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Background: With the development of monoclonal antibodies (mAbs) from the first generation of mice to the fourth generation of human origin, the efficacy and safety in the treatment of many diseases have been continuously improved. MAbs have been widely used in the treatment of cancer, chronic inflammatory diseases, etc. However, the treatment response of mAbs varies greatly among individuals, and drug exposure may be affected by a variety of physiological and pathological factors, such as combined use of drugs and progression of the disease. Therefore, studies tend to recommend therapeutic drug monitoring and individualized treatment strategies. Objective: In this paper, the commonly used methods of quantification of monoclonal antibodies were reviewed, especially liquid chromatography- mass spectrometry (LC-MS/MS) and enzymelinked immunosorbent assay (ELISA), to provide technical support for therapeutic drug detection and individualize dosing for patients. Conclusion: For patients achieving mAbs treatment, it is necessary to carry out therapeutic drug monitoring and take it as a routine monitoring index. We recommend that for pharmaceutical laboratories in hospitals, establishing an appropriate assay format, such as ELISA and LC-MS/MS is critical to determine drug concentration and antidrug antibody (ADA) for mAbs.

Soil enzyme activities and microbial communities have a good response to the remediation effect of heavy metal-contaminated soils. To evaluate the effect of three commonly used washing agents, ferric chloride (FC), ethylenediamine-tetra- methylenephosphonic acid (EDTMP) and ethylenediamine tetraacetic acid (EDTA) on soil enzyme activities and microbial community in cadmium (Cd)- contaminated agricultural soil collected around the mining area. The soil enzyme activities, microbial community, chemical forms of Cd and some physicochemical properties of the soil washed with different washing solutions were determined after two months incubation. The results showed that the three washing solutions had moderate removal efficiencies (22.83%-37.56%) for Cd in the tested soil and the breakdown product of EDTMP has a certain stabilizing effect on Cd. The geometric mean and the integrated total enzyme activity index showed that soil washing with FC and EDTA were more beneficial to the restoration of biochemical functions than that with EDTMP. The relative abundance of Gemmatimonadetes in the soil washed with EDTA was significantly higher than that with FC and EDTMP. The relative abundance of Firmicutes in the soil washed with EDTMP was significantly increased, and the relative abundance of Bacteroidetes in the soil washed with FC was significantly decreased. Pearson correlation analysis and redundancy analysis (RDA) indicated that the three washing solutions affected soil enzyme activities and microbial community by altering soil nutrient, total Cd concentration and Cd fractions in soils.

The hypoxic tumor microenvironment promotes both cancer progression and drug resistance.Prolyl hydroxylases are hypoxic sensor proteins that are frequently mutated or heterozygously deleted in breast cancers; however, how prolyl hydroxylation regulates breast cancer progression and drug resistance remains poorly understood. Here, we found that hypoxia promotes cancer progression and resistance to chemotherapy drugs, specifically through prolyl hydroxylation-dependent activation of MAPK signaling. We characterized a pVHL-independent mechanism wherein the prolyl hydroxylase EglN1 catalyzed prolyl hydroxylation of the proline-rich domain of RAS-specific guanine nucleotide exchange factor SOS1, thereby preventing its binding with the growth factor receptor bound protein 2 (GRB2) to block the formation of MAPK signaling microclusters in breast cancer. Inhibition of EglN1’s prolyl hydroxylase function—which occurs in hypoxic conditions and upon accumulation of fumarate—induced cancer-specific dysregulation of MAPK signaling, which promoted both breast cancer growth and resistance to MEK inhibitors. We harnessed this insight and demonstrated a therapeutic strategy that potently inhibits breast cancer growth and drug resistance based on pharmacologically disrupting the prolyl-hydroxylation-mediated interaction between SOS1 and GRB2.

Current studies have shown that the spatial‐temporal graph convolutional network (ST‐GCN) is effective for skeleton‐based action recognition. However, for the existing ST‐GCN‐based methods, their temporal kernel size is usually fixed over all layers, which makes them cannot fully exploit the temporal dependency between discontinuous frames and different sequence lengths. Besides, most of these methods use average pooling to obtain global graph feature from vertex features, resulting in losing much fine‐grained information for action classification. To address these issues, in this work, the authors propose a novel spatial attentive and temporal dilated graph convolutional network (SATD‐GCN). It contains two important components, that is, a spatial attention pooling module (SAP) and a temporal dilated graph convolution module (TDGC). Specifically, the SAP module can select the human body joints which are beneficial for action recognition by a self‐attention mechanism and alleviates the influence of data redundancy and noise. The TDGC module can effectively extract the temporal features at different time scales, which is useful to improve the temporal perception field and enhance the robustness of the model to different motion speed and sequence length. Importantly, both the SAP module and the TDGC module can be easily integrated into the ST‐GCN‐based models, and significantly improve their performance. Extensive experiments on two large‐scale benchmark datasets, that is, NTU‐RGB + D and Kinetics‐Skeleton, demonstrate that the authors’ method achieves the state‐of‐the‐art performance for skeleton‐based action recognition.

