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UTX/KDM6A, a histone H3K27 demethylase and a key component of the COMPASS complex, is frequently lost or mutated in cancer; however, its tumor suppressor function remains largely uncharacterized in multiple myeloma (MM). Here, we show that the conditional deletion of the X-linked Utxin germinal center (GC) derived cells collaborates with the activating BrafV600Emutation and promotes induction of lethal GC/post-GC B cell malignancies with MM-like plasma cell neoplasms being the most frequent. Mice that developed MM-like neoplasms showed expansion of clonal plasma cells in the bone marrow and extramedullary organs, serum M proteins, and anemia. Add-back of either wild-type UTXor a series of mutants revealed that cIDR domain, that forms phase-separated liquid condensates, is largely responsible for the catalytic activity-independent tumor suppressor function of UTX in MM cells. Utxloss in concert with BrafV600Eonly slightly induced MM-like profiles of transcriptome, chromatin accessibility, and H3K27 acetylation, however, it allowed plasma cells to gradually undergo full transformation through activation of transcriptional networks specific to MM that induce high levels of Mycexpression. Our results reveal a tumor suppressor function of UTX in MM and implicate its insufficiency in the transcriptional reprogramming of plasma cells in the pathogenesis of MM.

• Hot extrusion reduces grain sizes and simultaneously accelerates precipitation. • Pre-existing dislocation slips and hierarchical precipitates cause high strength. • Interaction among dislocations, stacking faults, and twins ensures acceptable ductility. Annealing-regulated precipitation strengthening combined with cold-working is one of the most efficient strategies for resolving the conflict between strength and ductility in metals and alloys. However, precipitation control and grain refinement are mutually contradictory due to the excellent phase stability of multicomponent alloys. This work utilizes the high-temperature extrusion and annealing to optimize the microstructures and mechanical properties of the Co 34 Cr 32 Ni 27 Al 3.5 Ti 3.5 multicomponent alloy. Hot extrusion effectively reduces grain sizes and simultaneously accelerates the precipitation of coherent L1 2 nanoparticles inside the face-centered cubic (FCC) matrix and grain boundary precipitations (i.e., submicron Cr-rich particles and L1 2 -Ni 3 (Ti, Al) precipitates), resulting in strongly reciprocal interaction between dislocation slip and hierarchical-scale precipitates. Subsequent annealing regulates grain sizes, dislocations, twins, and precipitates, further allowing to tailor mechanical properties. The high yield strength is attributed to the coupled precipitation strengthening effects from nanoscale coherent L1 2 particles inside grains and submicron grain boundary precipitates under the support of pre-existing dislocations. The excellent ductility results from the synergistic activation of dislocations, stacking faults, and twins during plastic deformation. The present study provides a promising approach for regulating microstructures, especially defects, and enhancing the mechanical properties of multicomponent alloys. [ABSTRACT FROM AUTHOR]

The L12-strengthened Co34Cr32Ni27Al4Ti3medium-entropy alloy (MEA) with precipitations of grain boundaries has been developed through selective laser melting (SLM) followed by cold rolling and annealing, exhibiting excellent strength-ductility synergy. The as-printed alloy exhibits low yield strength (YS) of ~ 384 MPa, ultimate tensile strength (UTS) of ~ 453 MPa, and uniform elongation (UE) of 1.5% due to the existence of the SLM-induced defects. After cold rolling and annealing, the YS, UTS, and UE are significantly increased to ~ 739 MPa, ~ 1230 MPa, and ~ 47%, respectively. This enhancement primarily originates from the refined grain structure induced by cold rolling and annealing. The presence of coherent spherical γ' precipitates (L12phases) and Al/Ti-rich precipitates at the grain boundaries, coupled with increased lattice defects such as dislocations, stacking faults, and ultrafine deformation twins, further contribute to the property’s improvement. Our study highlights the potential of SLM in producing high-strength and ductile MEA with coherent L12nanoprecipitates, which can be further optimized through subsequent rolling and annealing processes. These findings offer valuable insights for the development of high-performance alloys for future engineering applications.

ABSTRACTLiver injury from any number of causes (e.g. chemical material, drugs and diet, viral infection) is a global health problem, and its mechanism is not clearly understood. MicroRNAs (miRNAs) expression profiling is gaining popularity because miRNAs, as key regulators in gene expression networks, can influence many biological processes and have also shown promise as biomarkers for disease. Previous studies reported the regulation effects of miRNAs in liver injury, whereas function and molecular mechanisms of miR-322-5p were still unclear. Therefore, our study focused on the biological role of miR-322-5p in carbon tetrachloride (CCl4)-induced liver injury proliferation, apoptosis, and cell cycle. A mouse model of CCl4-induced liver injury was established, and the transcriptomes and miRNAs transcriptomes of 2d and 5d liver tissues after injury were sequenced. The expression of miR-322-5p and the cell cycle genes were detected in liver tissues and Hepa1-6 cell line by miRNA RT-PCR, qRT-PCR. The effects of miR-322-5p on liver cell proliferation, cell cycle and apoptosis were evaluated using MTS assays and flow cytometry analysis. The relationship between miR-322-5p and Wee1 was predicted and confirmed by bioinformatics analysis and a dual luciferase reporter assay. Functional experiments, including an MTS assay and flow cytometric analysis, were performed to study the effects of Wee1. MiR-322-5p was upregulated in injury liver tissues, and downregulated miR-322-5p was proved to inhibit proliferation, apoptosis and arrest cell cycle at G2/M in vitro. The dual-luciferase reporter assay results indicated that miR-322-5p has a binding site at position 285 in the Wee1 3´UTR. The effects of miR-322-5p in proliferation and cell cycle regulation can be abolished by Wee1 through rescue experiments. By directly targeting Wee1 influenced the expression of several cell cycle factors, including Cyclin dependent kinase 1 (Cdk1), cyclin B1 (Ccnb1) and Cell division cyclin 25C (Cdc25C). MiR-322-5p may function as a suppressive factor by negatively controlling Wee1, thus, highlighting the potential role of miR-322-5p as a therapeutic target for liver injury.Abbreviations:ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GSH: Glutathione, γ-glutamyl cysteinel + glycine; CCl4: Carbon tetrachloride; HE: Haematoxylin and eosin; KEGG: Kyoto Encyclopedia of Genes and Genomes

The purpose of this study was to develop an ophthalmic preparation (LA/Res/HP-β-CD) containing alpha-lipoic acid (LA) and resveratrol (Res)/hydroxypropyl-β-cyclodextrin (HP-β-CD) inclusion complex and to investigate the effect of LA/Res/HP-β-CD on medicating the dry eye disease. The inclusion complex of Res/HP-β-CD was prepared by solvent evaporation method to solve the poor water-solubility of Res, and the optimal proportion of resveratrol and lipoic acid in formulation was screened by hydroxyl radical scavenging test in vitro. Comparing with Res/HP-β-CD, the preparations of LA/Res/HP-β-CD had longer t1/2and larger AUC in tears, had more advantages in increasing Res concentration in cornea, conjunctiva and sclera, improving tear secretion and tear film stability, repairing the corneal epithelial and conjunctiva injury, improving mucin and inorganic salt components of tears, reducing pro-inflammatory factor IL-1β in the cornea, enhancing Vitamin D level of eyes. These results showed that LA improved the therapeutic effect of Res, and the combined preparations would exhibit a potential application prospect in treating dry eye disease.

