Predicting wheat yield from 2001 to 2020 in Hebei Province at county and pixel levels based on synthesized time series images of Landsat and MODIS.

To obtain seasonable and precise crop yield information with fine resolution is very important for ensuring the food security. However, the quantity and quality of available images and the selection of prediction variables often limit the performance of yield prediction. In our study, the synthesized images of Landsat and MODIS were used to provide remote sensing (RS) variables, which can fill the missing values of Landsat images well and cover the study area completely. The deep learning (DL) was used to combine different vegetation index (VI) with climate data to build wheat yield prediction model in Hebei Province (HB). The results showed that kernel NDVI (kNDVI) and near-infrared reflectance (NIRv) slightly outperform normalized difference vegetation index (NDVI) in yield prediction. And the regression algorithm had a more prominent effect on yield prediction, while the yield prediction model using Long Short-Term Memory (LSTM) outperformed the yield prediction model using Light Gradient Boosting Machine (LGBM). The model combining LSTM algorithm and NIRv had the best prediction effect and relatively stable performance in single year. The optimal model was then used to generate 30 m resolution wheat yield maps in the past 20 years, with higher overall accuracy. In addition, we can define the optimum prediction time at April, which can consider simultaneously the performance and lead time. In general, we expect that this prediction model can provide important information to understand and ensure food security.

Research on land cover classification of multi-source remote sensing data based on improved U-net network.

In recent years, remote sensing images of various types have found widespread applications in resource exploration, environmental protection, and land cover classification. However, relying solely on a single optical or synthetic aperture radar (SAR) image as the data source for land cover classification studies may not suffice to achieve the desired accuracy in ground information monitoring. One widely employed neural network for remote sensing image land cover classification is the U-Net network, which is a classical semantic segmentation network. Nonetheless, the U-Net network has limitations such as poor classification accuracy, misclassification and omission of small-area terrains, and a large number of network parameters. To address these challenges, this research paper proposes an improved approach that combines both optical and SAR images in bands for land cover classification and enhances the U-Net network. The approach incorporates several modifications to the network architecture. Firstly, the encoder-decoder framework serves as the backbone terrain-extraction network. Additionally, a convolutional block attention mechanism is introduced in the terrain extraction stage. Instead of pooling layers, convolutions with a step size of 2 are utilized, and the Leaky ReLU function is employed as the network's activation function. This design offers several advantages: it enhances the network's ability to capture terrain characteristics from both spatial and channel dimensions, resolves the loss of terrain map information while reducing network parameters, and ensures non-zero gradients during the training process. The effectiveness of the proposed method is evaluated through land cover classification experiments conducted on optical, SAR, and combined optical and SAR datasets. The results demonstrate that our method achieves classification accuracies of 0.8905, 0.8609, and 0.908 on the three datasets, respectively, with corresponding mIoU values of 0.8104, 0.7804, and 0.8667. Compared to the traditional U-Net network, our method exhibits improvements in both classification accuracy and mIoU to a certain extent.

Neurodynamics of Awareness Detection in Tibetan Immigrants: Evidence from Electroencephalography Analysis.

The psychological effects of long-term exposure to high-altitude environments have attracted great attention. These effects are usually attributed to the diminished cognitive resources due to high-altitude exposure. This study employed electroencephalography (EEG) to investigate the effects of exposure duration on awareness detection tasks. Neither reaction time nor accuracy showed the direct effects of the exposure duration, so did the model indexes obtained from drift diffusion model analysis. However, event-related potentials (ERP) analysis revealed that exposure duration was associated with changes in the visual awareness negativity (VAN) and the late positivity (LP) components, which in turn affected reaction time. Specifically, longer exposure durations were associated with lower VAN and higher LP, resulting in shorter reaction times and greater drift rate. In contrast to previous studies, the reverse relationship between VAN and LP may reflect a compensatory response to the reduced cognitive resources caused by high-altitude exposure. Additionally, increased LP and shorter reaction times with exposure duration may reflect a resistance to the high-altitude environment. We also conducted time-frequency analysis and found that theta power did not vary with exposure duration, suggesting that the reduction in cognitive resources remains stable in these individuals over time. Overall, our study provides new insights into the dynamic effects of high-altitude environments on awareness detection in the presence of reduced cognitive resources.

