Identification and analysis of differently expressed transcription factors in aristolochic acid nephropathy.

BACKGROUND: Aristolochic acid nephropathy (AAN) is a rapidly progressive interstitial nephropathy caused by Aristolochic acid (AA). AAN is associated with the development of nephropathy and urothelial carcinoma. It is estimated that more than 100 million people worldwide are at risk of developing AAN. However, the underlying mechanisms driving renal deterioration in AAN remain poorly understood, and the treatment options are limited. METHODS: We obtained GSE27168 and GSE136276 series matrix data from the Gene Expression Omnibus (GEO) related to AAN. Using the R Studio environment, we applied the limma package and WGCNA package to identify co-differently expressed genes (co-DEGs). By GO/KEGG/GSVA analysis, we revealed common biological pathways. Subsequently, co-DEGs were subjected to the String database to construct a protein-protein interaction (PPI) network. The MCC algorithms implemented in the Cytohubba plugin were employed to identify hub genes. The hub genes were cross-referenced with the transcription factor (TF) database to identify hub TFs. Immune infiltration analysis was performed to identify key immune cell groups by utilizing CIBERSORT. The expressions of AAN-associated hub TFs were verified in vivo and in vitro. Finally, siRNA intervention was performed on the two TFs to verify their regulatory effect in AAN. RESULTS: Our analysis identified 88 co-DEGs through the "limma" and "WGCNA" R packages. A PPI network comprising 53 nodes and 34 edges was constructed with a confidence level >0.4. ATF3 and c-JUN were identified as hub TFs potentially linked to AAN. Additionally, expressions of ATF3 and c-JUN positively correlated with monocytes, basophils, and vessels, and negatively correlated with eosinophils and endothelial cells. We observed a significant increase in protein and mRNA levels of these two hub TFs. Furthermore, it was found that siRNA intervention targeting ATF3, but not c-JUN, alleviated cell damage induced by AA. The knockdown of ATF3 protects against oxidative stress and inflammation in the AAN cell model. CONCLUSION: This study provides novel insights into the role of ATF3 in AAN. The comprehensive analysis sheds light on the molecular mechanisms and identifies potential biomarkers and drug targets for AAN treatment.

Confined covalent organic framework anchored Fe sites derived highly uniform electrocatalysts for rechargeable aqueous and solid-state Zn-air batteries.

Exploiting clean, highly efficient energy storage and conversion device like Zn-air battery is of significance for alleviating the energy and environmental crises of this society. Metal organic coordination polymers/frameworks have been regarded as ideal templates to synthesize non-noble metal catalysts for a long time. However, the high density of metal nodes inevitably leads to the heavy aggregation of metal nanoparticles during thermolysis transformation process, which greatly hinders the maximizing of electrochemical performances. Herein, covalent organic framework (COF) has been employed to anchor the quantificational Fe ions (COF-Fe) and then confined into the macropores of g-C3N4 to improve the dispersion of metal active sites and avoid severe aggregation during high temperature pyrolysis. After calcination, the metal nanoparticles highly dispersed Fe-CFN catalysts can be obtained. The optimal Fe-CFN-800 catalysts exhibit excellent ORR and OER performances with the potential difference between ORR and OER of merely 0.723 V. Moreover, experimental way and DFT theoretical calculations are also employed to disclose the reaction mechanism. Finally, the all-solid-state and aqueous Zn-air batteries assembled with the optimized Fe-CFN-800 as cathode present excellent performances with high peak power density, flexible rate performance, strong discharge stability and long-term charge-discharge cycling performance.

E-GWAS: an ensemble-like GWAS strategy that provides effective control over false positive rates without decreasing true positives.