In this article, an effective method, called an adaptive covariance strategy based on reference points (RPCMA-ES) is proposed for multi-objective optimization. In the proposed algorithm, search space is divided into independent sub-regions by calculating the angle between the objective vector and the reference vector. The reference vectors can be used not only to decompose the original multi-objective optimization problem into a number of single-objective subproblems, but also to elucidate user preferences to target a preferred subset of the whole Pareto front (PF). In this respect, any single objective optimizers can be easily used in this algorithm framework. Inspired by the multi-objective estimation of distribution algorithms, covariance matrix adaptation evolution strategy (CMA-ES) is involved in RPCMA-ES. A state-of-the-art optimizer for single-objective continuous functions is the CMA-ES, which has proven to be able to strike a good balance between the exploration and the exploitation of search space. Furthermore, in order to avoid falling into local optimality and make the new mean closer to the optimal solution, chaos operator is added based on CMA-ES. By comparing it with four state-of-the-art multi-objective optimization algorithms, the simulation results show that the proposed algorithm is competitive and effective in terms of convergence and distribution.

In multi-objective and many-objective optimization, weight vectors are particularly crucial to the performance of decomposition-based optimization algorithms. The uniform weight vectors are not suitable for complex Pareto fronts (PFs), so it is necessary to improve the distribution of weight vectors. Besides, the balance between convergence and diversity is a difficult issue as well in multi-objective optimization, and it becomes increasingly important with the augment of the number of objectives. To address these issues, a self-adaptive weight vector adjustment strategy for decomposition-based multi-objective differential evolution algorithm (AWDMODE) is proposed. In order to ensure that the guidance of weight vectors becomes accurate and effective, the adaptive adjustment strategy is introduced. This strategy distinguishes the shapes and adjusts weight vectors dynamically, which can ensure that the guidance of weight vectors becomes accurate and effective. In addition, a self-learning strategy is adopted to produce more non-dominated solutions and balance the convergence and diversity. The experimental results indicate that AWDMODE outperforms the compared algorithms on WFG suites test instances, and shows a great potential when handling the problems whose PFs are scaled with different ranges in each objective.

BackgroundDiagnosis of a genetic disease and determination of the causative molecular lesion rely on the availability of the disease-associated pedigrees. Microphthalmia is a congenital eye defect due to an insufficiently developed visual system; its prevalence is 1–3 in 10 000 live births.ObjectiveWe analysed a pedigree exhibiting autosomal dominant inheritance of microphthalmia to determine the genetic lesion; used AlphaFold2 to predict the changes in the protein’s 3-Dimensional structure; and compared wild-type and variant proteins in cultured cells or Drosophila model was used to explore the cellular or developmental function of the encoded product.ResultsWe identified a novel missense variation, F52L, in MAB21L1 that is absent in population databases and present exclusively in the individuals diagnosed with microphthalmia in this pedigree. Common structural changes were predicted for the disease-associated variants clustered at amino acids 49–52, and these variant products were also predominantly trapped in the cytoplasm of cultured human lens epithelia. To recapitulate its dominant effect in development, we expressed the Drosophila homologue corresponding to MAB21L1F52Land caused malformation of sensory organs.ConclusionMutations at the residues 49–52 of MAB21L1 compromise eye development. We recommend includingMAB21L1in the genetic testing panel for congenital eye disorders.