Association between the acceleration of access to visual awareness of grating orientation with higher heart rate at high-altitude.

Many studies have indicated a strong relationship between cardiac and brain activities, both of which are sensitive to high-altitude exposure. This study combined a consciousness access task and electrocardiograms (ECG) to uncover conscious awareness in response to high-altitude exposure and its relation to cardiac activity. When compared with the low-altitude groups, the behavioral results showed that the high-altitude participants shortened the time of access to visual awareness of grating orientation, which was accompanied by a faster heart rate, excluding the influence of pre-stimulus heart rate, extent of cardiac deceleration after presenting the stimulus, and task difficulty. Although there were post-stimulation cardiac deceleration and post-response acceleration at both high and low altitudes, a slight increase in heart rate after stimulation at high altitudes may indicate that participants at high altitudes could quickly readjust their attention to the target stimulus. More importantly, the drift diffusion model (DDM) was used to fit the access time distribution of all participants. These results suggest that shorter time at high altitudes might be due to the lower threshold, suggesting that less evidence in high-altitude participants was required to access visual consciousness. The participants' heart rates also negatively predicted the threshold through a hierarchical drift diffusion modeling (HDDM) regression. These findings imply that individuals with higher heart rates at high altitudes have a greater cognitive burden.

[Accumulation Characteristics and Influencing Factors of Heavy Metals in Cultivated Land Surface Soil in Lanzhou].

In this study, As, Cd, Cr, Hg, and Pb in the surface soil of cropland in Lanzhou were studied, and the combination of descriptive statistics, single-factor accumulation index, comprehensive accumulation index, geostatistical method, and a geographically weighted regression model (GWR) was used to investigate their accumulation status, spatial distribution, and influencing factors, in order to provide scientific basis for the precise control of heavy metal accumulation risk in the study area. The results showed that:①the single-factor accumulation index showed that the accumulation of Hg and Cd in the study area was the largest, followed by that of Pb and As, and that of Cr was the smallest; the comprehensive accumulation index showed that the accumulation rate of heavy metals was as high as 98.11%, of which 54.81% was mild accumulation and 43.30% was moderate and above accumulation. However, there was no heavy metal pollution in the surface soil of cultivated land in Lanzhou. ② Spatial autocorrelation analysis showed that there was no heavy metal pollution in the surface soil of Lanzhou, but there was accumulation in a few areas. The spatial autocorrelation analysis showed that the spatial autocorrelation of the Cr, Hg, and Pb single-factor accumulation indices was moderate, indicating that they were influenced by both random and structural factors; the spatial autocorrelation of the other two heavy metals was weak, indicating that they were mainly influenced by random factors, among which human factors were more influential. The Hg single-factor accumulation index was high in the middle and low in the fourth; the integrated accumulation index increased from northwest to southeast and decreased from the middle to both sides. ③ Geographically weighted regression (GWR) analysis showed that altitude, slope length, distance from rivers, soil organic matter (SOM) content, precipitation, air temperature, and surface temperature all showed positive driving effects, whereas the rest of the factors showed negative driving effects and significant spatial heterogeneity and instability (P<0.05). The magnitudes of the factor effects were in the order of soil characteristics>topographic characteristics>climate characteristics>location characteristics>socioeconomic characteristics>vegetation characteristics, with the largest contribution of SOM content, followed by that of altitude and air temperature, and the smallest of normalized difference vegetation index (NDVI) values. Compared with the other feature factors, the location feature factors had stronger spatial heterogeneity.

Intramolecular H-Bonds in an Organocatalyst Enabled an Asymmetric Michael/Alkylation Cascade Reaction to Construct Spirooxindoles Incorporating a Densely Substituted Cyclopropane Motif.

A cascade Michael addition/alkylation reaction between 3-chlorooxindoles and α-cyano chalcones catalyzed using a multifunctional quinine-derived aminoindanol-thiourea substance was investigated. A series of spirooxindoles incorporating a densely substituted cyclopropane motif were efficiently obtained with moderate to excellent diastereo- and enantioselectivity and further transformed to products with versatile structural diversity. Density functional theory (DFT) calculations indicated that the tentative intramolecular hydrogen bonds in the chiral catalyst were crucial for the stereocontrol.