BACKGROUND: Genome-wide association studies (GWAS) are an effective way to explore genotype-phenotype associations in humans, animals, and plants. Various GWAS methods have been developed based on different genetic or statistical assumptions. However, no single method is optimal for all traits and, for many traits, the putative single nucleotide polymorphisms (SNPs) that are detected by the different methods do not entirely overlap due to the diversity of the genetic architecture of complex traits. Therefore, multi-tool-based GWAS strategies that combine different methods have been increasingly employed. To take this one step further, we propose an ensemble-like GWAS strategy (E-GWAS) that statistically integrates GWAS results from different single GWAS methods. RESULTS: E-GWAS was compared with various single GWAS methods using simulated phenotype traits with different genetic architectures. E-GWAS performed stably across traits with different genetic architectures and effectively controlled the number of false positive genetic variants detected without decreasing the number of true positive variants. In addition, its performance could be further improved by using a bin-merged strategy and the addition of more distinct single GWAS methods. Our results show that the numbers of true and false positive SNPs detected by the E-GWAS strategy slightly increased and decreased, respectively, with increasing bin size and when the number and the diversity of individual GWAS methods that were integrated in E-GWAS increased, the latter being more effective than the bin-merged strategy. The E-GWAS strategy was also applied to a real dataset to study backfat thickness in a pig population, and 10 candidate genes related to this trait and expressed in adipose-associated tissues were identified. CONCLUSIONS: Using both simulated and real datasets, we show that E-GWAS is a reliable and robust strategy that effectively integrates the GWAS results of different methods and reduces the number of false positive SNPs without decreasing that of true positive SNPs.

Identification and validation of hub genes in drug induced acute kidney injury basing on integrated transcriptomic analysis.

Background: Drug-induced acute kidney damage (DI-AKI) is a clinical phenomenon of rapid loss of kidney function over a brief period of time as a consequence of the using of medicines. The lack of a specialized treatment and the instability of traditional kidney injury markers to detect DI-AKI frequently result in the development of chronic kidney disease. Thus, it is crucial to continue screening for DI-AKI hub genes and specific biomarkers. Methods: Differentially expressed genes (DEGs) of group iohexol, cisplatin, and vancomycin's were analyzed using Limma package, and the intersection was calculated. DEGs were then put into String database to create a network of protein-protein interactions (PPI). Ten algorithms are used in the Cytohubba plugin to find the common hub genes. Three DI-AKI models' hub gene expression was verified in vivo and in vitro using PCR and western blot. To investigate the hub gene's potential as a biomarker, protein levels of mouse serum and urine were measured by ELISA kits. The UUO, IRI and aristolochic acid I-induced nephrotoxicity (AAN) datasets in the GEO database were utilized for external data verification by WGCNA and Limma package. Finally, the Elisa kit was used to identify DI-AKI patient samples. Results: 95 up-regulated common DEGs and 32 down-regulated common DEGs were obtained using Limma package. A PPI network with 84 nodes and 24 edges was built with confidence >0.4. Four hub genes were obtained by Algorithms of Cytohubba plugin, including TLR4, AOC3, IRF4 and TNFAIP6. Then, we discovered that the protein and mRNA levels of four hub genes were significantly changed in the DI-AKI model in vivo and in vitro. External data validation revealed that only the AAN model, which also belonged to DI-AKI model, had significant difference in these hub genes, whereas IRI and UUO did not. Finally, we found that plasma TLR4 levels were higher in patients with DI-AKI, especially in vancomycin-induced AKI. Conclusion: The immune system and inflammation are key factors in DI-AKI. We discovered the immunological and inflammatory-related genes TLR4, AOC3, IRF4, and TNFAIP6, which may be promising specific biomarkers and essential hub genes for the prevention and identification of DI-AKI.

Development and application of an efficient genomic mating method to maximize the production performances of three-way crossbred pigs.

Creating synthetic lines is the standard mating mode for commercial pig production. Traditional mating performance was evaluated through a strictly designed cross-combination test at the 'breed level' to maximize the benefits of production. The Duroc-Landrace-Yorkshire (DLY) three-way crossbred production system became the most widely used breeding scheme for pigs. Here, we proposed an 'individual level' genomic mating procedure that can be applied to commercial pig production with efficient algorithms for estimating marker effects and for allocating the appropriate boar-sow pairs, which can be freely accessed to public in our developed HIBLUP software at https://www.hiblup.com/tutorials#genomic-mating. A total of 875 Duroc boars, 350 Landrace-Yorkshire sows and 3573 DLY pigs were used to carry out the genomic mating to assess the production benefits theoretically. The results showed that genomic mating significantly improved the performances of progeny across different traits compared with random mating, such as the feed conversion rate, days from 30 to 120 kg and eye muscle area could be improved by -0.12, -4.64 d and 2.65 cm2, respectively, which were consistent with the real experimental validations. Overall, our findings indicated that genomic mating is an effective strategy to improve the performances of progeny by maximizing their total genetic merit with consideration of both additive and dominant effects. Also, a herd of boars from a richer genetic source will increase the effectiveness of genomic mating further.