Light Sheet Fluorescence Microscopy (LSFM) is increasingly popular in neuroimaging for its ability to capture high-resolution 3D neural data. However, the presence of stripe noise significantly degrades image quality, particularly in complex 3D stripes with varying widths and brightness, posing challenges in neuroscience research. Existing stripe removal algorithms excel in suppressing noise and preserving details in 2D images with simple stripes but struggle with the complexity of 3D stripes. To address this, we propose a novel 3D U-net model for Stripe Removal in Light sheet fluorescence microscopy (USRL). This approach directly learns and removes stripes in 3D space across different scales, employing a dual-resolution strategy to effectively handle stripes of varying complexities. Additionally, we integrate a nonlinear mapping technique to normalize high dynamic range and unevenly distributed data before applying the stripe removal algorithm. We validate our method on diverse datasets, demonstrating substantial improvements in peak signal-to-noise ratio (PSNR) compared to existing algorithms. Moreover, our algorithm exhibits robust performance when applied to real LSFM data. Through extensive validation experiments, both on test sets and real-world data, our approach outperforms traditional methods, affirming its effectiveness in enhancing image quality. Furthermore, the adaptability of our algorithm extends beyond LSFM applications to encompass other imaging modalities. This versatility underscores its potential to enhance image usability across various research disciplines.

With prominence of the typical features of digital era, particularly that people’s activities and social lives are becoming more digitalized, and humans have developed a new digital identity, the presentation and regulation of digital identity becomes an emerging theme. Based on these features of digital era, a slew of challenges have arisen, including the protection of personal privacy, preventing algorithmic bias, and balancing the imbalance between the right of public acquisition and data controlled by a few. Consequently, protecting digital rights should be embedded in public policies, to better balance rights and interests among various stakeholders. Establishing dual protection mechanisms for public and private law is therefore fitting and proper, and the future legislation may target the scenario-based protection of personal rights.

In a program to identify pain treatments with low addiction potential, we isolated five steroids, conosteroids A–E (1–5), from the hypobranchial gland of the mollusk Conus geographus. Compounds 1–5were active in a mouse dorsal root ganglion (DRG) assay that suggested that they might be analgesic. A synthetic analogue 6was used for a detailed pharmacological study. Compound 6significantly increased the pain threshold in mice in the hot-plate test at 2 and 50 mg/kg. Compound 6at 500 nM antagonizes type-A γ-aminobutyric acid receptors (GABAARs). In a patch-clamp experiment, out of the six subunit combinations tested, 6exhibited subtype selectivity, most strongly antagonizing α1β1γ2and α4β3γ2receptors (IC501.5 and 1.0 μM, respectively). Although the structures of 1–6differ from those of known neuroactive steroids, they are cell-type-selective modulators of GABAARs, expanding the known chemical space of neuroactive steroids.

The corrosion inhibition effect of the extract (i.e., SPLE) of sweet potato leaf on metallic zinc in hydrochloric acid solution was studied by weight loss method. The results showed that SPLE had a good corrosion inhibition effect on metallic zinc in hydrochloric acid solution with a concentration of 0.1–0.5 mol L–1, and the adsorption on the surface of metallic zinc conforms to the Langmuir adsorption isotherm. The corrosion inhibition rate increased with the increase of SPLE concentration but decreased with the increase of temperature and hydrochloric acid concentration. The adsorption enthalpy ΔHadsand corrosion kinetic parameters (rate constant k, kinetic constant B) were obtained by Van’t Hoff equation and Mathur empirical formula, the corrosion inhibition behavior of SPLE was discussed based on this parameter.

Calcium homeostasis is implicated in some cancers, leading to the possibility that selective control of calcium might lead to new cancer drugs. On the basis of this idea, we designed an assay using a glioblastoma cell line and screened a collection of 1000 unique bacterial extracts. Isolation of the active compound from a hit extract led to the identification of boholamide A (1), a 4-amido-2,4-pentadieneoate (APD)-class peptide. Boholamide A (1) applied in the nanomolar range induces an immediate influx of Ca2+in glioblastoma and neuronal cells. APD-class natural products are hypoxia-selective cytotoxins that primarily target mitochondria. Like other APD-containing compounds, 1is hypoxia selective. Since APD natural products have received significant interest as potential chemotherapeutic agents, 1provides a novel APD scaffold for the development of new anticancer compounds.

For the user moving with high velocity in heterogeneous networks (HetNets), two aspects that cause performance degradation should be considered, one is the channel aging, the other is the handoffs. Nevertheless, only one of these two aspects is involved for performance evaluation in most of researches. In this letter, the optimal access scheme determination is investigated considering these two aspects caused by user mobility. Firstly, the vertical and horizontal handoff probability in HetNets are analyzed. Then the closed-form expressions of coverage probability considering the channel aging for both open access and closed access are derived. Combining the handoff probability and the coverage probability, a fixed data rate scheme is adopted to determine the optimal access strategy. Numerical results verify our analysis, and show that open access performs better than closed access in dense femto-tier base stations (FBSs), whereas closed access is suggested in relatively sparse FBSs. Further, for a large bias factor, the optimal access strategy depends on both the signal-to-interference ratio threshold and the user velocity.