Uncovering the tissue molecular architecture at single-cell resolution could help better understand organisms’ biological and pathological processes. However, bulk RNA-seq can only measure gene expression in cell mixtures, without revealing the transcriptional heterogeneity and spatial patterns of single cells. Herein, we introduce Bulk2Space (https://github.com/ZJUFanLab/bulk2space), a deep learning framework-based spatial deconvolution algorithm that can simultaneously disclose the spatial and cellular heterogeneity of bulk RNA-seq data using existing single-cell and spatial transcriptomics references. The use of bulk transcriptomics to validate Bulk2Space unveils, in particular, the spatial variance of immune cells in different tumor regions, the molecular and spatial heterogeneity of tissues during inflammation-induced tumorigenesis, and spatial patterns of novel genes in different cell types. Moreover, Bulk2Space is utilized to perform spatial deconvolution analysis on bulk transcriptome data from two different mouse brain regions derived from our in-house developed sequencing approach termed Spatial-seq. We have not only reconstructed the hierarchical structure of the mouse isocortex but also further annotated cell types that were not identified by original methods in the mouse hypothalamus.

In this paper, we present a new method based on Accelerating the Super-Resolution Convolutional Neural Network (FSRCNN) and residual network for the aim of image super-resolution. In our works, we fuse the network structure of FSRCNN and skip connections as the first step of our method, this part can transfer the original features to the training results effectively, in addition, we also change the deconvolution layer to a sub-pixel convolution layer. Our experimental results show that our method is easy to converge in training works and the image reconstruction result also has better quality. The proposed method has better effects corresponding to the reconstruct images on the Set5, Setl4 andGeneral-100 data sets, its average PSNR can increase about 0.38dB.

Purpose Retinitis pigmentosa GTPase regulator (RPGR)-related X-linked retinitis pigmentosa is associated with one of the most severe phenotypes among inherited retinal disease. The aim of this study was to investigate Clustered Regularly Interspaced Short Palindromic Repeat/Cas9-mediated gene editing therapy in a mouse model of Rpgr. Methods The Rpgr-/yCas9+/WT male mice were used for this study. At 6 months of age, they received a single subretinal injection of adeno-associated virus vectors carrying sgRNA and donor template separately, and therapeutic effect was examined after 1, 6, and 12 months. Results Rpgr knockout mouse showed slow but progressive age-related retinal degeneration, which emulates the disease occurring in humans. Significant photoreceptor preservation was observed in the treated part of the retina, in sharp contrast to the untreated part of the retina in the same eye after 6 and 12 months. It was surprising that precise modification at the target locus as demonstrated by genomic DNA sequencing in the post-mitotic photoreceptor was observed. Moreover, the therapeutic effect lasts for up to 12 months and no off-target effects were shown. Conclusions Our study strongly demonstrates that gene editing therapy is a promising therapeutic strategy to treat inherited retinal degeneration.

Hydrothermal treatment (HT), as a novel promising technology, still could not make fly ash (FA) from municipal solid waste incineration (MSWI) meet the standard of non-hazardous waste, due to the unsuccessful formation of aluminosilicate minerals caused by the lack of Si and Al in FA. In this research the mechanism of zeolites formation and stabilization/migration of heavy metals during hydrothermal process affected by external addition of coal fly ash (CFA), bentonite, and kaolin as silicon-aluminum source, were studied. Tobermorite could be synthesized, attributing to the proper element proportion of Ca/(Si + Al) adjusted by 30% of additives addition. Heavy metals were detected on the surface of tobermorite crystalline. The leaching toxicity of Pb, Zn, Cu, Cd, Cr in FA were significantly reduced after HT, associated with the transformation into the residue fraction. The decrease of heavy metals in liquid phase and the decrease of leaching toxicity in solid phase were observed, indicating that heavy metals were really stabilized in the treated FA, rather than transferred into liquid. Higher reaction temperature could promote the formation of tobermorite, but increase the leaching toxicity and migration of heavy metals. Addition of 30% of CFA and temperature of 150 °C would be the recommended technological parameters.

Rhizodeposition is an important component of carbon cycling in terrestrial ecosystems. However, there remains tremendous uncertainty in its quantification due to the methodological limitations. In the present study, we propose a method to evaluate the rhizodeposition by plants by observing carbon flux. We investigated the ecosystem CO2 flux variability and calculated the rhizodeposition of carbon by the rice rhizosphere, by using the carbon flux, meteorological data, and biomass observation from 2003 to 2011 at the Taoyuan Agro-ecological Experimental Station, a representative subtropical paddy ecosystem. Our data indicated that the process of rhizodeposition is the major reason for the discrepancy between the biomass and net primary productivity of the paddy ecosystem under intensive human interference. Both the amount and ratio of rhizodeposition of carbon in this paddy ecosystem were assessed; this provides important theoretical and methodological support for further investigating rhizodepositi...