Trametinib for patients with recurrent low-grade serous ovarian cancer: A cost-effectiveness analysis.

OBJECTIVE: The GOG 281/LOGS trial found that trametinib prolonged progression-free survival (PFS) in patients with recurrent low-grade serous ovarian cancer (LGSOC), compared with standard of care (SOC). The current study aimed to evaluate the cost-effectiveness of trametinib versus standard of care for recurrent LGSOC from the US payer perspective. METHODS: A Markov model was adopted to compare the cost and effectiveness of trametinib and standard of care group in patients with recurrent LGSOC. Life years (LYs), quality-adjusted LYs (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) were calculated. One-way, and probabilistic sensitivity analyses were performed to explore the model robustness. RESULT: Trametinib group provided an additional 0.58 QALYs (1.14 LYs) and an incremental cost of $248,214 compared with the SOC group. The incremental cost-effectiveness ratio was $424,097 per QALY. The results of one-way sensitivity analyses suggested that our model was sensitive to the hazard ratio of OS and PFS between trametinib and SOC group, utility of PFS and the cycle cost of trametinib. Probabilistic sensitivity analyses revealed that there was 6% probability of the trametinib group being cost-effective at a willingness-to-pay (WTP) threshold of $150,000 per QALY. CONCLUSIONS: From the US payer perspective, trametinib is not cost-effective for patients with recurrent LGSOC at the assumed WTP threshold of $150,000 per QALY. Based on the value standpoint, price reduction of trametinib is expected to improve the cost-effectiveness of trametinib in patients with recurrent LGSOC.

Flexible Polymer Ultra-Fine Fiber with Extreme Toughness.

Fiber materials with multilevel interior structures have myriad applications in many fields due to their unique properties. In this study, we develop a bioinspired flexible ultrafine polymer fiber via an integrated microfluidic-electrospinning technology. The fiber possesses periodic hollow and tubular chambers with a shell layer of approximately 150 nm in thickness extremely like natural bamboo. The single fiber with a diameter of ∼1.5 µm exhibits the Young's modulus ranging from 2 to 7 MPa measured with atomic force microscopy (AFM). The fiber with periodic hollow chambers and extreme toughness can find many applications in medicine, industry, and agriculture.

A nano-micro alternating multilayer scaffold loading with rBMSCs and BMP-2 for bone tissue engineering.

In this study, we develop a nano-micro alternating multilayer scaffold for bone tissue engineering by incorporation of monodispersed calcium alginate microbeads into electrospun polymer nanofibers. Both rat bone marrow mesenchymal stem cells (rBMSCs) and bone morphogenetic protein-2 (BMP-2) are simultaneously loaded into the microbeads, which are generated from a microfluidic device. The layer number of the scaffold can be readily controlled by alternately repeating the electrospinning and the microfluidic processes. Alkaline phosphatase (ALP) activity and Alizarin Red S staining results demonstrate that this rBMSCs and BMP-2 loaded nano-micro alternating multilayer scaffold presents an outstanding osteogenic effect in vitro. Histological and immunohistochemical assessments further reveal that this multilayer scaffold has a significant capability of ectopic bone formation in vivo, enabling this newly developed scaffold to be suitable for wide applications in tissue engineering.

[Inhibition of decomposing leaf litter of Cinnamomum camphora on growth of Capsicum annu- um and the alleviation effect of nitrogen application].

Effects of decomposing leaf litter of Cinnamomum camphora on growth, physiological and phenological traits of Capsicum annuum, and modification of these effects by nitrogen application were investigated using a pot experiment. C. camphora leaf litter was applied at rate of 0, 25, 50 100 g per pot, resulting into four treatments, i.e., CK (the control), L25, L50, and L100. Nitrogen application was firstly performed on the 39th d of decomposition (3.0 g urea was added to each pot six times). Leaf area, plant height, basal diameter and biomass production of C. annuum were all inhibited sharply by exposure to the leaf litter, and the inhibition effect increased with the increasing leaf litter in terms of both the intensity and the stability. Treated with L25, budding number reduced by 88.7% averagely during 55th-75th d, and the rate of fructification plant decreased by 40% on the 96th d of decomposition, while neither buds nor fruits were observed when exposed to L50 and L100 at that time. Pigment contents and net photosynthetic rate (Pn) were impacted due to leaf litter addition, and malonaldehyde (MDA) was only markedly promoted by L100. Inhibition on growth and development of C. annuum caused by leaf litter decomposition could be alleviated by nitrogen application. Leaf area treated with leaf litter recovered to the control level on the 52nd d after nitrogen application, and similar results appeared on the 83rd d after nitrogen application for other growth traits. Budding and fructification status were also visibly improved.

