Search

Benzoates as toxic intermediate are naturally produced by fungal intracellular metabolism, and CYP53 can specific transform the substrates. In the study, we constructed the CYP53 homology model and analyzed the corresponding active region. At the same time, the molecular docking and the structure-based pharmacophore model (SBP) were performed to explore the bind mode of representative CYP53 inhibitors. On the basis, a series of phenylpyridines derivatives were designed as novel CYP53 inhibitors, and their molecular structures were synthesized and evaluated. Compared with the positive control groups, their antifungal activity showed the obvious upward trend. In particular, target compounds (13a, 15b) possessed the excellent biological activity against pathogenic fungi and drug-resistant fungi in vivo and in vitro. The preliminary action mechanism has confirmed that target compounds could inhibit CYP53 activity, and block the metabolism of toxic intermediates (Benzoates). This further induced the accumulation of reactive oxygen species (ROS) through the pattern of mitochondrial depolarization, which eventually caused fungal lysis and death. In summary, the study provided the reasonable computational models, and effectively guided the generation of novel CYP53 antifungal inhibitors.

Nickel-based superalloys are widely used in key hot-end components such as aero engines and industrial gas turbines due to their excellent comprehensive properties. Real-time monitoring of engine blades and other structures in high-temperature environments can promptly discover possible internal damage to the structure. Optical fiber sensing technology has unique advantages that traditional electrical sensors do not have, such as anti-electromagnetic interference, small size, light weight, and corrosion resistance. The technology is gradually replacing traditional methods and becoming an important means of structural health monitoring. We propose an optical fiber sensor and assembly method that can be used to measure the strain of a nickel-based directionally solidified superalloy in a high-temperature environment more accurately. The proposed technology is simple to manufacture and also has low cost and a high survival rate, which is of great significance for high-temperature strain measurements in aerospace and other fields.

MicroRNAs (miRNAs) are a class of about 22 nucleotide endogenous non-coding small RNAs that play important roles in plant development and defense responses to biotic and abiotic stress. Tomato spotted wilt orthotospovirus (TSWV) is among the most devastating plant viruses worldwide, causing leaf spotting and wilting symptoms in many plants. In this study, high-throughput sequencing technology was used to identify miRNAs in peppers that were regulated by TSWV infection, and bioinformatics techniques were used to analyze the function of these miRNAs and their target genes. The sequencing results showed that, in the pepper plants infected by TSWV, a total of 101 miRNAs were differentially expressed, and several differentially expressed miRNAs were verified by the qRT-PCR method. Based on the GO function and KEGG pathway enrichment analysis, the functions of these miRNAs and their target genes were predicted. These target genes play a regulatory role in pathways such as plant-pathogen interactions and plant hormone signal transduction. Our results provide information about pepper miRNAs and will help to further understand the mechanism of TSWV-host interactions.

With the increase of fungal infection and drug resistance, it is becoming an urgent task to discover the highly effective antifungal drugs. In the study, we selected the key ergosterol bio-synthetic enzymes (Squalene epoxidase, SE; 14 α-demethylase, CYP51) as dual-target receptors to guide the construction of novel antifungal compounds, which could achieve the purpose of improving drug efficacy and reducing drug-resistance. Three different series of amide naphthyl compounds were generated through the method of skeleton growth, and their corresponding target products were synthesized. Most of compounds displayed the obvious biological activity against different Candida spp. and Aspergillus fumigatus. Among of them, target compounds 14a-2 and 20b-2 not only possessed the excellent broad-spectrum anti-fungal activity (MIC50, 0.125–2 μg/mL), but also maintained the anti-drug-resistant fungal activity (MIC50, 1–4 μg/mL). Preliminary mechanism study revealed the compounds (14a-2, 20b-2) could block the bio-synthetic pathway of ergosterol by inhibiting the dual-target (SE/CYP51) activity, and this finally caused the cleavage and death of fungal cells. In addition, we also discovered that compounds 14a-2 and 20b-2 with low toxic and side effects could exert the excellent therapeutic effect in mice model of fungal infection, which was worthy for further in-depth study.

Valine is an important essential amino acid of laying hens. Dietary supplemented with BCAAs ameliorated gut microbiota, whereas elevated blood levels of BCAAs are positively associated with obesity, insulin resistance, and diabetes in both humans and rodents. General controlled nonrepressed (GCN2) kinase plays a crucial role in regulating intestinal inflammation and hepatic fatty acid homeostasis during amino acids deficiency, while GCN2 deficient results in enhanced intestinal inflammation and developed hepatic steatosis. However, how long-term dietary valine impacts gut health and the development of nonalcoholic fatty liver disease (NAFLD) remains unknown. Hence, in the present study, we elucidated the effects of dietary valine on intestinal barrier function, microbial homeostasis, and the development of NAFLD. A total of 960 healthy 33-weeks-old laying hens were randomly divided into five experimental groups and fed with valine at the following different levels in a feeding trial that lasted 8 weeks: 0.59, 0.64, 0.69, 0.74, and 0.79%, respectively. After 8 weeks of treatment, related tissues and cecal contents were obtained for further analysis. The results showed that diet supplemented with valine ameliorated gut health by improving intestinal villus morphology, enhancing intestinal barrier, decreasing cecum pathogenic bacteria abundances such as Fusobacteriota and Deferribacterota, and inhibiting inflammatory response mediated by GCN2. However, long-term intake of high levels of dietary valine (0.74 and 0.79%) accelerated the development of NAFLD of laying hens by promoting lipogenesis and inhibiting fatty acid oxidation mediated by GCN2-eIF2α-ATF4. Furthermore, NAFLD induced by high levels of dietary valine (0.74 and 0.79%) resulted in strengthening oxidative stress, ER stress, and inflammatory response. Our results revealed that high levels of valine are a key regulator of gut health and the adverse metabolic response to NAFLD and suggested reducing dietary valine as a new approach to preventing NAFLD of laying hens.