ABSTRACTRice mapping with remote sensing imagery provides an alternative means for estimating crop-yield and performing land management due to the large geographical coverage and low cost of remotely sensed data. Rice mapping in Southern China, however, is very difficult as rice paddies are patchy and fragmented, reflecting the undulating and varied topography. In addition, abandoned lands widely exist in Southern China due to rapid urbanization. Abandoned lands are easily confused with paddy fields, thereby degrading the classification accuracy of rice paddies in such complex landscape regions. To address this problem, the present study proposes an innovative method for rice mapping through combining a convolutional neural network (CNN) model and a decision tree (DT) method with phenological metrics. First, a pre-trained LeNet-5 Model using the UC Merced Dataset was developed to classify the cropland class from other land cover types, i.e. built-up, rivers, forests. Then, paddy rice field was separated from abandoned land in the cropland class using a DT model with phenological metrics derived from the time-series data of the normalized difference vegetation index (NDVI). The accuracy of the proposed classification methods was compared with three other classification techniques, namely, back propagation neural network (BPNN), original CNN, pre-trained CNN applied to HJ-1 A/B charge-coupled device (CCD) images of Zhuzhou City, Hunan Province, China. Results suggest that the proposed method achieved an overall accuracy of 93.56%, much higher than those of other methods. This indicates that the proposed method can efficiently accommodate the challenges of rice mapping in regions with complex landscapes.

Lithium-ion battery State of Health (SOH) estimation is an essential issue in battery management systems. In order to better estimate battery SOH, Extreme Learning Machine (ELM) is used to establish a model to estimate lithium-ion battery SOH. The Swarm Optimization algorithm (PSO) is used to automatically adjust and optimize the parameters of ELM to improve estimation accuracy. Firstly, collect cyclic aging data of the battery and extract five characteristic quantities related to battery capacity from the battery charging curve and increment capacity curve. Use Grey Relation Analysis (GRA) method to analyze the correlation between battery capacity and five characteristic quantities. Then, an ELM is used to build the capacity estimation model of the lithium-ion battery based on five characteristics, and a PSO is introduced to optimize the parameters of the capacity estimation model. The proposed method is validated by the degradation experiment of the lithium-ion battery under different conditions. The results show that the battery capacity estimation model based on ELM and PSO has better accuracy and stability in capacity estimation, and the average absolute percentage error is less than 1%.

The NAC (NAM, ATAF1/2, and CUC2) is a defense-associated transcription factor (TF) family that positively regulates defense responses to pathogen infection. TaNAC069positively regulates resistance in wheat to Puccinia triticina(Pt). However, the molecular mechanism of its interaction with a Pteffector is not clear. We found that Pteffector Pt-1234 interacts with TaNAC069 to subvert host immunity during Ptinfection. Quantitative real-time PCR analysis showed that expression of Pt-1234was significantly up-regulated during the early stage of Ptinfection. Protein-mediated cell death assays in wheat showed that the Pt-1234 protein was unable to induce cell death in wheat near-isogenic lines carrying different leaf rust resistance genes, whereas it suppressed BAX-induced cell death in leaves of Nicotiana benthamiana. Silencing of Pt-1234by host-induced gene silencing (HIGS) significantly reduced the virulence of Ptin the susceptible wheat variety Thatcher. The C subdomain of TaNAC069 was responsible for its interaction with Pt-1234, and the E subdomain was required for TaNAC069-mediated defense responses to Ptin planta. These findings indicate that Ptutilizes Pt-1234 to interact with wheat transcription factor TaNAC069 through its C subdomain, thereby modulating wheat immunity.

Based on the principle of multi-stage vibration isolation and active vibration absorption, a multi-stage passive vibration-isolating system and active motor vibration-absorbing system are designed for the electric wheel system of wheel-hub motor-driven electric vehicle, and the 1/4 suspension structural diagrams of the two vibration-isolating systems are drawn. Secondly, the corresponding multi-degrees-of-freedom vertical vibration model is established according to the different structural diagrams, and the dynamic differential equation of the multi-degrees-of-freedom vibration system is deduced. Then, by programming the MATLAB software is used to solve the acceleration of the vehicle body, the dynamic deflection of the suspension spring, and the amplitude, and the frequency characteristic curve of the relative dynamic load of the wheel of the 1/4 suspension system are drawn and the results are compared and analyzed. Finally, the ADAMS software is used for remodeling; the simulation experiment of ADAMS multi-body dynamics verified the correctness of the theoretical results of MATLAB software. The results show that the ADAMS simulation experiment results are consistent with the MATLAB theoretical results, and their correctness is verified. The vibration isolation effect of the active vibration-absorbing system is better and can improve the riding comfort and safety of the vehicle; hence it is worth popularizing and drawing.

Classification and regression tree (CART) has been widely implemented to estimate impervious surface, an important indicator of urbanization and environmental quality. Although the CART algorithm gains higher overall accuracy than linear regression models, only very few studies have noticed that reliability of CART is affected by systematic errors. Especially, CART typically overestimates impervious surfaces in low-density urban areas and underestimates them in high-density urban areas. The primary objective of this study is to develop an improved integrated method to estimate impervious surface with higher accuracy by reducing the systematic errors of CART. This improved method was applied to three urban areas, Chicago (United States), Venice (Italy), and Guangzhou (China) to examine its effectiveness. When compared with the conventional CART, overall mean average error (MAE) and root mean square error (RMSE) of improved method are decreased by 22.64% and 20.93%, respectively, and R2rises from 0.9 to 0.96. In high-density impervious surfaces, where intensely developed urban area is located, the MAE and RMSE for the improved method are 0.066 and 0.088, respectively, largely improved from 0.100 to 0.130. Since accurate estimation of high-density impervious surfaces is the fundamental issue for monitoring and understanding the urban environment, the improved method demonstrated in this study is significant.

Associated with the rapid economic development of China, the level of urbanization is becoming a serious concern. Harbin, the capital city of Heilongjiang Province, China and one of the political, economic, cultural, and transportation centers of the northeastern region of China, has experienced rapid urbanization recently. To examine the spatial patterns of long-term urbanization and explore its driving forces, we employed the impervious surface fraction derived from remote sensing image as a primary indicator. Specifically, urban impervious surface information for the central city of Harbin in 1984, 1993, 2002, and 2010 was extracted from Landsat Thematic Mapper image using a Linear Spectral Mixture Analysis (LMSA). Then, the spatial and temporal variation characteristics and the driving factors of percent impervious surface area (ISA) changes were analyzed throughout this 26-year period (1984 to 2010). Analysis of results suggests that: (1) ISAs in the central city of Harbin constantly increased, particularly from 1993 to 2010, a rapid urbanization period; (2) the gravity center of impervious surface area in the central city was located in Nangang District in 1984, moving southeast from 1984 to 1993, northwest from 1993 to 2002, and continuing toward the southeast from 2002 to 2010; and (3) the urban growth of the central city can be characterized as edge-type growth.