Thermally Switched Release from a Nanogel-in-Microfiber Device.

A nanogel-in-microfiber device, whose release can be switched on and off in response to a temperature change, is successfully developed. The release behaviors are realized through the deswelling and swelling of the nanogels in shell layer of fiber by alternatively elevating and lowering the environmental temperature.

Controlled dual delivery of BMP-2 and dexamethasone by nanoparticle-embedded electrospun nanofibers for the efficient repair of critical-sized rat calvarial defect.

There is an urgent need to develop biomimetic bone tissue engineering scaffolds for the repair of critical-sized calvarial defect. In this study, we developed a new nanoparticle-embedded electrospun nanofiber scaffold for the controlled dual delivery of BMP-2 and dexamethasone (DEX). The scaffold was achieved by (1) the encapsulation of BMP-2 into bovine serum albumin (BSA) nanoparticles to maintain the bioactivity of BMP-2 and (2) the co-electrospinning of the blending solution composed of the BSA nanoparticles, DEX and the poly(ε-caprolactone)-co-poly(ethylene glycol) (PCE) copolymer. The in vitro studies showed that the bioactivity of DEX and BMP-2 was preserved in the dual-drug-loaded nanofiber scaffold, and a sequential release pattern in which most of the DEX was released in the original eight days and the BMP-2 release lasted up to 35 days was achieved. The in vitro osteogenesis study demonstrated that the drug-loaded groups exhibited a strong ability to induce differentiation toward osteoblasts. In vivo osteogenesis studies also revealed that the degrees of repair of rat calvarial defect achieved with the drug-loaded nanofiber scaffolds were significantly better than those obtained with the blank materials; in particular, the dual-drug-loaded nanofiber scaffold manifested the best repair efficacy due to a synergistic effect of BMP-2 and DEX. Therefore, the dual-drug-loaded nanofiber scaffold is deemed a strong potential candidate for the repair of bone defects in bone tissue engineering.

The influence of estradiol on histomorphology of skin flaps with ischemia reperfusion injury / 中华整形外科杂志

<p><b>OBJECTIVE</b>To study the influence of estradiol on histomorphology of skin flaps with ischemia reperfusion injury.</p><p><b>METHODS</b>48 adult male Wistar rats aged 12-14 weeks old, were randomly divided into control group (group I), ischemia-reperfusion group (group II), saline group (group III), estradiol group (group IV). Superficial epigastric artery axial flap, 3 cm x 6 cm in size, was made in the left lower quadrant abdominal of each rat. Flap model with ischemia-reperfusion injury was established by using the nondestructive micro vascular clamp to clamp the superficial epigastric artery. The general condition of the flap was observed after operation. At 7 days after operation, the survival rate of the flap was detected, the flaps were harvested to receive histology and ultrastructural observation. The neutrophils level of the superficial epigastric vein were tested.</p><p><b>RESULTS</b>7 days after operation, the survival rate of the flap in group IV was significantly higher than that in group II, III (P < 0.05). The neutrophils level in group IV was lower than that in group II, III (P < 0.05). The histological observation showed that the degree of tissue swelling and inflammatory exudation in group IV was more slight than that in group II, III. Presence of high neutrophils density were observed in group II, III, while slight inflammation and necrosis were observed in group IV. In group I, collagen fibers in flap are regularly arranged with no significant necrosis. Oganelles structure disappeared and apoptotic bodies were shown in group II and group III, even the lysosome could be seen in the cell. Collagen fibers in flap are regularly arranged with slight swelling and no obvious ultrastructural necrocytosis was seen in the cell of group IV.</p><p><b>CONCLUSION</b>The estradiol can significantly increase flap survival rate by inhibiting neutrophils infiltration and improving the pathological changes of organization structure in flap.</p>