The aim of this study was to explore the effects of dietary arachidonic acid on serum fatty acid profile, hepatic antioxidant capacity, and lipid metabolism in pigeon squabs by supplementing arachidonic acid in their parental diets. A completely randomized design was conducted consisting of control group, 0.05% dietary arachidonic acid supplementation group, 0.1% dietary arachidonic acid supplementation group, and 0.2% dietary arachidonic acid supplementation group. Six randomly selected squabs from each group were sampled on Day 21 post-hatch. Results indicated that moderate level (0.05%) of arachidonic acid in parental diets for pigeon squabs improved lipid metabolism via regulation on serum lipid profile and fatty acid composition and tended to reduce hepatic lipid accumulation in the premise of negligible damage to antioxidant status. Unfortunately, excessive parental supplementation of dietary arachidonic acid might be harmful to squab health. The regulatory effects of arachidonic acid were sensitive to the arachidonic acid doses. In conclusion, parental dietary arachidonic acid at 0.05% could be beneficial for squabs to maintain health as reflective aspects in ameliorative serum lipid profile, fatty acid composition, and reduced hepatic lipid accumulation.

Background There is accumulating evidence to suggest that microRNAs (miRNAs) are associated with the progressive optic neuropathy including glaucoma. Apoptosis of retinal ganglion cells (RGCs) is a hallmark of glaucoma. The present study focused on the effects of miR-145-5p on RGC apoptosis in glaucoma. Methods We established a glaucoma rat model by intraocular injection of N-methyl-D-aspartic acid (NMDA). RGCs were isolated from newborn rats and treated with NMDA. Hematoxylin and eosin staining was performed to detect morphological changes in the retinas of rats. The expression of miR-145-5p and tripartite motif-containing 2 (TRIM2) in RGCs was measured by RT-qPCR. The viability of RGCs was measured by an MTT assay. Flow cytometry analysis and TUNEL assays were conducted to assess the apoptosis of RGCs. The interaction between miR-145-5p and TRIM2 was investigated using a luciferase reporter assay. Results Rats injected with NMDA showed a thinner ganglion cell layer (GCL) and inner plexiform layer (IPL) as well as increased expression of miR-145-5p. Silencing of miR-145-5p significantly increased the GCL and IPL in the glaucoma rat model. Moreover, miR-145-5p expression was upregulated in RGCs ex vivo in response to NMDA. Silencing of miR-145-5p promoted cell viability and suppressed apoptosis in NMDA-treated RGCs. Mechanistically, miR-145-5p targeted the TRIM2 3' untranslated region to suppress its expression. TRIM2 was upregulated in NMDA-treated RGCs and protected RGCs against NMDA-induced apoptosis. Furthermore, miR-145-5p suppressed the PI3K/AKT pathway by downregulating TRIM2 in NMDA-treated RGCs. Conclusions Suppression of miR-145-5p inhibited the apoptosis of RGCs via TRIM2-mediated activation of the PI3K/AKT signaling pathway in NMDA-induced glaucoma.

The vacuolar ATPase (V-ATPase) plays an important role in phagocytic acidification, and its V0-V1 complex transports protons across the membrane to the phagocytic body. ATPase H+ transporting V0 subunit B (ATP6V0B) is a subunit of the V0 membrane integration domain of V-ATPase in mammals. At present, the role of the atp6v0b gene in teleost has not yet been defined. Here, we studied the role of atp6v0b gene in half-smooth tongue sole (Cynoglossus semilaevis) in response to Vibrio vulnificus infection. Liver ultrapathology data showed an increase in lysosomes and formation of autophagosome vesicles following an infection with Vibrio vulnificus, demonstrating binding of the lysosome to the autophagosome. The atp6v0b gene encodes 211 amino acids in the half-smooth tongue sole. The atp6v0b gene is constitutively expressed in all examined tissues of healthy half-smooth tongue sole, with the highest expression in blood and gill. A challenge test of the half-smooth tongue sole to different concentrations of Vibrio vulnificus was also done. The result showed that the relative upregulation of atp6v0b in liver, spleen, blood and heart with the highest expression in high infection group (group H) at 24h, which then decreased gradually as the reaction progressed to 72h. In contrast, muscle experienced the highest atp6v0b expression at 72h. Taken together, our data highlights the role of atp6v0b in regulating the immune response against Vibrio vulnificus.

Simple Summary In the past, many studies have been carried out to investigate the effect of dietary valine supplementation on laying hens’ production performance and egg quality. However, knowledge concerning the optimal valine requirement during the peak lay period is limited and mainly restricted to the production performance of the hens. Within this context, the present study aimed to assess the impact of dietary valine levels on production performance, egg quality, antioxidant capacity, and immunity, as well as on intestinal amino acid absorption (i.e., serum free amino acids, digestive enzymes, and amino acid transporters). Dietary valine supplementation exerts positive effects on the production performance of the laying hens by promoting amino acid nutrient uptake and utilization. However, dietary valine supplementation might inhibit the absorption of dietary protein by downregulating peptide transporter expression of the small intestine, eventually resulting in the reduction of egg quality. Abstract The present study aimed to assess the impact of dietary valine levels on layer production performance, egg quality, immunity, and intestinal amino acid absorption of laying hens during the peak lay period. For this purpose, a total of 960 33-week-old Fengda No.1 laying hens were randomly divided into five experimental groups and fed with valine at the following different levels in a feeding trial that lasted 8 weeks: 0.59, 0.64, 0.69, 0.74, and 0.79%, respectively. Productive performances were recorded throughout the whole rearing cycle and the egg quality, serum indexes, and small intestine transporters expression were assessed at the end of the experiment after slaughter (41 weeks) on 12 hens per group. Statistical analysis was conducted by one-way ANOVA followed by LSD multiple comparison tests with SPSS 20.0 (SPSS, Chicago, IL, USA). The linear and quadratic effects were tested by SPSS 20.0. Egg mass, laying rate, broken egg rate, and feed conversion ratio were significantly improved with increasing dietary valine levels. However, the egg weight, eggshell thickness, albumen height, Haugh unit, and egg yolk color were significantly decreased with increasing dietary valine levels. Serum catalase (CAT), immunoglobulin A (IgA) and IgM levels, and malondialdehyde (MDA) levels were negative responses to valine-treated laying hens. Dietary supplemented valine enhanced the trypsin activity of duodenum chime and promoted the mRNA expression levels of ATB0,+, and LAT4 in the jejunum and corresponding serum free Ile, Lys, Phe, Val, and Tyr level. However, valine treatment significantly downregulated the mRNA expression levels of PePT1, B0AT1, LAT1, and SNAT2 in the small intestines and corresponding serum free Arg, His, Met, Thr, Ala, Asp, Glu, Gly, and Ser level. Our results suggest that 0.79% valine dietary supplementation can improve production performance by promoting amino acid nutrient uptake and utilization, and suggest a supplement of 0.79% valine to diet.