Heat stress as an environmental hazard which can seriously affect productivity, health, or even survival of individuals has long been studied. Despite the endeavors that have been made to address the issue quantitatively with various heat stress indices, they are often measured at scatter sites. This research devotes to revealing human heat stress within continuous space with remote sensing technology. The study began with the retrieval of dry-bulb temperature from land surface temperature (LST) with empirical models. As wet-bulb temperature was calculated from dry-bulb temperature and relative humidity, discomfort index (DI) as an indicator of heat stress was revealed for the study area at 1 km spatial resolution for three summer days. Results indicated that DI can be derived within continuous space with remotely sensed data, and its spatial distribution can be dramatically affected by relative humidity. Further comparison between DI and LST indicated that LST as a widely utilized indicator of surface thermal condition fails to address human heat stress as environmental factors such as relative humidity are not taken into account.

The outcome of treatment-refractory and/or relapsed pediatric T cell acute lymphoblastic leukemia (T-ALL) is extremely poor, and the genetic basis for this is not well understood. Here we report comprehensive profiling of 121 cases of pediatric T-ALL using transcriptome and/or targeted capture sequencing, through which we identified new recurrent gene fusions involving SPI1 (STMN1-SPI1 and TCF7-SPI1). Cases positive for fusions involving SPI1 (encoding PU.1), accounting for 3.9% (7/181) of the examined pediatric T-ALL cases, showed a double-negative (DN; CD4−CD8−) or CD8+single-positive (SP) phenotype and had uniformly poor overall survival. These cases represent a subset of pediatric T-ALL distinguishable from the known T-ALL subsets in terms of expression of genes involved in T cell precommitment, establishment of T cell identity, and post-β-selection maturation and with respect to mutational profile. PU.1 fusion proteins retained transcriptional activity and, when constitutively expressed in mouse stem/progenitor cells, induced cell proliferation and resulted in a maturation block. Our findings highlight a unique role of SPI1 fusions in high-risk pediatric T-ALL.

Genomic imprinting can lead to allele-specific expression (ASE), where one allele is preferentially expressed more than the other. Perturbations in genomic imprinting or ASE genes have been widely observed across various neurological disorders, notably autism spectrum disorder (ASD). In this study, we crossed rhesus cynomolgus monkeys to produce hybrid monkeys and established a framework to evaluate their allele-specific gene expression patterns using the parental genomes as a reference. Our proof-of-concept analysis of the hybrid monkeys identified 353 genes with allele-biased expression in the brain, enabling us to determine the chromosomal locations of ASE clusters. Importantly, we confirmed a significant enrichment of ASE genes associated with neuropsychiatric disorders, including ASD, highlighting the potential of hybrid monkey models in advancing our understanding of genomic imprinting.

Circadian oscillation of gut microbiota exerts significant influence on host physiology, but the host factors that sustain microbial oscillations are rarely reported. We compared the gut microbiome and metabolome of wild-type and BMAL1-deficient cynomolgus monkeys during a diurnal cycle by performing 16S rRNA sequencing and untargeted fecal metabolomics and uncovered the influence of intestinal H2O2on microbial compositions. Ablation of BMAL1 induced expansion of Bacteroidotaat midnight and altered microbial oscillations. Some important fecal metabolites changed significantly, and we investigated their correlations with microbes. Further analyses revealed that disturbed rhythmicity of NOX1-derived intestinal H2O2was responsible for the altered microbial oscillations in BMAL1-deficient monkeys. Mechanistic studies showed that BMAL1 transactivated NOX1via binding to the E1-E2 site in its promoter. Notably, BMAL1-dependent activation of NOX1was conserved in cynomolgus monkeys and humans. Our study demonstrates the importance of intestine clock-controlled H2O2rhythmicity on the rhythmic oscillation of gut microbiota.

AbstractLight detection and ranging (LiDAR) is a promising technology for extracting forest biophysical parameters, including tree height, total volume, biomass, etc. However, tree crown width estimation at the individual level is challenging due to overlapping crown surfaces in urban forests. The objective of this study, therefore, is to develop an approach for estimating tree crown width at the individual tree level using airborne LiDAR data in an urban area. To reach this objective, we constructed a general geometric model for each tree, centering at the tree position on the ground to fit the LiDAR-derived crown surface and then predicted crown width using tree height and shape-related parameters as independent variables and the ground measurement of all the crown widths identified by LiDAR data as dependent variables. Analyses of results suggest that tree crown widths in a mixed forest can be successfully extracted through model-based linear regression analysis, which can explain 88.5 % of variance associated with crown width for all 135 trees. Moreover, the best model and the algorithm identified in this research can be applied to forests of similar composition and a satisfactory accuracy without any ground measurement can be expected.

EZH2 is a component of polycomb repressive complex 2 (PRC2) and functions as an H3K27 methyltransferase. Loss-of-function mutations in EZH2 are associated with poorer outcomes in patients with myeloproliferative neoplasms (MPNs), particularly those with primary myelofibrosis (MF [PMF]). To determine how EZH2 insufficiency is involved in the pathogenesis of PMF, we generated mice compound for an Ezh2 conditional deletion and activating mutation in JAK2 (JAK2V617F) present in patients with PMF. The deletion of Ezh2 in JAK2V617F mice markedly promoted the development of MF, indicating a tumor suppressor function for EZH2 in PMF. The loss of Ezh2 in JAK2V617F hematopoietic cells caused significant reductions in H3K27 trimethylation (H3K27me3) levels, resulting in an epigenetic switch to H3K27 acetylation (H3K27ac). These epigenetic switches were closely associated with the activation of PRC2 target genes including Hmga2, an oncogene implicated in the pathogenesis of PMF. The treatment of JAK2V617F/Ezh2-null mice with a bromodomain inhibitor significantly attenuated H3K27ac levels at the promoter regions of PRC2 targets and down-regulated their expression, leading to the abrogation of MF-initiating cells. Therefore, an EZH2 insufficiency not only cooperated with active JAK2 to induce MF, but also conferred an oncogenic addiction to the H3K27ac modification in MF-initiating cells that was capable of being restored by bromodomain inhibition.

Spectral mixture analysis (SMA) is a major approach for estimating fractional land covers through modeling the relationship between the spectral signatures of a mixed remote sensing pixel and those of the comprised pure land covers (also termed as endmembers). When SMA is implemented, endmember variability has proven to have significant impact on the accuracy of land cover fraction estimates. To address the endmember variability problem, this article developed a geostatistical temporal mixture analysis (GTMA) technique, with which spatially varying per-pixel endmember sets were estimated using an ordinary kriging interpolation technique. The method was applied to time-series moderate-resolution imaging spectroradiometer normalized difference vegetation index imagery in Wisconsin and North Carolina, United States to estimate regional impervious surface distributions. Analysis of results suggests that GTMA has achieved a promising accuracy. Detailed analysis indicates that a better performance has been achieved in less-developed areas than developed areas, and slight underestimation and slight overestimation have been detected in developed areas and less-developed areas, respectively. Moreover, while the performance of GTMA is comparable to those of phenology-based TMA and phenology-based multiple endmember TMA over the entire study area and in less-developed areas, a much better performance has been achieved in developed areas. Finally, this article argues that endmember variability may be more essential in developed areas when compared to less-developed areas.