Osteoarthritis (OA) is a chronic arthritic disease that causes the overproduction of inflammatory factors such as nitric oxide (NO). This study develops a NO nanosensor to predict the OA development. The nanosensor is synthesized by encapsulating the NO sensing molecules (i.e., 4-amino-5-methylamino-2',7'-difluorofluorescein Diaminofluorescein-FM (DAF-FM)) within the biodegradable poly(lactic-co-glycolic acid) nanoparticles. In vitro, the nanosensor allows the monitoring of the NO release in interleukin-1β-stimulated chondrocytes and the alleviated effect of NG-monomethyl-l-arginine (a NO inhibitor) and andrographolide (an anti-inflammatory agent). In the rat OA model, it permits the quantification of NO level in joint fluid. The proposed NO nanosensor may facilitate a noninvasive and real-time evaluation of the OA development.

Resource recovery of municipal solid waste (MSW) incinerator fly ash is widely concerned. Tobermorite, an important but rare naturally mineral, could not be directly hydrothermal synthesized from it owing to its high content of Ca but low concentration of Si and Al. The selected external silicon-aluminum additives including coal fly ash (CFA), bentonite, kaolin and diatomite were solely or combined added. With the addition of 30% mass composite additive in which the ratio of quality for CFA and diatomite is 1:1, tobermorite could be synthesized most effectively in 48h at 150°C, mainly attributing to the proper element proportion adjusted by additives. Tobermorite seed added could not only promote the large formation of tobermorite, but also inhibit the production of hibschite and kaotoite. Since Ca/(Si + Al) = 1.20 and Al/(Si + Al) = 0.20, addition of 30% mass of composite additive and 3% mass of tobermorite seed would be the recommended technological parameter.

Neuroinflammation has been implicated in the mechanism underlying the progression of neurodegeneration and infectious neuropathology. Growing evidence suggest that hydroxytyrosol (3,4-dihydroxyphenil-ethanol, HT), one of the main polyphenols presented in extra virgin olive oil (EVOO), has shown potential anti-inflammatory and neuroprotective effects. However, the potential anti-neuroinflammation activity and underlying mechanism of HT remain poorly understood. The present study aimed to investigate the effects of HT on lipopolysaccharide (LPS)-induced inflammation in both in vitro and in vivo models and the associated molecular mechanism. Our results revealed that HT significantly reduced the production of pro-inflammatory mediators in BV2 microglia and primary microglia cells. Phenotypic analysis showed that HT significantly reduced M1 marker CD86 expression and increased M2 marker CD206 expression. In addition, HT significantly decreased the levels of phospho-NF-κB p65 and phospho-extracellular signal-regulated kinase (ERK) in a dose-dependent manner. Moreover, HT suppressed the LPS-induced Toll like receptor 4 (TLR4) in BV2 microglia. In vivo administration of HT following LPS injection significantly reduced some proinflammatory mediator levels and microglia/astrocyte activation in the brain. Together, these results suggest that HT suppressed the LPS-induced neuroinflammatory responses via modulation of microglia M1/M2 polarization and downregulation of TLR-4 mediated NF-κB activation and ERK signaling pathway.

Owing to the high Ca content but low concentration of Si and Al in fly ash (FA) generated from municipal solid waste incineration (MSWI), hydrothermal treatment (HT) of MSWI FA directly could not result in the synthesis of calcium-containing aluminosilicate minerals zeolites such as tobermorite, an important material for the hydrothermal solidification of heavy metals. According to the research results from the effect of the extra silicon–aluminum source added, with the higher amount (30%) of the composite additive in which the ratio of quality for coal fly ash (CFA) and diatomite is 1:1, tobermorite could be successfully synthesized, which is mainly attributed to the proper element proportion of Ca to Si and Al and Al to Si and Al, adjusted by additives. Furthermore, the tobermorite seed added also could not help the formation of tobermorite, even at a higher reaction temperature of 200 °C, due to the improper element proportion with a 10% mass of the composite additive. With a 30% mass of the composite ...