SummaryWhole genome sequencing of patient populations is identifying thousands of new variants in UnTranslated Regions(UTRs). While the consequences of UTR mutations are not as easily predicted from primary sequence as coding mutations are, there are some known features of UTRs modulate their function. utR.annotation is an R package that can be used to annotate potential deleterious variants in the UTR regions for both human and mouse species. Given a CSV or VCF format variant file, utR.annotation provides information of each variant on whether and how it alters known translational regulators including:upstream Open Reading Frames (uORFs), upstream Kozak sequences, polyA signals, the Kozak sequence at the annotated translation initiation site, start codon, and stop codon, conservation scores in the variant position, and whether and how it changes ribosome loading based on a model from empirical data.Availability and implementationutR.annotation is freely available on Bitbucket (https://bitbucket.org/jdlabteam/utr.annotation/src/master/) and CRAN (to be updated)Supplementary informationSupplementary data are available athttps://wustl.box.com/s/yye99bryfin89nav45gv91l5k35fxo7z

BackgroundThe stability of p53 is mainly controlled by ubiquitin-dependent degradation, which is triggered by the E3 ubiquitin ligase MDM2. The chromatin modifier lymphoid-specific helicase (LSH) is essential for DNA methylation and cancer progression as a transcriptional repressor. The potential interplay between chromatin modifiers and transcription factors remains largely unknown.ResultsHere, we present data suggesting that LSH regulates p53in cisthrough two pathways: prevention proteasomal degradation through its deubiquitination, which is achieved by reducing the lysine 11-linked, lysine 48-linked polyubiquitin chains (K11 and K48) on p53; and revival of the transcriptional activity of p53 by forming a complex with PKM2 (pyruvate kinase 2). Furthermore, we confirmed that the LSH–PKM2 interaction occurred at the intersubunit interface region of the PKM2 C-terminal region and the coiled-coil domains (CC) and ATP-binding domains of LSH, and this interaction regulated p53-mediated transactivationin cisin lipid metabolism, especially lipid catabolism.ConclusionThese findings suggest that LSH is a novel regulator of p53 through the proteasomal pathway, thereby providing an alternative mechanism of p53 involvement in lipid metabolism in cancer.

Elucidating mechanisms in tumor suppressors and epigenetic modifiers are needed to gain insights into the etiology and treatment of cancer, the interplay between long intergenic non-coding RNAs (lncRNAs) and chromatin remodeling remains unclear. Here, we showed that GIAT4RA, a poorly characterized lncRNA LOC102723729, was significantly decreased in lung cancer cells and tissues; while no association was observed with clinical risk factors, expression was linked with clinical stage and lymphatic metastasis. Higher expression of GIAT4RA was linked with overall survival in NSCLC. GIAT4RA inhibited many characteristics of tumorigenesis including cell growth, clonal formation, migration and invasion, epithelial-mesenchymal transition, tumor sphere and tumor growth in vivo. Mechanistically, GIAT4RA was essential for the degradation of chromatin modifier lymphoid-specific helicase (LSH) by counteracting the deubiquintination in proteasome pathway by binding to 227-589 AA of LSH. GIAT4RA interfered with ubiquitin hydrolase Uchl3-mediated interaction and stabilization of LSH. LSH knockdown rescued GIAT4RA-promoted features, and LSH overexpression prevented GIAT4RA-induced phenotypes. Taken together, lncRNA GIAT4RA plays a critical role in NSCLC adenocarcinoma as a ubiquitination regulator and tumor suppressor.

Chemiluminescent (CL) reagent N-(4-aminobutyl)-N-ethylisoluminol (ABEI)-functionalized CaCO3 microspheres with a dual catalytic system consisting of Co2+ and horseradish peroxidase (HRP) (HRP/ABEI/Co2+-CaCO3 MPs) were synthesized via a facile method for the first time. Co2+ was linked onto HRP/ABEI/Co2+-CaCO3 MPs through both coordination and electrostatic interactions, while ABEI and HRP were encapsulated into HRP/ABEI/Co2+-CaCO3 MPs via electrostatic interaction and adsorption. The as-prepared HRP/ABEI/Co2+-CaCO3 MPs possessed a spherical shape with a mean size of 1.3 ± 0.3 μm and porous structure. They exhibited highly intensive "glow-type" CL emission, which was visible by naked eyes in a dark room for 10 h. The HRP/ABEI/Co2+-CaCO3 with dual catalytic system produced more intensive "glow-type" CL emission in the first 3 h as compared with ABEI/Co2+-CaCO3 and HRP/ABEI/CaCO3, both of which merely possessed a single catalyst in their systems. Moreover, the CL intensity of HRP/ABEI/Co2+-CaCO3 MPs during the first hour outperforms all the previously reported long-lasting chemiluminescence-functionalized micro/nanomaterials (CF-M/NMs), such as the firefly-mimicking intensive and long-lasting ABEI/Co2+/chitosan hydrogels. The outstanding CL performance of HRP/ABEI/Co2+-CaCO3 MPs is attributed to high loading of CL reagents and catalysts in CaCO3 MPs and high catalytic efficiency and good stability of the dual catalytic system consisting of Co2+ complex and HRP. The HRP/ABEI/Co2+-CaCO3 MPs are neutral materials with highly intensive and persistent emission as well as good biocompatibility, rendering them excellent biomaterials for various bioassays. We envisage that this excellent material holds great promise in vast application fields, such as bioassays, bioimaging, environmental monitoring, and life science etc.