The aim of this study was to develop the dexamethasone acetate loaded by cubosomes (DA-Cub) and its gel (DA-Cub gel) and improve the drug transdermal penetration and intradermal retention. Dexamethasone acetate cubosomes (DA-Cub) was prepared by hot melt ultrasonic method. The particle size was (110.8 ± 0.87) nm, zeta potential was (−25.9 ± 1.31) mV, and encapsulation efficiency was (97.97 ± 1.06)%. DA-Cub and its gel were characterized by polarizing microscope, transmission electron microscope, differential scanning calorimetry, fourier transform infrared spectroscopy and small-angle x-ray scattering. Both DA-Cub and its gels had sustained-release effect. The accumulation of DA-Cub and DA-Cub gel in rat skin in vitro increased significantly compared with general gels and commercial cream, so the intradermal retention of DA-Cub increased significantly. Compared with the commercial cream, DA-Cub provided higher penetration rate and intradermal retention. HE staining and reflectance fourier transform infrared spectroscopy were used to investigate the effect of transdermal administration of cubosomes on skin surface. DA-Cub and DA-Cub gel could make the cuticle thinner, change the structure of keratin and the intercellular space enlarged, thus promoting the penetration of drugs. DA-Cub has significant therapeutic effect and is expected to become a new low toxic and long-acting preparation.

Recent genome sequencing revealed inactivating mutations in EZH2, which encodes an enzymatic component of polycomb-repressive complex 2 (PRC2), in patients with myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), and MDS/MPN overlap disorders. We herein demonstrated that the hematopoietic-specific deletion of Ezh2 in mice induced heterogeneous hematopoietic malignancies. Myelodysplasia was detected in mice following the deletion of Ezh2, and resulted in the development of MDS and MDS/MPN. Thrombocytosis was induced by Ezh2 loss and sustained in some mice with myelodysplasia. Although less frequent, Ezh2 loss also induced T-cell acute lymphoblastic leukemia and the clonal expansion of B-1a B cells. Gene expression profiling showed that PRC2 target genes were derepressed upon the deletion of Ezh2 in hematopoietic stem and progenitor cells, but were largely repressed during the development of MDS and MDS/MPN. Chromatin immunoprecipitation–sequence analysis of trimethylation of histone H3 at lysine 27 (H3K27me3) revealed a compensatory function of Ezh1, another enzymatic component of PRC2, in this process. The deletion of Ezh1 alone did not cause dysplasia or any hematologic malignancies in mice, but abolished the repopulating capacity of hematopoietic stem cells when combined with Ezh2 loss. These results clearly demonstrated an essential role of Ezh1 in the pathogenesis of hematopoietic malignancies induced by Ezh2 insufficiency, and highlighted the differential functions of Ezh1 and Ezh2 in hematopoiesis.

Recent genome sequencing revealed inactivating mutations in EZH2, which encodes an enzymatic component of polycomb-repressive complex 2 (PRC2), in patients with myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), and MDS/MPN overlap disorders. We herein demonstrated that the hematopoietic-specific deletion of Ezh2in mice induced heterogeneous hematopoietic malignancies. Myelodysplasia was detected in mice following the deletion of Ezh2, and resulted in the development of MDS and MDS/MPN. Thrombocytosis was induced by Ezh2 loss and sustained in some mice with myelodysplasia. Although less frequent, Ezh2 loss also induced T-cell acute lymphoblastic leukemia and the clonal expansion of B-1a B cells. Gene expression profiling showed that PRC2 target genes were derepressed upon the deletion of Ezh2in hematopoietic stem and progenitor cells, but were largely repressed during the development of MDS and MDS/MPN. Chromatin immunoprecipitation–sequence analysis of trimethylation of histone H3 at lysine 27 (H3K27me3) revealed a compensatory function of Ezh1, another enzymatic component of PRC2, in this process. The deletion of Ezh1alone did not cause dysplasia or any hematologic malignancies in mice, but abolished the repopulating capacity of hematopoietic stem cells when combined with Ezh2 loss. These results clearly demonstrated an essential role of Ezh1 in the pathogenesis of hematopoietic malignancies induced by Ezh2insufficiency, and highlighted the differential functions of Ezh1 and Ezh2 in hematopoiesis.

In this paper, the historical trend of urban growth and the associated drivers were examined through econometric analysis for the rapidly growing Grafton area in the State of Wisconsin. Specifically, panel data analysis was carried out to examine the drivers of urban growth such as demographic factors, location of jobs, travel time, housing types, property values, etc. Results reveal that panel data analysis, particularly the random effects model, was successful in analyzing the drivers of urban growth at the census block group level. This study found that population, local jobs, household income, and house price were positively associated with urban growth. The study also found that urban growth in the study area is not decided by the access to the nearest central city, but other factors, such as the rural atmosphere of the region, local jobs, and emerging centers of employment opportunities, have significant influences on urban development.

Forest net primary productivity (NPP) is a key parameter for forest monitoring and management. In this study, monthly and annual forest NPP in the northeastern China from 1982 to 2010 were simulated by using Carnegie-Ames-Stanford Approach (CASA) model with normalized difference vegetation index (NDVI) sequences derived from Advanced Very High Resolution Radiometer (AVHRR) Global Inventory Modeling and Mapping Studies (GIMMS) and Terra Moderate Resolution Imaging Spectroradiometer (MODIS) products. To address the problem of data inconsistency between AVHRR and MODIS data, a per-pixel unary linear regression model based on least squares method was developed to derive the monthly NDVI sequences. Results suggest that estimated forest NPP has mean relative error of 18.97% compared to observed NPP from forest inventory. Forest NPP in the northeastern China increased significantly during the twenty-nine years. The results of seasonal dynamic show that more clear increasing trend of forest NPP occurred in spring and autumn. This study also examined the relationship between forest NPP and its driving forces including the climatic and anthropogenic factors. In spring and winter, temperature played the most pivotal role in forest NPP. In autumn, precipitation acted as the most important factor affecting forest NPP, while solar radiation played the most important role in the summer. Evaportranspiration had a close correlation with NPP for coniferous forest, mixed coniferous broadleaved forest, and broadleaved deciduous forest. Spatially, forest NPP in the Da Hinggan Mountains was more sensitive to climatic changes than in the other ecological functional regions. In addition to climatic change, the degradation and improvement of forests had important effects on forest NPP. Results in this study are helpful for understanding the regional carbon sequestration and can enrich the cases for the monitoring of vegetation during long time series.