[Risk Assessment and Attribution Analysis of "Five Toxic" Heavy Metals in Cultivated Land in Lanzhou].

Heavy metals in cultivated soil may migrate and transform through the food chain to harm the ecological environment and human health. At present, the ecological environment and human health risks of heavy metals in cultivated soil in Lanzhou city remain unclear, which impacts the effective management and control of heavy metals. The potential ecological risk hazard index was used to evaluate the ecological environmental risks of As, Cd, Cr, Hg, and Pb in the surface soil of cultivated land in Lanzhou, and the health risk model proposed by USEPA and the recommended standard were used to evaluate their human health risk. The main factors influencing the spatial differentiation of human health risk were explored by using geographic detectors. The risk of heavy metals to the ecological environment of the cultivated land surface soil in the study area was mainly medium (65.25%), and small portions were low (13.80%) and high (20.95%). The low-risk areas were mainly located in the southeast of Yongdeng County, the middle and north of Yuzhong County, and the southwest of Gaolan County. Moderate risk areas were distributed in three counties and five districts. The high-risk areas were located in the north and southeast of Yongdeng County, the south of Chengguan District, the northeast of Qilihe, the east of Xigu District, and the middle of Yuzhong County. The non-carcinogenic and carcinogenic risks of five types of heavy metal exposure pathways were as follows:oral ingestion>skin contact>respiratory ingestion; generally speaking, children were at higher risk than adults. The non-carcinogenic risk in children was higher than that in adults; however, there was no such risk for local residents, as they were all less than 1. At the same time, the carcinogenic risk of As was greater than 1×10-5 (children 2.04×10-5) and less than 1×10-4 (adults 1.91×10-5), respectively. This indicated an acceptable medium risk to the local residents, and the risk to children was again greater than that to adults. Geographical detector analysis showed that average precipitation during the sampling season had the greatest impact on the spatial differentiation of human health risks of As and Cd, GDP had the greatest impact on the spatial differentiation of human health risks of Cr, and distance from the railway had the greatest impact on the spatial differentiation of human health risks of Hg and Pb. Interaction detection showed that all factors were enhanced by double factors. In addition to leading factors, other factors such as pH, slope, and altitude also enhanced the influence of leading factors on the spatial differentiation of heavy metal risk in cultivated soil.

Metformin Can Enhance the Inhibitory Effect of Olaparib in Bladder Cancer Cells.

Background: Bladder cancer is a common urinary system tumor. In the treatment of clinical patients, it is particularly important to find an effective treatment method to inhibit tumor growth. The world's first PARP inhibitor olaparib is mainly used for the treatment of BRCA1/BRCA2 mutated tumors. Metformin, an antidiabetic drug, has been reported to reduce cancer incidence in humans and improve survival in cancer patients. Methods: Cell viability and proliferation were detected by CCK-8 assay and colony formation assay; cell apoptosis was detected by flow cytometry; cell migration and invasion abilities were detected by scratch assay and Transwell assay; STAT3/C-MYC signaling pathway protein were detected by western blotting. Results: Olaparib combined with metformin has better effects on the proliferation, clone formation, migration, invasion, and apoptosis of bladder cancer cells than single drug, indicating that metformin can enhance the inhibitory effect of olaparib on tumor growth and regulate the expression of STAT3/C-MYC signaling pathway proteins. Conclusion: The results of this study showed that metformin could significantly enhance the antitumor effect of olaparib on bladder cancer cells, and these effects were mediated by downregulating STAT3/C-MYC signaling pathway proteins. This finding may have potential clinical application in the treatment of bladder cancer.

Thermal Analysis and Crystal Structure of Poly(Acrylonitrile-Co-Itaconic Acid) Copolymers Synthesized in Water.