The purpose of this review was to compare the efficacy and safety of everolimus plus endocrine therapy with endocrine therapy for hormone receptor-positive, human epidermal growth factor 2 negative advanced breast cancer patients. We comprehensively searched the PubMed, the Cochrane Library, EMBASE, Web of Science, Chinese biomedicine literature database, WanFang Data, CNKI, and VIP database for relevant articles. The retrieval time limit is from building the database to July 2018. The computer search was supplemented with a manual search of reference lists for all available review articles. We scanned references of all included studies for additional studies. We included 7 randomized trials involving 1527 patients. Meta-analysis results are as follows: Everolimus plus endocrine therapy group is significantly better than endocrine therapy group in progression-free survival and clinical benefit rate, (hazard ratio [HR] = 0.48, 95% confidence interval [CI 0.42-0.55], P0.00001) and (risk ratio = 1.9, 95% CI [1.60-2.26], P0.00001). But there was no significant difference between the 2 groups in overall response rate and time to definitive deterioration (risk ratio = 4.37, 95% CI [0.79-24.27], P = 0.21) and (HR = 0.74, 95% CI [0.49-1.11], P = 0.15). In terms of safety, the incidence rate in everolimus plus endocrine therapy was higher than that in endocrine therapy group. Most frequently reported adverse events associated with everolimus treatment were stomatitis, rash, fatigue, diarrhea, decreased appetite, cough, dyspnea, and pneumonitis. The incidences of grade 3-4 adverse events were stomatitis, fatigue, diarrhea, pneumonitis, and hyperglycemia. Everolimus increased the efficacy of endocrine therapy in treatment advanced endocrine receptor-positive, human epidermal growth factor 2 negative breast cancer patients, and the safety profile of the combination is acceptable.

Massive amounts of water and land embodied in crops are transferred via food trade. This study established a network-based framework for the water–land nexus in food trade to investigate the spatial linkages of water, land, and food. Based on the gravity model and linear programming optimization, the food trade model was first built to simulate crop trade. Then water consumption and land use for various crops in different regions were inventoried to establish the food-related virtual water network and food-related virtual land network. Grey water related to water quality, blue and green water related to water quantity, were incorporated into the food-related virtual water accounting framework to identify the role of food trade in the spatial reallocation of water. Similarly, the food-related virtual land network was built based on the land use for different crops and the food trade model. Finally, a case study was conducted using ecological network analysis to analyze the properties and connections within the food-related virtual water/land networks of China. The results showed that the green and grey water consumption associated with food production, the effects of which have previously been neglected, account for a huge proportion of the total water consumption, especially in water-scarce provinces. The controllers/dependents in the networks that have strong control relationships with other provinces were identified. The proposed network-based framework for the water–land nexus may help boost synergies associated with spatial reallocation of water and land via food trade and explore pathways for sustainable management of water, land, and food resources.

A large amount of land and water was needed for food production. In China, the geographical mismatch of land and water resources is increasing the structural tensions among spatial water and land reallocation in national food supply chain. Unreasonable national food production layout would threat land and water security. To improve food production self-sufficiency, an optimization model of national food production layout was established based on the agricultural food production comparative advantage index (ACI) and the linear programming optimization. ACI was built based on the local land, water endowment and socio-economic features, to evaluate the suitability for agricultural food production in each province. In this study, the objective function is maximization of the provincial agricultural food production comparative advantage index, and minimization of the provincial water and land footprint of agricultural food production. The constraint condition includes the natural resources, social demand, ecological environment and production condition. The optimal results showed that the maize production in Tianjin, Shanxi and Shaanxi has an obvious decrease and the production of soybean in Guangdong, Hainan and Yunnan increase after optimization. The corresponding adapting strategy was suggested to ensure the land, water security as well as sustainable food supplying. The objective of this study is to illustrate how an optimization model could be possibly used to adapt unreasonable food production layout for achieving the synergies between land, water and food.

The regulatory loop between long noncoding RNAs (lncRNAs) and microRNAs has a dynamic role in transcriptional and translational regulation, and is involved in cancer. However, the regulatory circuitry between lncRNAs and microRNAs in tumorigenesis remains elusive. Here we demonstrate that a nuclear lncRNA LINC00336 is upregulated in lung cancer and functions as an oncogene by acting as a competing endogenous RNA (ceRNAs). LINC00336 bound RNA-binding protein ELAVL1 (ELAV-like RNA-binding protein 1) using nucleotides 1901–2107 of LINC00336 and the RRM interaction domain and key amino acids (aa) of ELAVL1 (aa 101–213), inhibiting ferroptosis. Moreover, ELAVL1 increased LINC00336 expression by stabilizing its posttranscriptional level, whereas LSH (lymphoid-specific helicase) increased ELAVL1 expression through the p53 signaling pathway, further supporting the hypothesis that LSH promotes LINC00336 expression. Interestingly, LINC00336 served as an endogenous sponge of microRNA 6852 (MIR6852) to regulate the expression of cystathionine-β-synthase (CBS), a surrogate marker of ferroptosis. Finally, we found that MIR6852 inhibited cell growth by promoting ferroptosis. These data show that the network of lncRNA and ceRNA has an important role in tumorigenesis and ferroptosis.

Benefitting from continuous progress in computer architecture and computer vision algorithms, the visual tracking field has earned its rapid development in recent years. This paper surveys this interesting field through bibliographic analysis on the Web-of-Science literature from 1990 to 2019. Specifically, statistical analysis methods are used to obtain the most productive authors and countries/regions, the most cited papers, and so on. In order to realize an in-depth analysis, the co-authors, co-keywords and keyword-author co-occurrence networks are built to intuitively exhibit the evolution of research hotspots and the collaboration patterns among world-wide researchers. Brief introductions of the topics that occur frequently in co-keywords networks are provided as well. Furthermore, existing challenges and future research directions within the visual tracking field are discussed, revealing that tracking-by-detection and deep learning will continue receiving much attention. In addition, the parallel vision approach should be adopted for training and evaluating visual tracking models in a virtual-real interaction manner.