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous disorder characterized by night blindness, visual field constriction, and severely reduced visual acuity. Despite a number of genes being implicated in RP pathogenesis, the genetic etiology of the disease remains unknown in many patients. In this study, our aim was to identify the disease-causing mutation of a large Chinese family with autosomal dominant RP (adRP). Targeted exon capture sequencing was initially performed to screen mutations in known disease-causing genes, followed by exome sequencing. In doing so, a heterozygous mutation in ADIPOR1 (c.929A > G) that results in an amino acid substitution (p.Y310C) was identified to co-segregate with the disease phenotype in this family. Adipor1 is wildly expressed throughout the body, but appears to be enriched in the photoreceptor inner and outer segments. The p.Y310C mutation, predicted to affect the structure and function of the protein, was confirmed to affect protein folding and its subcellular localization in vitro. In addition, knockdown of adipor1 expression in a zebrafish model with morpholino (MO) preferentially reduced the number of rod photoreceptors, with no effect on the number of cones, a phenotype that is characteristic of RP. Furthermore, the knockdown phenotype was partially rescued by injecting wild-type, but not mutant, human ADIPOR1 mRNA. We conclude that ADIPOR1 is a novel adRP-causing gene and plays an important role in rod development and maintenance.

In this study, homogenized Mg-13Gd-4Y–2Zn-0.5Zr alloys were applied to multi-directional forging (MDF) process at decreasing temperatures from 480 °C to 420 °C by 4 passes. The microstructure, texture evolution and mechanical properties of the alloys during the MDF process were investigated. The result showed that the average grain size was refined remarkably to 4.0 μm and the microstructure distribution became homogeneous after 3 passes with cumulative strain of 9. After 4 passes with cumulative strain of 12, the average grain size increases to 5.4 μm. It is observed that large number of dynamic recrystallized (DRXed) grains and spherical precipitated phases of Mg5(Gd,Y,Zn) occurred during the MDF processing. The area fraction of DRXed grains was increased to 97.3% that can be regarded as achieving complete dynamic recrystallization (DRX) after 3 passes. The grain refinement was mainly caused by DRX, and the DRX was induced via particle stimulation nucleation (PSN) mechanism. Moreover, part of lamellar long-period stacking ordered (LPSO) phases were kinked and brought about numerous kink bands during multi-directional forging (MDF) process, which had an important impact on the grain refinement. As the MDF passes and cumulative strain increase, the basal texture transformed from strong basal texture to a random distribution gradually. The maximum ultimate tensile strength (UTS) and tensile yield strength (TYS) were 399 MPa and 308 MPa after 3 passes. The maximum failure elongation (FE) was 18.1% after 4 passes.

Fly ash (FA) produced during municipal solid waste incineration (MSWI) contains hazardous polychlorinated biphenyls (PCBs). Hydrothermal treatment (HT) is a promising technology for the degradation of organic compounds and was used in this study to detoxify PCBs in FA. This study examined the effects of HT reaction temperature, as well as the addition of coal fly ash and diatomite as a composite silicon‑aluminum additive and tobermorite seed crystals as an inducer, on the efficiency of PCB detoxification. The percent removal of dioxin-like PCBs and of their toxic equivalency both showed a positive correlation with tobermorite content in HT products. We attributed this to an improved Ca/(Si + Al) molar ratio achieved by adding 30% silicon‑aluminum additives before HT. The percent removal of PCBs at a reaction temperature of 200 °C was higher than at 150 °C. Experimental treatments containing added tobermorite seed produced the highest levels of PCB removal, and tobermorite seed addition had a greater influence on PCB detoxification efficiency. The highest percent removal of toxic equivalency of dioxin-like PCBs was 99.8% and was attributed to the improvement in tobermorite purity as achieved by addition of 30% silicon‑aluminum additive, 3% seed, and a reaction temperature of 200 °C.

Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous diseases involving more than 280 genes and no less than 20 different clinical phenotypes. In this study, our aims were to identify the disease-causing gene variants of 319 Chinese patients with IRD, and compare the pros and cons of targeted panel sequencing and whole exome sequencing (WES). Patients were assigned for analysis with a hereditary eye disease enrichment panel (HEDEP) or WES examination based on time of recruitment. This HEDEP was able to capture 441 hereditary eye disease genes, which included 291 genes related to IRD. As RPGR ORF15 was difficult to capture, all samples were subjected to Sanger sequencing for this region. Among the 163 disease-causing variants identified in this study, 73 had been previously reported, and the other 90 were novel. Genes most commonly implicated in different inheritances of IRDs in this cohort were presented. HEDEP and WES achieved diagnostic yield with 41.2% and 33.0%, respectively. In addition, nine patients were found to carry pathogenic mutations in the RPGR ORF15 region with Sanger sequencing. Our study demonstrates that HEDEP can be used as a first-tier test for patients with IRDs.