The composition and structure of polyacrylonitrile (PAN) precursors play an important role during thermal stabilization, which influences the properties of the resulting carbon fibers. In this paper, PAN homopolymer and PAN-itaconic (IA) copolymers with different IA contents were synthesized by aqueous phase precipitation polymerization. The effects of IA content on the structure and thermal properties were studied using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The morphology of PAN polymers showed that the average size of the PAN particles increased with the increase of IA content in the feed. The content of the IA comonomer on the copolymers was quantitatively characterized by the relative absorbance intensity (A1735/A2243) in FTIR spectrum. With the increase of IA content in the feed, PAN-IA copolymers exhibited lower degree of crystallinity and crystal size than the control PAN homopolymer. The results from DSC curves indicated that PAN-IA1.0 copolymers had lower initial exothermic temperature (192.4 °C) and velocity of evolving heat (6.33 J g-1 °C-1) in comparison with PAN homopolymer (Ti = 238.1 °C and ΔH/ΔT = 34.6 J g-1 °C-1) in an air atmosphere. TGA results suggested that PAN-IA1.0 copolymers had higher thermal stability than PAN homopolymer, which can form a ladder structure easier during thermal processing. Therefore, PAN-IA1.0 copolymers would be a suitable candidate for preparing high performance PAN based carbon fibers.

Anxiety-Related Coping Styles, Social Support, and Internet Use Disorder.

Objective: The Internet can offer a seemingly safe haven for those being disappointed by relationships in the "offline world". Although the Internet can provide lonely people with opportunities to seek for help and support online, complete withdrawal from the offline world comes with costs. It is discussed if people can even become "addicted" to the Internet. Of note, meanwhile, many researchers prefer the term Internet use disorder (IUD) instead of using the term "Internet addiction". To illustrate the importance of one's own social network supporting a person in everyday life, we investigated, for the first time to our knowledge, how social resources in terms of quality and quantity might represent a buffer against the development of IUD. Furthermore, anxiety related coping styles are investigated as a further independent variable likely impacting on the development of an IUD. Method: In the present work, N = 567 participants (n = 164 males and n = 403 females; Mage = 23.236; SDage = 8.334) filled in a personality questionnaire assessing individual differences in cognitive avoidant and vigilant anxiety processing, ergo, traits describing individual differences in everyday coping styles/modes. Moreover, all participants provided information on individual differences in tendencies toward IUD, the perceived quality of social support received, and the size of their social network (hence a quantity measure). Results: Participants with larger social networks and higher scores in the received social support reported the lowest tendencies toward IUD in our data. A vigilant coping style was positively correlated with tendencies toward IUD, whereas no robust associations could be observed between a cognitive avoidant coping style and tendencies toward IUD. Hierarchical linear regression underlined an important predictive role of the interaction term of vigilance in ego-threat scenarios and perceived quality of social support. Conclusion: The current study not only yields support for the hypothesis that the size of one's own social network as well as the perceived quality of social support received in everyday life present putative resilience factors against developing IUD. It also supports the approach that special coping styles are needed to make use of the social support offered.

The Structure and Properties of Polyacrylonitrile Nascent Composite Fibers with Grafted Multi Walled Carbon Nanotubes Prepared by Wet Spinning Method.

Polyacrylonitrile (PAN) grafted amino-functionalized multi walled carbon nanotubes (amino-MWCNTs) were synthesized by in situ polymerization under aqueous solvent. The grafted MWCNT/PAN nascent composite fibers were prepared by the wet spinning method. Fourier transform infrared spectroscopy and Raman spectroscopy indicated that the amino-MWCNTs and PAN macromolecular chains had interfacial interactions and formed chemical bonds. The grafting content of the PAN polymer on the amino-MWCNTs was up to 73.2% by thermo gravimetric analysis. The incorporation of the grafted MWCNTs improved the degree of crystallization and crystal size of PAN nascent fibers, and changed the thermal properties during exothermic processing in an air atmosphere. Morphology analysis and testing of mechanical properties showed that the grafted MWCNT/PAN nascent composite fibers with a more uniform diameter distribution and larger diameter had higher tensile strength and tensile modulus than the control PAN nascent fibers.

Novel findings on ultrastructural protection of skeletal muscle fibers during hibernation of Daurian ground squirrels: Mitochondria, nuclei, cytoskeleton, glycogen.