It is very important to find good nanomaterials as substrates for the immobilization of chemiluminescence (CL) reagents and catalysts in order to achieve high efficiency in CL functionalized nanomaterials. In this work, N-(4-aminobutyl)-N-ethylisoluminol (ABEI) and Co2+ bifunctionalized polydopamine (Co2+–ABEI–PDA) nanospheres were prepared via a facile strategy by using functional group-rich PDA as a platform for the effective immobilization of ABEI and Co2+ in a robust way for the first time. The Co2+–ABEI–PDA nanospheres were uniform spherical particles with an average diameter of 248 ± 48 nm. The as-prepared Co2+–ABEI–PDA nanospheres exhibited excellent CL efficiency. The CL intensity of Co2+–ABEI–PDA was nearly 4000 times higher than that of ABEI functionalized polydopamine (ABEI–PDA) nanospheres without catalyst in the system. Besides, the CL intensity of Co2+–ABEI–PDA was 320 times higher than that of the Co2+ and ABEI bifunctionalized CaCO3 microspheres. The highly intensive CL mechanism was studied in detail. The inhibition effect towards the free radical scavenging ability of PDA derived from Co2+ coordinated to catechol groups on PDA was observed, resulting in CL recovery. In addition, an optimized ratio of ABEI and Co2+ and a decreased spatial distance between them were achieved in Co2+–ABEI–PDA, which produced a superior catalytic effect to the ABEI–H2O2 system, leading to the outstanding performance of Co2+–ABEI–PDA. The Co2+–ABEI–PDA nanospheres show great application prospects in cold light sources, biosensing and bioimaging etc.

The human leukocyte antigen (HLA) molecules encoded within the human major histocompatibility complex are a group of highly conserved cell surface proteins, which are related to antigen recognition. HLA genes display a high degree of genetic polymorphism, which is the basis of individual differences in immunity. Specific HLA genotypes have been highly associated with typical adverse drug reactions. HLA-A*31:01 and HLA-B*15:02 are associated with carbamazepine-induced severe cutaneous adverse reactions, HLA-B*57:01 is related to abacavir-induced drug-induced hypersensitivity syndrome and flucloxacillin/pazopanib-induced drug-induced liver injury, while HLA-B*35:01 is a potential biomarker for predicting polygonum multiflorum-induced liver injury. It is not clear how small drug molecules to interact with HLA molecules and T cell receptors (TCR). There are four mechanistic hypotheses, including the hapten/prohapten theory, the pharmacological interaction concept, the altered peptide repertoire model, and the altered TCR repertoire model.人类主要组织相容性复合体编码的人类白细胞抗原(human leukocyte antigen，HLA)分子是一组高度保守且与抗原识别有关的细胞表面蛋白。HLA基因具有高度基因多态性，构成免疫个体差异的基础，与药物不良反应关系密切，如HLA-A*31:01和HLA-B*15:02基因与卡马西平诱导的严重皮肤不良反应有关，HLA-B*57:01基因与阿巴卡韦诱导的药物超敏反应综合征以及氟氯西林和帕唑帕尼诱导的药物性肝损伤有关；HLA-B*35:01基因可作为中药何首乌肝损伤的潜在分子标志物。小分子药物与HLA分子和T细胞受体相互作用的机制尚不清楚，现有的4种认可度较高的机制假说分别为半抗原学说、药理相互作用学说、改变肽库学说和改变T细胞受体学说。.

IntroductionIn this study, the molecular mechanisms underlying the therapeutic effect of metformin (MET) and ivabradine (IBD) in the treatment of concomitant chronic heart failure (CHF) and diabetes mellitus (DM) were investigated.Material and methodsBasic and cardiac indexes were measured to study the therapeutic effect of MET and IBD. Real-time PCR, IHC assays, in-silicon analysis, luciferase assays, real-time PCR and Western blot assays were conducted to clarify the molecular mechanisms underlying the interaction between MET and IBD.ResultsMET administration restored the normal values of general/cardiac indexes in CHF rats. The abnormal values of echocardiographic indexes in CHF rats with STZ-induced DM were all corrected by a certain degree after the MET administration. Moreover, the injection of STZ up-regulated the expression of plasma NE/BNP-45, while the IBD administration reduced the levels of NE/BNP-45 in CHF rats. Furthermore, the administration of MET also reduced the NE level in CHF rats, indicating that both MET and IBD can exert a therapeutic effect on CHF rats. Additionally, in-silicon analysis and luciferase assays verified the role of H19 and HCN4 as target genes of miR-423-5p. In fact, the transfection of MET or H19 siRNA1/2 into HL-1 and H9C2 cells down-regulated the levels of H19 and HCN4 while increasing the level of miR-423-5p.ConclusionsMET reduces H19 expression via inducing methylation of its promoter, and the inhibited H19 expression suppresses HCN4 expression by up-regulating miR-423-5p expression. As a result, the suppressed expression of HCN4 reduces heart rate and exhibits a therapeutic effect in the treatment of concomitant CHF and DM.

Quaking RNA binding protein (QKI) is essential for oligodendrocyte development as myelination requires myelin basic protein mRNA regulation and localization by the cytoplasmic isoforms (e.g., QKI-6). QKI-6 is also highly expressed in astrocytes, which were recently demonstrated to have regulated mRNA localization. Here, we define the targets of QKI in the mouse brain via CLIPseq and we show that QKI-6 binds 3′UTRs of a subset of astrocytic mRNAs. Binding is also enriched near stop codons, mediated partially by QKI-binding motifs (QBMs), yet spreads to adjacent sequences. Using a viral approach for mosaic, astrocyte-specific gene mutation with simultaneous translating RNA sequencing (CRISPR-TRAPseq), we profile ribosome associated mRNA from QKI-null astrocytes in the mouse brain. This demonstrates a role for QKI in stabilizing CLIP-defined direct targets in astrocytes in vivo and further shows that QKI mutation disrupts the transcriptional changes for a discrete subset of genes associated with astrocyte maturation., Quaking RNA binding protein (QKI) is known for its role in oligodendrocyte maturation. Here, the authors define the QKI targets in the mouse brain and show that loss of QKI disrupts the expression of cell maturation-associated genes in astrocytes in vivo.

Flavonoids that exhibit various biological activities such as antioxidant, antitumor, antiviral, antibacterial and anti-inflammatory properties are found in a wide range of medicinal plants. Among the flavonoid-producing plants identified so far, the genus

L-proline catabolism is emerging as a key pathway that is critical to cellular metabolism, growth, survival, and death. Proline dehydrogenase (PRODH) enzyme, which catalyzes the first step of proline catabolism, has diverse functional roles in regulating many pathophysiological processes, including apoptosis, autophagy, cell senescence, and cancer metastasis. Notably, accumulated evidence demonstrated that PRODH plays complex role in many types of cancers. In this review, we briefly introduce the function of PRODH, then its expression in different types of cancer. We next discuss the regulation of PRODH in cancer, the downstream pathways of PRODH and the therapies that are under investigation. Finally, we propose novel insights for future perspectives on the modulation of PRODH.