Numerous studies have recently reported mutations involving multiple components of the messenger RNA (mRNA) splicing machinery in patients with myelodysplastic syndrome (MDS). SF3B1 is mutated in 70% to 85% of refractory anemia with ringed sideroblasts (RARS) patients and is highly associated with the presence of RARS, although the pathological role of SF3B1 mutations in MDS-RARS has not been elucidated yet. Here, we analyzed the function of pre-mRNA splicing factor Sf3b1 in hematopoiesis. Sf3b1+/− mice maintained almost normal hematopoiesis and did not develop hematological malignancies during a long observation period. However, Sf3b1+/− cells had a significantly impaired capacity to reconstitute hematopoiesis in a competitive setting and exhibited some enhancement of apoptosis, but they did not show any obvious defects in differentiation. Additional depletion of Sf3b1 with shRNA in Sf3b1+/− hematopoietic stem cells (HSCs) severely compromised their proliferative capacity both in vitro and in vivo. Finally, we unexpectedly found no changes in the frequencies of sideroblasts in either Sf3b1+/− erythroblasts or cultured Sf3b1+/− erythroblasts expressing shRNA against Sf3b1. Our findings indicate that the level of Sf3b1 expression is critical for the proliferative capacity of HSCs, but the haploinsufficiency for Sf3b1 is not sufficient to induce a RARS-like phenotype.

Numerous studies have recently reported mutations involving multiple components of the messenger RNA (mRNA) splicing machinery in patients with myelodysplastic syndrome (MDS). SF3B1is mutated in 70% to 85% of refractory anemia with ringed sideroblasts (RARS) patients and is highly associated with the presence of RARS, although the pathological role of SF3B1mutations in MDS-RARS has not been elucidated yet. Here, we analyzed the function of pre-mRNA splicing factor Sf3b1in hematopoiesis. Sf3b1+/−mice maintained almost normal hematopoiesis and did not develop hematological malignancies during a long observation period. However, Sf3b1+/−cells had a significantly impaired capacity to reconstitute hematopoiesis in a competitive setting and exhibited some enhancement of apoptosis, but they did not show any obvious defects in differentiation. Additional depletion of Sf3b1with shRNA in Sf3b1+/−hematopoietic stem cells (HSCs) severely compromised their proliferative capacity both in vitro and in vivo. Finally, we unexpectedly found no changes in the frequencies of sideroblasts in either Sf3b1+/−erythroblasts or cultured Sf3b1+/−erythroblasts expressing shRNA against Sf3b1. Our findings indicate that the level of Sf3b1expression is critical for the proliferative capacity of HSCs, but the haploinsufficiency for Sf3b1is not sufficient to induce a RARS-like phenotype.

In classifying very high spatial resolution (VHR) hyperspectral imagery, intra-class variation often adversely affects classification accuracy, mainly due to a low signal-to-noise ratio (SNR) and high spatial heterogeneity. To address this problem, this article develops a neighbourhood-constrained k-means (NC-k-means) algorithm by incorporating the pure neighbourhood index into the traditional k-means algorithm. The performance of the NC-k-means algorithm was assessed through a series of simulated images and a real hyperspectral image. The results indicate that the classification accuracy of NC-k-means algorithm is consistently better than that of the traditional k-means algorithm, in particular for the images with significant spatial autocorrelations among neighbouring pixels.

Gambogic acid (GA) is a natural compound derived from Chinese herbs that has been approved by the Chinese Food and Drug Administration for clinical trials in cancer patients; however, its molecular targets have not been thoroughly studied. Here, we report that GA inhibits tumor proteasome activity, with potency comparable to bortezomib but much less toxicity. First, GA acts as a prodrug and only gains proteasome-inhibitory function after being metabolized by intracellular CYP2E1. Second, GA-induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer effect without off-targets. Finally, because expression of the CYP2E1 gene is very high in tumor tissues but low in many normal tissues, GA could therefore produce tissue-specific proteasome inhibition and tumor-specific toxicity, with clinical significance for designing novel strategies for cancer treatment.

A novel spherical nanosilica matrix (SNM) together with chitosan (CTS) encapsulated SNM (CTS-SNM) was developed in order to investigate the feasibility of using chitosan to regulate drug release rate from porous silica and obtain an oral sustained drug delivery system. To achieve this goal, we synthesized a spherical nanosilica matrix (SNM) and incorporated chitosan chains on the SNM surface. Solvent evaporation method was adopted to load the model drug carvedilol into SNM and CTS-SNM. The physicochemical properties of the drug carriers and drug-loaded composites were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), nitrogen adsorption, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The structural changes in CTS-SNM in simulated gastrointestinal fluid as well as the relationships between swelling effect of chitosan and in vitro drug release behaviors were investigated. Pharmacokinetic and bioavailability aspects were also discussed. The results showed that the powerful dispersing effect of SNM and the blocking action due to the swelling of chitosan were the two main factors contributing to the sustained drug release behavior. The swelling effect of chitosan in an acidic environment together with the shrinking effect in a relatively alkaline environment allowed regulation of drug release behavior in simulated gastrointestinal fluid. An in vivo study showed that the bioavailability of CAR was improved 182% compared with that of the commercial capsule when SNM was used as the drug carrier. As for CAR-CTS-SNM, the Tmaxof CAR was delayed by about 3.4 h and the bioavailability was slightly increased in comparison with the commercial capsule. We believe that SNM and CTS-SNM developed in this study will help increase the use of polymers and inorganic materials in pharmaceutical applications and stimulate the design of oral drug delivery systems for immediate or sustained release of poorly water-soluble drugs.

Asthma is the most common chronic respiratory disease seriously endangering the health of children. But disease awareness and self-management skills are relatively poor in children; parents play an important role in the control of childhood asthma.

