Search

Abstract Oral mucosal wounds exhibit accelerated healing with reduced scarring compared to cutaneous wounds, representing an optimal wound healing paradigm. However, the specific cellular subtypes orchestrating the efficient healing of mucosal tissues remain elusive. Through a comprehensive analysis integrating bulk-mRNA and single-cell sequencing data during the wound healing process in oral mucosa and skin, we have delineated a distinct set of genes markedly upregulated during tissue repair. This collection of wound healing-associated genesets was highly enriched in a specific keratinocyte subpopulation identified as STAT3-activated SPRR1B+ keratinocytes. Notably, despite the inherent rapidity of oral mucosal healing, the induction of SPRR1B+ keratinocytes is evident in both skin and mucosal wound healing processes in murine model. Intriguingly, these wound healing-promoting SPRR1B+ keratinocytes, which are induced via STAT3 activation, inherently abundant in unwounded normal mucosa but absent in normal skin. SPRR1B knockdown significantly inhibits mucosal keratinocyte migration, a critical attribute for effective wound healing. In summary, through analysis of human oral and skin wound healing processes at single-cell resolution, coupled with validation in murine model, suggests STAT3-activated SPRR1B+ keratinocytes are associated with the rapid mucosal repair process. This discovery underscores the potential application of SPRR1B+ keratinocytes in the therapeutic management of chronic or non-healing wounds.

Abstract Protein methylation is a functionally important post-translational modification that occurs on diverse amino acid residues. The current proteomics approaches are inefficient to discover the methylation on residues other than Arg and Lys, which hinders the deep understanding of the functional role of rare protein methylation. Herein, we present a methyl-specific metabolic labeling approach for global methylome mapping, which enable the acquisition of methylome dataset covering diverse methylation types. Interestingly, of the identified methylation events, His methylation is found to be preferably occurred in C3H1 zinc fingers (ZFs). These His methylation events are determined to be Nπ specific and catalyzed by CARNMT1. The His methylation is found to stabilize the structure of ZFs. U2AF1 is used as a proof-of-concept to highlight the functional importance of His methylation in ZFs in RNA binding and RNA metabolism. The results of this study enable novel understanding of how protein methylation regulates cellular processes.

Abstract. Epitranscriptomics focuses on the RNA-modification-mediated post-transcriptional regulation of gene expression. The past decade has witnessed tremendous progress in our understanding of the landscapes and biological functions of RNA modifications, as prompted by the emergence of potent analytical approaches. The hematopoietic system provides a lifelong supply of blood cells, and gene expression is tightly controlled during the differentiation of hematopoietic stem cells (HSCs). The dysregulation of gene expression during hematopoiesis may lead to severe disorders, including acute myeloid leukemia (AML). Emerging evidence supports the involvement of the mRNA modification system in normal hematopoiesis and AML pathogenesis, which has led to the development of small-molecule inhibitors that target N6-methyladenosine (m6A) modification machinery as treatments. Here, we summarize the latest findings and our most up-to-date information on the roles of m6A and N7-methylguanine in both physiological and pathological conditions in the hematopoietic system. Furthermore, we will discuss the therapeutic potential and limitations of cancer treatments targeting m6A.

Abstract. Background:. The conversion of adenosine (A) to inosine (I) through deamination is the prevailing form of RNA editing, impacting numerous nuclear and cytoplasmic transcripts across various eukaryotic species. Millions of high-confidence RNA editing sites have been identified and integrated into various RNA databases, providing a convenient platform for the rapid identification of key drivers of cancer and potential therapeutic targets. However, the available database for integration of RNA editing in hematopoietic cells and hematopoietic malignancies is still lacking. Methods:. We downloaded RNA sequencing (RNA-seq) data of 29 leukemia patients and 19 healthy donors from National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database, and RNA-seq data of 12 mouse hematopoietic cell populations obtained from our previous research were also used. We performed sequence alignment, identified RNA editing sites, and obtained characteristic editing sites related to normal hematopoietic development and abnormal editing sites associated with hematologic diseases. Results:. We established a new database, "REDH", represents RNA editome in hematopoietic differentiation and malignancy. REDH is a curated database of associations between RNA editome and hematopoiesis. REDH integrates 30,796 editing sites from 12 murine adult hematopoietic cell populations and systematically characterizes more than 400,000 edited events in malignant hematopoietic samples from 48 cohorts (human). Through the Differentiation, Disease, Enrichment, and knowledge modules, each A-to-I editing site is systematically integrated, including its distribution throughout the genome, its clinical information (human sample), and functional editing sites under physiological and pathological conditions. Furthermore, REDH compares the similarities and differences of editing sites between different hematologic malignancies and healthy control. Conclusions:. REDH is accessible at http://www.redhdatabase.com/. This user-friendly database would aid in understanding the mechanisms of RNA editing in hematopoietic differentiation and malignancies. It provides a set of data related to the maintenance of hematopoietic homeostasis and identifying potential therapeutic targets in malignancies.