Recent studies have illuminated the importance of several key signaling pathways in regulating the dynamic surveillance and phagocytic activity of microglia. Yet little is known about how these signals result in the assembly of phagolysosomal machinery near targets of phagocytosis, especially in processes distal from the microglial soma. Neurons, astrocytes, and oligodendrocytes locally regulate protein translation within distal processes. Therefore, we tested whether there is regulated local translation within peripheral microglia processes (PeMPs). We show that PeMPs contain ribosomes which engage in de novo protein synthesis, and these associate with a subpool of transcripts involved in pathogen defense, motility, and phagocytosis. Using a live slice preparation, we further show that acute translation blockade impairs the formation of PeMP phagocytic cups, the localization of lysosomal proteins within them, and phagocytosis. Collectively, these data argue for a regulated local translation in PeMPs and indicate a need for new translation to support dynamic microglial function.

Background: Glaucoma is the main reason for irreversible blindness, and pathological increased intraocular pressure is the leading risk factor for glaucoma. It is reported that trabecular meshwork cell injury is closely associated with the elevated intraocular pressure. The current study aimed to investigate the role of SNHG3 in human trabecular meshwork (HTM) cells under oxidative stress. Methods: A series of experiments including real-time quantitative polymerase chain reaction (RT-qPCR), subcellular fractionation assay, western blot analysis, cell counting kit-8 (CCK-8) assay, RNA pull down, flow cytometry analysis, and RIP assay were employed to explore the biological function and regulatory mechanism of SNHG3 in HTM cells under oxidative stress.Results: First, we observed that H2O2 induced SNHG3 upregulation in HTM cells. Then, we found that SNHG3 silencing alleviated H2O2-induced oxidative damage in HTM cells. Moreover, SNAI2 knockdown alleviated the oxidative damage induced by H2O2 in HTM cells. Mechanistically, SNHG3 bound with ELAVL2 to stabilize SNAI2. Finally, SNAI2 overexpression counteracted the effect of SNHG3 silencing on H2O2-induced HTM cells. Conclusion: Our results demonstrated that SNHG3 cooperated with ELAVL2 to modulate cell apoptosis and extracellular matrix (ECM) accumulation by stabilizing SNAI2 in HTM cells under oxidative stress.

We tackle a new task conditional image retrieval, where the query includes an image and a corresponding additional text, with the aim to search the most similar target images in the whole gallery database. The additional text describes the additional conditions for the query image. Previous methods always represent the query pairs by fusing features at the deeper layer, which neglects the fine-grained relationships between the image and the different stages of the sentence. In this paper, we propose a Multi-Grained Fusion (MGF) module to mine the multi-grained relationships in the query pairs to fuse features more effectively. To further improve the performance, we propose an unsupervised Online Groups Matching (OGM) loss to make the feature include more identity information. Extensive experiments show that our method outperforms other state-of-the-art approaches.

Sequential atmospheric polarization patterns can provide information for navigation when cues from a satellite source are not available. However, the real scenarios with extreme environments often cause corruption of captured atmospheric polarization data which makes the navigation unreliable. So this encourages us to focus on the atmospheric polarization patterns prediction (APP) topic. In this paper, we try to investigate and fill the gap in this task. We first propose a dataset called the Temporal Polarization 1072 (TP1072) dataset to compensate for the lack of the dataset, which makes future research more possible. And further, we propose a novel and efficient deep learning sequential prediction model named Multi-Scale Spatial Transform Network (MSST-Net) for that topic. The overall model includes a Spatial Transform decoder (STD) and an adversarial learning-based Physical Property Learning (PPL) strategy. The STD makes the model can perceive the sequential pattern easily which significantly increases prediction accuracy. And the PPL constrains the overall model to achieve more accurate physical property. The extensive experiments prove that both two modules are complement with each other and also demonstrate that our model can effectively capture the spatio-temporal cues of the atmospheric polarization mode.

Single image deraining is always an important problem in the field of image processing. With the development of deep learning over the years, image rain removal has also made substantial progress. However, the existing deep learning networks tend to regard rain streaks as a neat pattern, without considering the direction and physical characteristics of rain streaks, and they can not completely remove long rain streaks. To solve these problems, We proposed an Angle-based Nonlocal Recurrent Network(ANRN), which consists of Angle information extraction block and non-local recurrent convolution block. Angle information extraction block can effectively model rain streaks, and generates abstract feature maps and weights based on the amount of rain streaks, making full use of the direction and physical characteristics of rain streaks. In order to get rid of long rain streaks, we have used a non-local recurrent convolution structure, which can better connect long distance contextual information and reduce the size of the network. We did a large number of experiments in both synthetic and real data sets, and the results had shown that our network can remove rain streaks in various directions and densities, perform better on long rain streaks, and is superior to current state-of-the-art methods.

This paper presents an improved accumulation damage model which is closer to the actual conditions based on the Manson-Halford (M-H) model. The model considers both the effect of load interaction and the phenomenon of strength degradation of materials induced by loading history. In addition, a new logarithmic residual strength model is proposed and its accuracy is verified by two sets of strength degradation experimental data. Finally, five sets of experimental data under two-level and multi-level loadings are compared with the prediction results. It is shown that the improved model has better applicability and higher accuracy.

The alteration of gene expression due to variations in the sequences of transcriptional regulatory elements has been a focus of substantial inquiry in humans and model organisms. However, less is known about the extent to which natural variation contributes to post-transcriptional regulation. Allelic Expression Imbalance (AEI) is a classical approach for studying the association of specific haplotypes with relative changes in transcript abundance. Here, we piloted a new TRAP based approach to associate genetic variation with transcript occupancy on ribosomes in specific cell types, to determine if it will allow examination of Allelic Translation Imbalance (ATI), and Allelic Translation Efficiency Imbalance, using as a test case mouse astrocytesin vivo. We show that most changes of the mRNA levels on ribosomes were reflected in transcript abundance, though ∼1.5% of transcripts have variants that clearly alter loading onto ribosomes orthogonally to transcript levels. These variants were often in conserved residues and altered sequences known to regulate translation such as upstream ORFs, PolyA sites, and predicted miRNA binding sites. Such variants were also common in transcripts showing altered abundance, suggesting some genetic regulation of gene expression may function through post-transcriptional mechanisms. Overall, our work shows that naturally occurring genetic variants can impact ribosome occupancy in astrocytesin vivoand suggests that mechanisms may also play a role in genetic contributions to disease.

