, which communicate and interact in a variety of ways-synchronous or asynchronous, buffered or unbuffered, etc. Obviously, when designing such systems, a modeling language needs to reflect this heterogeneity. Today's modeling environments usually offer a variant of what we call amorphous heterogeneity to address this problem. This paper argues that modeling systems in this manner leads to unexpected and hard-to-analyze interactions between the communication mechanisms and proposes a more structured approach to heterogeneity, called hierarchical heterogeneity, to solve this problem. It proposes a model structure and semantic framework that support this form of heterogeneity, and discusses the issues arising from heterogeneous component interaction and the desire for component reuse. It introduces the notion of domain polymorphism as a way to address these issues.
Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies. In this strategy, the T cell genome is modified by integration of viral vectors or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells. Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient's second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient's CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.
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