Abstract: Eu-doped Mg x Zn1−x O hexagonal nanocrystals with wurtzite-type structure were fabricated on quartz substrates by electron beam evaporation using Mg0.15Zn0.85O: Eu y (0⩽y⩽0.08) target combined thermal annealing followed with rapid cooling. The influence of Eu on the microstructure and optical properties of Mg x Zn1−x O hexagonal nanocrystals had been investigated using X-ray diffraction spectra, X-ray photoelectron energy spectra, scanning electron microscopy, absorption spectra, and photoluminescence spectra. It was found that Eu-doped Mg x Zn1−x O hexagonal nanocrystals annealed at 700°C exhibited (002) preferred orientation, whereas undoped Mg x Zn1−x O hexagonal nanocrystals annealed at 700°C did not exhibit preferential growth. The Mg concentration of Eu-doped and undoped Mg x Zn1−x O hexagonal nanocrystals annealed at 700°C were both 0.08. However, an evident phase separation of the Eu-doped Mg x Zn1−x O hexagonal nanocrystals with Mg0.08Zn0.92O/Mg0.03Zn0.97O/air SQW core-shell structures was observed. The binding energy of exciton in Mg0.03Zn0.97O (66 meV) was larger than that in Mg0.08Zn0.92O (50 meV) that was further evidence of Mg0.08Zn0.92O/Mg0.03Zn0.97O/air SQW core-shell structures formed.

Abstract: ZnO thin films were deposited on fused silica via pulsed laser deposition (PLD) at substrate temperatures from 300°C to 800°C and ambient oxygen pressures ranging from 10−2 mTorr to 240 mTorr. X-ray diffraction (XRD) and Raman spectra indicated that wurtzite ZnO was obtained in all cases. The highly c-oriented ZnO films were obtained for oxygen pressures above 11 mTorr. The room-temperature photoluminescence (PL) spectra demonstrated that all the films exhibited strong near-band-edge (NBE) emission, while deep-level (DL) emission was also observed in films deposited at oxygen pressures below 80 mTorr. From analysis of the XRD, Raman and photoluminescence PL data, an optimal condition was identified for the deposition of highly crystallized ZnO films.

In this paper, we investigated the electronic circular dichroism (ECD) of proton pump inhibitors (PPIs) using a method of combining experimental spectrum and time-dependent density functional theory (TD-DFT) calculations. In our research, an intriguing helicity-like phenomenon was discovered for the relationship between static dipole moment and ECD curves of different conformers in lansoprazole. The scope and validity of the precious phenomenon have been examined by four PPIs using the same method. Hence, it can be used as a reference to determine and verify the absolute configuration of PPIs-type and PPIs-like chiral sulfoxide.

Lu2(1–x)Eu2xO3nanoscintillators (x= 0.005, 0.01, 0.03, 0.05, 0.07, and 0.10) with red emission were synthesized by a coprecipitation method. It is found that their photo- and radioluminescence intensities increase with increasing Eu3+concentration until x= 0.05. According to their concentration-dependent luminescence intensity ratios (I610(C2)/I582(S6)), the existing energy transfer from Eu3+(S6) (occupying S6sites) to Eu3+(C2) (occupying C2sites) can be confirmed. Based on the spectral data and density functional theory (DFT) calculations, the origin of Lu2O3:Eu3+persistent luminescence at low concentration might be related to the tunneling processes between Eu3+(occupying C2and S6sites) and oxygen interstitials (Oi×). After dispersing afterglow-suppressed Lu2O3:Eu3+nanoscintillators into polymethyl methacrylate (PMMA) polymer-acetone solution, flexible PMMA-Lu2O3:Eu3+composite films with high thermal stability and radiation resistance were fabricated by a doctor blade method. As the flexible composite film was used as an imaging plate, static X-ray images with high spatial resolution (5.5 lp/mm) under an extremely low dose of ∼1.1 μGyaircan be acquired. When a watch with a moving second hand was used as an object, the dynamic X-ray imaging can be realized under a dose rate of 55 μGyair·s–1. Our results demonstrate that Lu2O3:Eu3+nanoscintillators can be regarded as candidate materials for dynamic digital radiographic imaging.

We report the identification of the tndbiosynthetic cluster from the marine-derived fungus Aspergillus flavipesand the in vivo characterization of a cryptic type I diterpene synthase. The heterologous expression of the bifunctional terpene synthase led to the discovery of a diterpene backbone, talarodiene, harboring a benzo[a]cyclopenta[d]cyclooctane tricyclic fused ring system. The conversion of geranylgeranyl diphosphate to talarodiene was investigated using 13C-labeling studies, and stable isotope tracer experiments showed the biotransformation of talarodiene into talaronoid C.

A new chrial organosulfide was synthesized through an unexpected Wagner–Meerwein rearrangement. This organosulfide could catalyze the epoxidation reaction of various aromatic aldehydes smoothly with benzyl bromide to give transdiaryl epoxides in satisfactory yields 60–84% with excellent diastereoselectivities trans:cis95:5–100:0 and good to excellent enantioselectivities 86–96% ee.

The Value of High Resolution Computed Tomography in the Diagnostics of Small Opacities and Complications of Silicosis in Mine Machinery Manufacturing Workers, Compared to Radiography: Jinkai Sun, et al. Division of Pneumoconiosis, School of Public Health, China Medical University, China—The purpose of this study was to assess the value and usefulness of high resolution computed tomography (HRCT) in the diagnostics of small opacities and complications of silicosis in mine machinery manufacturing workers, compared to conventional radiograms. The diagnosis of silicosis is mainly based on the radiological findings of workers exposed to the dust causing lung fibrosis. However, on radiograms many parenchymal structures overlap, which limits the sensitivity and specificity of the method. Difficulties in accurate interpretation of conventional radiograms in silicosis also result from their relatively low resolution. We randomly selected 30 I period silicosis patients from 77 I period silicosis patients working at a mine machinery manufacturing company. Out of 1078 non‐silicosis and 162 0+period silicosis subjects, 30 non‐silicosis and 30 0+period silicosis subjects were randomly selected and matched with the 30 I period silicosis subjects by age (± 3.0 yr) and occupational exposure time (± 2.0 yr). Chest Xrays were taken at maximal inspiration. For the HRCT examination, the GE Somatom plus apparatus was used. Eight, five and six subjects were respectively diagnosed as 0+, I or I+period silicosis based on HRCT among 90 subjects whose original diagnoses were nonsilicosis, 0+or I period silicosis based on radiography. The numbers of small opacities in HRCT scans were significantly higher than those seen in radiography in all lung zones (p<0.01). HRCT was more sensitive than radiography in detecting small opacities of midout zones of the lung, but no statistical significance was found between the two methods in the detection of small opacities of lower zones of the lung. A statistically significant increase in the detectability of bulla, emphysema, pleural, mediastinal and hilar changes was observed (p<0.05). HRCT might be more sensitive than radiography in detecting lung parenchymal changes suggestive of silicosis.