Mating triggers substantial changes in gene expression and leads to subsequent physiological and behavioral modifications. However, postmating transcriptomic changes responding to mating have not yet been fully understood. Here, we carried out RNA sequencing (RNAseq) analysis in the sweet potato whitefly, Bemisia tabaci MED, to identify genes in females in response to mating. We compared mRNA expression in virgin and mated females at 24 h. As a result, 434 differentially expressed gene transcripts (DEGs) were identified between the mated and unmated groups, including 331 up- and 103 down-regulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses revealed that many of these DEGs encode binding-related proteins and genes associated with longevity. An RT-qPCR validation study was consistent with our transcriptomic analysis (14/15). Specifically, expression of P450s (Cyp18a1 and Cyp4g68), ubiquitin-protein ligases (UBR5 and RNF123), Hsps (Hsp68 and Hsf), carboxylase (ACC-2), facilitated trehalose transporters (Tret1-2), transcription factor (phtf), and serine-protein kinase (TLK2) were significantly elevated in mated females throughout seven assay days. These combined results offer a glimpe of postmating molecular modifications to facilitate reproduction in B. tabaci females.

Ferroptosis is primarily caused by intracellular iron catalytic activity and lipid peroxidation. The potential interplay between ferroptosis and apoptosis remains poorly understood. Here, we show that the expression of a nuclear long non-coding RNA (lncRNA), LINC00618, is reduced in human leukemia and strongly increased by vincristine (VCR) treatment. Furthermore, LINC00618 promotes apoptosis by increasing the levels of BCL2-Associated X (BAX) and cleavage of caspase-3. LINC00618 also accelerates ferroptosis by increasing the levels of lipid reactive oxygen species (ROS) and iron, two surrogate markers of ferroptosis, and decreasing the expression of solute carrier family 7 member 11 (SLC7A11). Interestingly, VCR-induced ferroptosis and apoptosis are promoted by LINC00618, and LINC00618 accelerates ferroptosis in a manner dependent upon apoptosis. LINC00618 attenuates the expression of lymphoid-specific helicase (LSH), and LSH enhances the transcription of SLC7A11 after the recruitment to the promoter regions of SLC7A11, further inhibiting ferroptosis. Knowledge of these mechanisms demonstrates that lncRNAs related to ferroptosis and apoptosis are critical to leukemogenesis and chemotherapy., Graphical Abstract, We identified a previously unknown function of a specific lncRNA, LINC00618, which we show promotes apoptosis and ferroptosis by epigenetic mechanisms, thereby linking apoptosis and ferroptosis. In cooperation with vincristine, LINC00618 may represent a promising target for leukemia therapy.

We establish conditions to characterize probability measures by their $L^{p}$-quantization error functions in both $\mathbb{R}^{d}$ and Hilbert settings. This characterization is two-fold: static (identity of two distributions) and dynamic (convergence for the $L^{p}$-Wasserstein distance). We first propose a criterion on the quantization level $N$, valid for any norm on $\mathbb{R}^{d}$ and any order $p$ based on a geometrical approach involving the Voronoï diagram. Then, we prove that in the $L^{2}$-case on a (separable) Hilbert space, the condition on the level $N$ can be reduced to $N=2$, which is optimal. More quantization based characterization cases in dimension 1 and a discussion of the completeness of a distance defined by the quantization error function can be found at the end of this paper.

Quaking RNA binding protein(QKI) is essential for oligodendrocyte development as myelination requires MBP mRNA regulation and localization by the cytoplasmic isoforms(e.g. QKI-6). QKI-6 is also highly expressed in astrocytes, which were recently demonstrated to have regulated mRNA localization. Here, we show via CLIPseq that QKI-6 binds 3’ UTRs of a subset of astrocytic mRNAs, including many enriched in peripheral processes. Binding is enriched near stop codons, which is mediated partially by QKI binding motifs(QBMs) yet spreads to adjacent sequences. We developed CRISPR TRAPseq: a viral approach for mosaic, cell-type specific gene mutation with simultaneous translational profiling. This enabled study of QKI-deleted astrocytes in an otherwise normal brain. Astrocyte-targeted QKI deletion altered translation and maturation, while also increasing synaptic density within the astrocyte’s territory. Overall, our data indicate QKI is required for astrocyte maturation and demonstrate an approach for a highly targeted translational assessment of gene knockout in specific cell-types in vivo.

microRNAs are short, noncoding RNAs that can regulate hundreds of targets and thus shape the expression landscape of a cell. Similar to mRNA, they often exhibit cell type enriched expression and serve to reinforce cellular identity. In tissue with high cellular complexity, such as the central nervous system (CNS), it is difficult to attribute microRNA changes to a particular cell type. To facilitate interpretation of microRNA studies in these tissues, we used previously generated data to develop a publicly accessible and user-friendly database to enable exploration of cell type enriched microRNA expression. We provide illustrations of how this database can be utilized as a reference as well as for hypothesis generation. First, we suggest a putative role for miR-21 in the microglial spinal injury response. Second, we highlight data indicating that differential microRNA expression, specifically miR-326, may in part explain regional differences in inflammatory cells. Finally, we show that miR-383 expression is enriched in cortical glutamatergic neurons, suggesting a unique role in these cells. These examples illustrate the database’s utility in guiding research towards unstudied regulators in the CNS. This novel resource will aid future research into microRNA-based regulatory mechanisms responsible for cellular phenotypes within the CNS.

The intersex (ix) gene acts in concert with doublesex (dsx) at the end of the sex determination hierarchy to control somatic sexual differentiation in Drosophila melanogaster. Here, we report the Drosophila ix homolog in Bemisia tabaci (Btix) with differential splicing events. Four isoforms were found in B. tabaci adults, including two sex-specific transcripts (Btix F and Btix M ). Knockdown of Btix had no measurable effects on female morphological phenotypes but reduced the expression of the vitellogenin gene and resulted in the production of significantly fewer eggs, a lower eclosion rate, and a shorter body size of female progeny in comparison with control females. These results increase our understanding of the genes underlying sex determination in B. tabaci and reveal a potential target for RNA interference-based pest management.