We examined ultrastructure protective phenomena and mechanisms of slow and fast muscles in hibernating Daurian ground squirrels (Spermophilus dauricus). Some degenerative changes such as slightly decreased sarcomere length and vacuolization occurred in hibernation, but periaxonal capsular borders in intrafusal fibers remained distinct and the arrangement of extrafusal fibers and Z-lines unscathed. In soleus samples, the number of glycogenosomes more than tripled during hibernation. The expression of phosphorylated glycogen synthase remained unaltered while that of glycogen phosphorylase decreased during hibernation. The number of extensor digitorum longus glycogenosomes decreased and the expression of phosphorylated glycogen synthase decreased, while glycogen phosphorylase expression remained unaltered. The nuclei number remained unchanged. Kinesin and desmin, preventors of nuclear loss and damage, were maintained or just slightly reduced in hibernation. The single-fiber mitochondrial concentration and sub-sarcolemmal mitochondrial number increased in both muscle types. The expression of vimentin, which anchors mitochondria and maintains Z-line integrity, was increased during and after hibernation. Also, dynamin-related protein 1, mitochondrial fission factor, and adenosine triphosphate synthase were elevated in both muscle types. These findings confirm a remarkable ultrastructure preservation and show an unexpected increase in mitochondrial capacity in hibernating squirrels.

Rheological Behavior of Amino-Functionalized Multi-Walled Carbon Nanotube/Polyacrylonitrile Concentrated Solutions and Crystal Structure of Composite Fibers.

The rheological behavior of amino-functionalized multi-walled carbon nanotubes (amino-CNTs)/polyacrylonitrile (PAN) concentrated solutions in the dimethyl sulphoxide solvent and the effects of the amino-CNTs on the PAN precursor fibers by wet-spinning method were investigated. The amino-CNT/PAN concentrated solutions prepared by in situ solution polymerization with homogeneous dispersion of amino-CNTs have higher complex viscosity, storage modulus and loss modulus as compared to the control PAN concentrated solutions containing 22% PAN polymer by mass. The composite fibers with amino-CNTs of 1 wt % have lower degree of crystallization, crystal size and crystal region orientation compared to the control PAN precursor fibers. However, the amino-CNT/PAN composite fibers with diameter of about 10.5 µm exhibit higher mechanical properties than the control PAN precursor fibers with diameter of about 8.0 µm. Differential scanning calorimetry analysis demonstrated that the cyclization reaction in composite fibers have broad exothermic temperature range and low exothermic rate. These results indicate that the addition of amino-CNTs into PAN precursor fibers is beneficial to controlling the process of thermal stabilization and obtaining the higher performance of composite fibers.

Effects of Amino-Functionalized Carbon Nanotubes on the Crystal Structure and Thermal Properties of Polyacrylonitrile Homopolymer Microspheres.

Amino-functionalized multi-walled carbon nanotube (amino-CNT)/polyacrylonitrile (PAN) microspheres with diameter of about 300⁻400 nm were prepared by in situ polymerization under aqueous solution. The morphology, crystal structure, and thermal properties of amino-CNTs on a PAN homopolymer were investigated by scanning electron microscopy, transmission electron microscopy, Fourier transform infrared spectra, X-ray diffraction, and differential scanning calorimetry. The results showed that the amino-CNTs had a significant influence on the morphology of microspheres, and the PAN matrix were grafted onto the surface of amino-CNTs with interfacial bonding between them. The XRD studies showed that the crystal size of amino-CNT/PAN microspheres with lower crystallinity was bigger than in the control PAN homopolymer. The analysis of thermal properties indicated that the amino-CNT/PAN microspheres with lower glass transition temperature had a lower initial temperature and velocity of evolving heat during the exothermic processing as compared with the PAN homopolymer. These results suggested that the incorporation of amino-CNTs into the PAN homopolymer matrix was beneficial for controlling the heat released during the stabilization processing.

Increased expression of microRNA-301a in nonsmall-cell lung cancer and its clinical significance.

AIMS: Recently, accumulating evidence indicates that dysregulation of microRNAs is associated with the initiation and progression of cancer. Oncogenic miR-301a has been reported upregulation and associated with tumorigenesis and progression in various types of cancer. The aim of this study was to investigate the expression of miR-301a in nonsmall-cell lung cancer. (NSCLC), and to assess its association with malignancy, metastasis and prognosis. SUBJECTS AND METHODS: total of 88 NSCLC patients (females = 21 and males = 67), aged 15-81 years were included in the study. miR-301a expression in tumor tissue was estimated by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: miR-301a was significantly upregulated in NSCLC tissues compared with their paired adjacent nontumor tissues. (P < 0.001). Increased expression of miR-301a was detected in tumors with lymph node metastases. (P =0.003). In addition, high miR-301a expression was significantly associated with poorly differentiation. (P =0.015), lymph node metastasis. (P =0.013) and advanced tumor-node-metastasis. (TNM) stage. (P =0.018). A. comparison of survival curves of low versus high expressers of miR-301a revealed a highly significant difference in NSCLC, which suggests that overexpression of miR-301a is associated with a poorer disease-free survival (DFS) (P =0.002). Moreover, multivariate Cox proportional hazard regression analyses revealed that the miR-301a overexpression was an unfavorable prognostic factor for disease-free survival in addition to TNM stage. CONCLUSIONS: miR-301a may represent a novel prognostic indicator, a biomarker for the early detection of lymph node metastasis and a therapeutic target in NSCLC.