The Value of High Resolution Computed Tomography in the Diagnostics of Small Opacities and Complications of Silicosis in Mine Machinery Manufacturing Workers, Compared to Radiography: Jinkai Sun, et al. Division of Pneumoconiosis, School of Public Health, China Medical University, China—The purpose of this study was to assess the value and usefulness of high resolution computed tomography (HRCT) in the diagnostics of small opacities and complications of silicosis in mine machinery manufacturing workers, compared to conventional radiograms. The diagnosis of silicosis is mainly based on the radiological findings of workers exposed to the dust causing lung fibrosis. However, on radiograms many parenchymal structures overlap, which limits the sensitivity and specificity of the method. Difficulties in accurate interpretation of conventional radiograms in silicosis also result from their relatively low resolution. We randomly selected 30 I period silicosis patients from 77 I period silicosis patients working at a mine machinery manufacturing company. Out of 1078 non-silicosis and 162 0+period silicosis subjects, 30 non-silicosis and 30 0+period silicosis subjects were randomly selected and matched with the 30 I period silicosis subjects by age (± 3.0 yr) and occupational exposure time (± 2.0 yr). Chest X-rays were taken at maximal inspiration. For the HRCT examination, the GE Somatom plus apparatus was used. Eight, five and six subjects were respectively diagnosed as 0+, I or I+period silicosis based on HRCT among 90 subjects whose original diagnoses were non-silicosis, 0+or I period silicosis based on radiography. The numbers of small opacities in HRCT scans were significantly higher than those seen in radiography in all lung zones (p<0.01). HRCT was more sensitive than radiography in detecting small opacities of mid-out zones of the lung, but no statistical significance was found between the two methods in the detection of small opacities of lower zones of the lung. A statistically significant increase in the detectability of bulla, emphysema, pleural, mediastinal and hilar changes was observed (p<0.05). HRCT might be more sensitive than radiography in detecting lung parenchymal changes suggestive of silicosis.

Abstract: The theory and equations of the residual apparent polarization method are proposed and described in this article. Based on studies of existing mines, the residual apparent polarization \Gh \Ga sy , calculated from the induced-current middle-gradient apparent polarizations \Gh \Ga at large and small electrode spaces over the known deep Jiaojia-type gold mines, have been shown to separate the effects of mines from the anomalous polarizations generated from the strongly altered rocks in fracture zones.

Retinoids are important for growth plate chondrocyte maturation, but their downstream effectors remain unclear. Recently, CTGF (CCN2) was found to regulate chondrocyte function, particularly in the hypertrophic zone. The goal of the study was to determine whether CTGF is a retinoid signaling effector molecule, how it is regulated, and how it acts.

Retinoids are important for growth plate chondrocyte maturation, but their downstream effectors remain unclear. Recently, CTGF (CCN2) was found to regulate chondrocyte function, particularly in the hypertrophic zone. The goal of the study was to determine whether CTGF is a retinoid signaling effector molecule, how it is regulated, and how it acts.Introduction:Using a combination of in vivo and in vitro approaches, we carried out a series of studies at the cellular, biochemical, and molecular level to determine whether and how retinoid signaling is related to expression and function of connective tissue growth factor (CTGF) in chondrocyte maturation and endochondral ossification.Materials and Methods:Limbs of chick embryos in ovo were implanted with retinoic pan‐antagonist RO 41‐5253‐filled beads, and phenotypic changes were assessed by in situ hybridization. CTGFgene expression and roles were tested in primary cultures of immature and hypertrophic chondrocytes. Cross‐talk between retinoid signaling and other pathways was tested by determining endogenous levels of active ERK1/2 and p38 MAP kinases and phenotypic modulations exerted by specific antagonists of mitogen‐activated protein (MAP) kinases and BMP signaling (Noggin).Results:Interference with retinoid signaling blocked expression of CTGFand other posthypertrophic markers in long bone anlagen in vivo and hypertrophic chondrocyte cultures, whereas all‐trans‐retinoic acid (RA) boosted CTGFexpression and even induced it in immature proliferating cultures. Exogenous recombinant CTGF stimulated chondrocyte maturation, but failed to do so in presence of retinoid antagonists. Immunoblots showed that hypertrophic chondrocytes contained sizable levels of phosphorylated ERK1/2 and p38 MAP kinases that were dose‐ and time‐dependently increased by RA treatment. Experimental ERK1/2 inhibition led to a severe drop in baseline and RA‐stimulated CTGFexpression, whereas p38 inhibition increased it markedly. These responses were gene‐specific, because the opposite was seen with other hypertrophic chondrocyte genes such as collagen X and RA receptor γ (RARγ). Tests with Nogginshowed that RA induction of CTGFexpression was negatively influenced by BMP signaling, whereas induction of collagen X expression was BMP‐dependent.Conclusions:Retinoids appear to have a preeminent role in controlling expression and function of CTGF in hypertrophic and posthypertrophic chondrocytes and do so with differential cooperation and intervention of MAP kinases and BMP signaling.

Meckel's cartilage is a prominent feature of the developing mandible, but its formation and roles remain unclear. Because connective tissue growth factor (CTGF, CCN2) regulates formation of other cartilages, we asked whether it is expressed and what roles it may have in developing mouse Meckel's cartilage. Indeed, CTGF was strongly expressed in anterior, central, and posterior regions of embryonic day (E) 12 condensing Meckel's mesenchyme. Expression decreased in E15 newly differentiated chondrocytes but surged again in E18 hypertrophic chondrocytes located in anterior region and most‐rostral half of central region. These cells were part of growth plate‐like structures with zones of maturation resembling those in a developing long bone and expressed such characteristic genes as Indian hedgehog (Ihh), collagen X, MMP‐9, and vascular endothelial growth factor. At each stage examined perichondrial tissues also expressed CTGF. To analyze CTGF roles, mesenchymal cells isolated from E10 first branchial arches were tested for interaction and responses to recombinant CTGF (rCTGF). The cells readily formed aggregates in suspension culture and interacted with substrate‐bound rCTGF, but neither event occurred in the presence of CTGF neutralizing antibodies. In good agreement, rCTGF treatment of micromass cultures stimulated both expression of condensation‐associated macromolecules (fibronectin and tenascin‐C) and chondrocyte differentiation. Expression of these molecules and CTGF itself was markedly up‐regulated by treatment with transforming growth factor‐β1, a chondrogenic factor. In conclusion, CTGF is expressed in highly dynamic manners in developing Meckel's cartilage where it may influence multiple events, including chondrogenic cell differentiation and chondrocyte maturation. CTGF may aid chondrogenesis by acting down‐stream of transforming growth factor‐β and stimulating cell–cell interactions and expression of condensation‐associated genes. Developmental Dynamics 231:136–147, 2004. © 2004 Wiley‐Liss, Inc.