Wetland hydrology can greatly influence the variations in soil carbon and nitrogen stocks. Soil cores were sampled to a depth of 100 cm at 10 cm intervals above 20 cm soils and 20 cm intervals below 20 cm soils in river marginal wetlands with different flooding frequencies (i.e., permanently flooded, one-year, five-year, ten-year, and one-hundred-year floodplains) in 1999 and 2009, respectively. Soil organic carbon and total nitrogen were measured to investigate spatial and temporal variations in soil organic carbon and total nitrogen stocks in five floodplains with different flooding frequencies on a small scale. The results showed that SOCS ranged from 4.62 kg C/m2 to 13.21 kg C/m2 and TNS from 0.41 kg N/m2 to 2.01 kg N/m2 in the top 1m depth in five zones in both sampling years. Higher soil organic carbon and total nitrogen stocks were observed in these floodplain wetlands with higher flooding frequencies (i.e. permanently flooded, one-year, and five-year floodplains) than those in lower-flooding-frequency floodplains (i.e., ten-year and one-hundred floodplains), and the highest soil organic carbon and total nitrogen stocks in top 10 cm appeared in one-year floodplain rather than permanently flooded floodplain in both years. This indicated that higher flooding frequencies could contribute to soil carbon and nitrogen accumulation due to better hydrological conditions compared with lower flooding frequencies. Soil organic carbon and total nitrogen stocks in top 1m depth decreased by approximately 8–53% and by 22–55% from 1999 to 2009, respectively, of which the highest change rate occurred in one-hundred fooldplain and the lowest in permanently flooded floodplain. The decline in soil carbon and nitrogen stocks of deeper soils mainly caused by heavy alkalinity, reduced water table, and elevated temperature in a ten-year period possibly contribute to explaining the total carbon and nitrogen losses in soil profiles. Correlation analysis showed that soil organic carbon and total nitrogen levels in this region were significantly correlated with flooding frequencies, soil depth, soil pH value, bulk density, soil texture, and microbial biomass. It is necessary to pay much more attention to carbon and nitrogen stocks in deeper soils and find out the key factors that cause carbon and nitrogen loss in these floodplain wetlands to improve carbon sink function of wetland soils. The findings of this work provide a potential explanation for the “missing” carbon sinks at a larger scale.

BackgroundAlthough combination therapy with immune checkpoint inhibitors (ICIs) provides a promising efficacy in multiple cancers, their use is facing challenges for a high incidence of adverse effects. This meta-analysis was conducted to compare the risks of organ-specific immune-related adverse events (IRAEs) associated with ICI monotherapy versus combination therapy among cancer patients.MethodsElectronic databases were systematically searched to include eligible randomized controlled trials (RCTs). Any-grade and 3-5 grade IRAEs (colitis, pneumonitis, hepatitis, hypothyroidism, hyperthyroidism, and hypophysitis) were extracted for meta-analysis. Two reviewers independently assessed the methodological quality. The RevMan 5.3.5 software was used for meta-analysis.ResultsA total of 10 studies involving 8 RCTs with 2716 patients were included in this study. The most common any-grade adverse event was colitis (14.5%), followed by hypothyroidism (13.8%), hepatitis (10.4%), hypophysitis (10.0%), hyperthyroidism (9.3%), and pneumonitis (4.6%). Meta-analysis showed that ICI combination therapy significantly increased the risks of any-grade IRAEs in colitis [relative risk (RR), 3.56; 95% confidence interval (CI), 1.56–8.12; p < 0.05], pneumonitis (RR, 2.31; 95% CI, 1.54–3.45; p < 0.05), hepatitis (RR, 2.54; 95% CI, 1.65–3.91; p < 0.05), hypothyroidism (RR, 2.17; 95% CI, 1.71–2.76; p < 0.05), hyperthyroidism (RR, 3.13; 95% CI, 2.08–4.70; p < 0.05), and hypophysitis (RR, 3.54; 95% CI, 2.07–6.07; p < 0.05) compared with ICI monotherapy, as well as 3-5 grade IRAEs in colitis (RR, 2.50; 95% CI, 1.62–3.86; p < 0.05), pneumonitis (RR, 1.99; 95% CI, 1.00–3.93; p = 0.05), and hepatitis (RR, 2.70; 95% CI, 1.29–5.63; p < 0.05).ConclusionsThis meta-analysis demonstrated that, compared with ICI monotherapy, patients receiving ICI combination therapy significantly increased organ-specific IRAEs in colitis, hypothyroidism, hepatitis, hypophysitis, hyperthyroidism, and pneumonitis. The incidence and severity of organ-specific IRAEs were drug and dose independent.

Water use and energy consumption are strongly interwoven in networks of economic activity. Tracking energy and water flows among regions and quantifying their interdependencies are fundamental for synergetic management of these two essential resources. In this work, we built an accounting framework to assess the performance of energy–water nexus networks within China. Water consumption for various energy types and energy consumption in all stages of water use were inventoried for different regions. Then, direct and indirect energy and water embodied in monetary flows among regions were calculated via multiregional input–output analysis to build an embodied energy network, embodied water-related energy network, embodied water network, and embodied energy-related water network. Finally, a set of ecological network analysis indices were used to analyze the properties and connection of these four networks. The results show disparities of water-related energy/total energy ratios among regions and the nexus impact on regional energy and water systems. Beijing and Shanghai have large ratios of final demand consumption because of their large population and rapid economic development. Embodied water and energy consumption in capital stock in Hainan, Ningxia represented 15% of total consumption by booming investments. We found that embodied water was transferred from western to eastern regions and northern to southern regions. Major energy export–import pairs were Xinjiang–Shanghai, Hebei–Beijing, Xinjiang–Zhejiang, and Jiangsu–Shanghai. Regions with controller/relier roles in the network were identified in the context of nexus impact, for which Beijing and Shanghai have a strong control and dependence relationship with other regions. The proposed nexus network approach may help bridge the gap between nexus modeling and regional resource management.