BBT improves glucose homeostasis by ameliorating ß-cell dysfunction in type 2 diabetic mice.

Impaired glucose-stimulated insulin secretion (GSIS) and increasing ß-cell death are two typical dysfunctions of pancreatic ß-cells in individuals that are destined to develop type 2 diabetes, and improvement of ß-cell function through GSIS enhancement and/or inhibition of ß-cell death is a promising strategy for anti-diabetic therapy. In this study, we discovered that the small molecule, N-(2-benzoylphenyl)-5-bromo-2-thiophenecarboxamide (BBT), was effective in both potentiating GSIS and protecting ß-cells from cytokine- or streptozotocin (STZ)-induced cell death. Results of further studies revealed that cAMP/PKA and long-lasting (L-type) voltage-dependent Ca(2) (+) channel/CaMK2 pathways were involved in the action of BBT against GSIS, and that the cAMP/PKA pathway was essential for the protective action of BBT on ß-cells. An assay using the model of type 2 diabetic mice induced by high-fat diet combined with STZ (STZ/HFD) demonstrated that BBT administration efficiently restored ß-cell functions as indicated by the increased plasma insulin level and decrease in the ß-cell loss induced by STZ/HFD. Moreover, the results indicated that BBT treatment decreased fasting blood glucose and HbA1c and improved oral glucose tolerance further highlighting the potential of BBT in anti-hyperglycemia research.

Suppressive effects of oral administration of heat-killed Lactobacillus acidophilus on T helper-17 immune responses in a bovine ß-lactoglobulin-sensitized mice model.

The present study was planned to explore the effect of Lactobacillus (L.) acidophilus on the T helper-17 (Th17) immune response in a mouse model of ß-lactoglobulin (ß-lg) allergy. Bovine ß-lg sensitised BALB/c mice were orally administered with different doses of heat-killed L. acidophilus (low, 5×10(7) colony forming unit (CFU); medium, 5×10(8) CFU; high, 5×10(9) CFU) in 200 µL of phosphate buffered saline (PBS) three times a week, starting from 1 week before ß-lg sensitisation for 4 weeks. After the allergen challenge, the numbers of blood eosinophils and neutrophils were examined by light microscope; the levels of cytokine (interleukin (IL)-12, IL-4, tumor growth factor (TGF)-ß, IL-10, IL-6 and IL-17A), total immunoglobulin E (IgE) and ß-lg-specific IgE contents in the serum were measured with enzyme-linked immunosorbent assay (ELISA); The mRNA expression levels of TGF-ß, IL-17A,CD25, Foxp3, retinoic acid-related orphan receptor γt (RORγt) and IL-10 were analyzed using real-time polymerase chain reaction (PCR). The results showed that oral administration of L. acidophilus suppressed hypersensitivity responses, attenuated the numbers of inflammatory cells and inhibited IgE production. We found up-regulation of TGF-ß and down-regulation of IL-17A in the serum of L. acidophilus-treated group, along with IL-6 levels was significantly decreased than that of the allergy group (p<0.05). Moreover, the mRNA expression levels of CD25, forkhead box P3 and TGF-ß were significantly higher in the spleen of L. acidophilus-treated group, while the mRNA expression levels of IL-17A, RORγt and IL-10 were significantly lower than that in the allergy group (p<0.05). In conclusion, the suppression of major allergic symptoms by oral administration of L.acidophilus was probably due to improve the regulatory T (Treg)/Th17 balance and inhibit the IL-6 production.