The ultrasonic-assisted extraction process of polysaccharides from Stropharia rugosoannulata in Bo'ai County and the antibacterial and antioxidant activities were analyzed. On the basis of single factor experiments, with the polysaccharide yield as response value, the ultrasonic-assisted extraction process of polysaccharides from Stropharia rugosoannulata in Bo'ai County was optimized using Box-Behnken experimental design with three factors and three levels. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the polysaccharides extracted from Stropharia rugosoannulata in Bo'ai County were determined using the double dilution method and the plate coating method, respectively. The antioxidant activity was determined using ABTS method and FRAP methods. The results showed that the optimal ultrasonic-assisted extraction conditions were 62 ℃ (ultrasonic temperature), 1:30 g/mL (solid-liquid ratio) and 62 min (ultrasonic time). Under these conditions, the average yield of polysaccharide was 13.25%, which agreed well with the predicted value of 13.35%, the relative error was 0.75%. Among the five common pathogenic bacteria tested, the polysaccharide extract showed the strongest inhibitory effect on Salmonella typhimurium with the minimum inhibitory concentration of 6.25 mg/mL and the minimum bactericidal concentration of 12.5 mg/mL. Meanwhile, the polysaccharide extract showed strong ability to scavenge ABTS+ free radicals and reduce Fe3+, and showed dose-effect relationship within a certain concentration range, although weaker than the positive control (VC) at the same concentration. The results suggested that the regression models were stable and feasible for polysaccharide extraction from Stropharia rugosoannulata in Bo'ai County and the extract had strong antioxidant and antibacterial activities, but its antibacterial effect was selective.

Abstract Background Cholangiocarcinoma (CCA) is a highly aggressive malignant tumor, and its diagnosis is still a challenge. This study aimed to identify a novel bile marker for CCA diagnosis based on proteomics and establish a diagnostic model with deep learning. Methods A total of 644 subjects (236 CCA and 408 non-CCA) from two independent centers were divided into discovery, cross-validation, and external validation sets for the study. Candidate bile markers were identified by three proteomics data and validated on 635 clinical humoral specimens and 121 tissue specimens. A diagnostic multi-analyte model containing bile and serum biomarkers was established in cross-validation set by deep learning and validated in an independent external cohort. Results The results of proteomics analysis and clinical specimen verification showed that bile clusterin (CLU) was significantly higher in CCA body fluids. Based on 376 subjects in the cross-validation set, ROC analysis indicated that bile CLU had a satisfactory diagnostic power (AUC: 0.852, sensitivity: 73.6%, specificity: 90.1%). Building on bile CLU and 63 serum markers, deep learning established a diagnostic model incorporating seven factors (CLU, CA19-9, IBIL, GGT, LDL-C, TG, and TBA), which showed a high diagnostic utility (AUC: 0.947, sensitivity: 90.3%, specificity: 84.9%). External validation in an independent cohort (n = 259) resulted in a similar accuracy for the detection of CCA. Finally, for the convenience of operation, a user-friendly prediction platform was built online for CCA. Conclusions This is the largest and most comprehensive study combining bile and serum biomarkers to differentiate CCA. This diagnostic model may potentially be used to detect CCA.

Soilless cultivation of potatoes often utilizes organic coconut peat and inorganic vermiculite as growing substrates. The unique microbial communities and physicochemical characteristics inherent to each substrate significantly influence the microecological environment crucial for potato growth and breeding. This study analyzed environmental factors within each substrate and employed Illumina sequencing alongside bioinformatics tools to examine microbial community structures, their correlation with environmental factors, core microbial functions, and the dynamics of microbial networks across various samples. These included pure coconut peat (CP1) and pure vermiculite (V1), substrates mixed with organic fertilizer for three days (CP2 and V2), and three combinations cultivated with potatoes for 50 days (CP3, V3, and CV3—a 1:1 mix of coconut peat and vermiculite with organic fertilizer). Vermiculite naturally hosts a more diverse microbial community. After mixing with fertilizer and composting for 3 days, and 50 days of potato cultivation, fungal diversity decreased in both substrates. Coconut peat maintains higher bacterial diversity and richness compared to vermiculite, harboring more beneficial bacteria and fungi, resulting in a more complex microbial network. However, vermiculite shows lower bacterial diversity and richness, with an accumulation of pathogenic microorganisms. Among the 11 environmental factors tested, water-soluble nitrogen (WSN), total nitrogen (TN), available potassium (AK), total organic carbon (TOC) and air-filled porosity (AFP) were significantly associated with microbial succession in the substrate.The nutritional type composition and interaction patterns of indigenous microorganisms differ between vermiculite and coconut peat. Adding abundant nutrients significantly affects the stability and interaction of the entire microbial community, even post-potato cultivation. When using vermiculite for soilless cultivation, precise control and adjustment of nutrient addition quantity and frequency are essential.

Early discovery and monitoring of the active deformation areas of potential landslides are important for geohazard risk prevention. The objective of the study is to propose a one-step strategy for automatically mapping the active deformation areas of potential landslides from a Sentinel-1 SAR dataset. First, we built a generalized convolutional neural network (CNN) based on activity and topographic characteristics. Second, we conducted a comparative analysis of the performance of various multi-channel combiners for detecting the active deformation areas of the potential landslides. Third, we verified the transferability of the pretrained CNN model for an unknown region. We found that by incorporating topographic characteristics into a generalized convolutional neural network, we were able to enhance the accuracy of identifying the active deformation areas of potential landslides, rapidly mapping these areas. The methodology is robust and efficient, and it has the capability to automatically detect the active deformation areas of potential landslides, even in unknown or unfamiliar regions. This product can facilitate automated pipelines, updating and mapping active deformation areas for final users who are not InSAR experts. This implementation can be used for providing support to risk management activities.

Abstract Albeit the majority of eukaryotic genomes can be pervasively transcribed to a diverse population of lncRNAs and various subtypes of lncRNA are discovered. However, the genome‐wide study of miRNA‐derived lncRNAs is still lacking. Here, it is reported that over 800 miRNA gene‐originated lncRNAs (molncRNAs) are generated from miRNA loci. One of them, molnc‐301b from miR‐301b and miR‐130b, functions as an “RNA decoy” to facilitate dissociation of the chromatin remodeling protein SMARCA5 from chromatin and thereby sequester transcription and mRNA translation. Specifically, molnc‐301b attenuates erythropoiesis by mitigating the transcription of erythropoietic and translation‐associated genes, such as GATA1 and FOS. In addition, a useful and powerful CRISPR screen platform to characterize the biological functions of molncRNAs at large‐scale and single‐cell levels is established and 29 functional molncRNAs in hematopoietic cells are identified. Collectively, the focus is on miRNA‐derived lncRNAs, deciphering their landscape during normal hematopoiesis, and comprehensively evaluating their potential roles.

Abstract Objectives To identify genes that confer MS risk via the alteration of cis‐regulated protein abundance and verify their aberrant expression in human brain. Methods Utilizing a two‐stage proteome‐wide association study (PWAS) design, MS GWAS data (N = 41,505) was respectively integrated with two distinct human brain proteomes from the dorsolateral prefrontal cortex, including ROSMAP (N = 376) in the discovery stage and Banner (N = 152) in the confirmation stage. In the following, Bayesian colocalization analysis was conducted for GWAS and protein quantitative trait loci signals to prioritize candidate genes. Differential expression analysis was then used to verify the dysregulation of risk genes in white matter and gray matter for evidence at the transcription level. Results A total of 51 genes whose protein abundance had association with the MS risk were identified, of which 18 genes overlapped in the discovery and confirmation PWAS. Bayesian colocalization indicated six causal genes with genetic risk variants for the MS risk. The differential expression analysis of SHMT1 (PFDR = 4.82 × 10−2), FAM120B (PFDR = 8.13 × 10−4) in white matter and ICA1L (PFDR = 3.44 × 10−2) in gray matter confirmed the dysregulation at the transcription level. Further investigation of expression found SHMT1 significantly up‐regulated in white matter lesion, and FAM120B up‐regulated in both white matter lesion and normal appearing white matter. ICA1L was down‐regulated in both gray matter lesion and normal appearing gray matter. Interpretation Dysregulation of SHMT1, FAM120B and ICA1L may confer MS risk. Our findings shed new light on the pathogenesis of MS and prioritized promising targets for future therapy research.