Development of macromolecular prodrug for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that is considered to be one of the major public health problems worldwide. The development of therapies that target tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and co-stimulatory pathways that regulate the immune system have revolutionized the care of patients with RA. Despite these advances, many patients continue to experience symptomatic and functional impairment. To address this issue, more recent therapies that have been developed are designed to target intracellular signaling pathways involved in immunoregulation. Though this approach has been encouraging, there have been major challenges with respect to off-target organ side effects and systemic toxicities related to the widespread distribution of these signaling pathways in multiple cell types and tissues. These limitations have led to an increasing interest in the development of strategies for the macromolecularization of anti-rheumatic drugs, which could target them to the inflamed joints. This approach enhances the efficacy of the therapeutic agent with respect to synovial inflammation, while markedly reducing non-target organ adverse side effects. In this manuscript, we provide a comprehensive overview of the rational design and optimization of macromolecular prodrugs for treatment of RA. The superior and the sustained efficacy of the prodrug may be partially attributed to their Extravasation through Leaky Vasculature and subsequent Inflammatory cell-mediated Sequestration (ELVIS) in the arthritic joints. This biologic process provides a plausible mechanism, by which macromolecular prodrugs preferentially target arthritic joints and illustrates the potential benefits of applying this therapeutic strategy to the treatment of other inflammatory diseases.

Early detection and treatment of wear particle-induced inflammation and bone loss in a mouse calvarial osteolysis model using HPMA copolymer conjugates.

Wear particle-induced inflammation is considered to be the major cause of aseptic implant loosening and clinical failure after total joint replacement. Due to the frequent absence of symptoms, early detection and intervention prior to implant failure presents a significant challenge. To address this issue, a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based optical imaging contrast agent (P-IRDye) was developed and used for the detection of wear particle-induced inflammation employing a murine calvaria osteolysis model. The particle-induced osteolysis of calvaria was evaluated by H&E, tartrate-resistant acid phosphatase (TRAP) staining and µ-CT after necropsy. One-day post particle implantation, P-IRDye was administrated to the mice via tail vein injection. Live imaging of the animals 6 days after implantation revealed the preferential distribution and sustained retention of the macromolecular contrast agent at the site of particle implantation. Immunohistochemical staining and FACS analyses of the calvaria-associated soft tissue revealed extensive uptake of the HPMA copolymer by F4/80, Ly-6G (Gr1) and CD11c positive cells, which accounts for the retention of the macromolecular probes at the inflammatory sites. To test the potential of the system for therapeutic intervention, an acid-labile HPMA copolymer-dexamethasone conjugate (P-Dex) was prepared and shown to prevent the particle-induced inflammation and bone damage in the calvaria osteolysis model.

[Expression of hSef and FGF-2 in epithelial ovarian tumor].

OBJECTIVE: To detect the expression of human similar expression to FGF gene(hSef) and fibroblast growth factor-2(FGF-2) and their correlation with epithelial ovarian tumor. METHODS: Immunohistochemical SP staining was used to detect the expression of hSef and FGF-2 proteins in 31 cases of epithelial ovarian carcinoma (EOC), 18 cases of benign epithelial tumor (BET), 10 cases of normal ovarian (NO) tissues collected from July 2007 to May 2008. The expression of hSef mRNA in 24 cases of EOC, BET and NO collected from July 2008 to May 2009 were analyzed by RT-PCR. RESULTS: The results of immunohistochemical study showed that the expression of hSef in the EOC tissues were significantly lower than that in the NO and BET (P < 0.001). However, the expression of FGF-2 was higher (P = 0.002). The expression of hSef had a negative correlation with FGF-2 (r(s) = -0.324, P = 0.012). The RT-PCR results showed that there was a gradually declined trend of expression of hSef in NO, BET to EOC (P < 0.001), but the expression of FGF-2 in NO, BET to EOC was gradually increased (P < 0.001), with a significant negative correlation (NO: r(s) = -0.910, P < 0.001; BET: r(s) = -0.859, P < 0.001; EOC: r(s) = -0.888, P < 0.001). CONCLUSIONS: The expression of hSef is decreased in epithelial ovarian carcinoma tissue, but the expression of FGF-2 is increased. It is likely that low hSef expression is related to the the carcinogenesis and development of epithelial ovarian carcinoma by suppressing the promoting effects of FGF-2 to cell proliferation.