Automatic landslide detection based on very high spatial resolution remote sensing images is crucial for disaster prevention and mitigation applications. With the rapid development of deep-learning techniques, state-of-the-art semantic segmentation methods based on fully convolutional network (FCNN) have achieved outstanding performance in the landslide detection task. However, most of the existing articles only utilize visual features. Even if the advanced FCNN models are applied, there is still a certain amount of falsely detected and miss detected landslides. In this article, we innovatively introduce landslide susceptibility as prior knowledge and propose an innovative susceptibility-guided landslide detection method based on FCNN (SG-FCNN) to detect landslides from single temporal images. In addition, an unsupervised change detection method based on the mean changing magnitude of objects (MCMO) is further proposed and integrated with the SG-FCNN to detect newly occurred landslides from bitemporal images. The effectiveness of the proposed SG-FCNN and MCMO has been tested in Lantau Island, Hong Kong. The experimental results show that the SG-FCNN can significantly reduce the amount of falsely detected and miss detected landslides compared with the FCNN. It can conclude that applying landslide susceptibility as prior knowledge is much more effective than using visual features only, which introduces a new methodology of landslide detection and lifts the detection performance to a new level.

RNA-binding proteins (RBPs) are widely involved in the transcriptional and posttranscriptional regulation of multiple biological processes. The transcriptional regulatory ability of RBPs was indicated by the identification of chromatin-enriched RBPs (Che-RBPs). One of these proteins, KH-type splicing regulatory protein (KHSRP), is a multifunctional RBP that has been implicated in mRNA decay, alternative splicing, and miRNA biogenesis and plays an essential role in myeloid differentiation by facilitating the maturation of miR-129. In this study, we revealed that KHSRP regulates monocytic differentiation by regulating gene transcription and RNA splicing. KHSRP-occupied specific genomic sites in promoter and enhancer regions to regulate the expression of several hematopoietic genes through transcriptional activation and bound to pre-mRNA intronic regions to modulate alternative splicing during monocytic differentiation. Of note, KHSRP had co-regulatory effects at both the transcriptional and posttranscriptional levels on MOGOH and ADARB1. Taken together, our analyses revealed the dual DNA- and RNA-binding activities of KHSRP and have provided a paradigm to guide the analysis of other functional Che-RBPs in different biological systems.

Water cycle in a basin is constantly changing. It is an important basis for the allocation of water resources to survey the state of water cycle and analyze the water balance. The significant hydrological change period of the basin from 2000 to 2019 is taken as the research period in this study, and the data, including TRMM and GPM satellite precipitation, remote sensing evapotranspiration, in situ data of meteorological and hydrological gauges, are synthetically used to analyze the water cycle balance of the watershed. The results show that (1) the Qilian mountain area is the main runoff producing area, with an average annual discharge of about 45.11×108 m3 to the middle reaches, and the middle reaches is the main consumption area of the runoff water resources. About 66% (29.92×108 m3) of the upstream incoming water is used in the middle reaches, and about 34% (15.19×108 m3) is used to supplement the downstream area. (2) The Minle-Zhangye basin is the main consumption area of water resources in the middle reaches, with an average annual consumption of about 43.97×108 m3 including water from upper reaches and precipitation at local area (accounting for 75% of the consumption in the middle reaches), and the evapotranspiration consumption of farmland in the middle reaches is about 20.3×108 m3 (accounting for 35% of the evapotranspiration water in the middle reache areas). (3) The increase in precipitation of the upper reach is the main reason for the increase in runoff in the upper reaches of the main stream of the Heihe River. The contribution rate of precipitation to the increase of runoff is 96%, resulting in an average increase of runoff of 0.35×108 m3/a, and potential evapotranspiration has little contribution to the increase of the runoff. (4) According to the current water resource consumption, if the upstream runoff decreases in the future, there will be a risk of prominent contradiction between water used for agricultural development in the middle reaches and water used for ecological protection in the downstream area. Remote sensing observation of the surface water cycle can be used as one of the technologies of the basin water balance analysis to analyze the spatial distribution of basin surface water resources, reveal the temporal change trend and the causes, and support the rational allocation of water resources. The actual evapotranspiration on the land surface is the main source of the analysis uncertainty, and the key to improve the reliability of water balance analysis is to accurately estimate the actual evapotranspiration of different types of landcover. The estimation method of land actual evapotranspiration based on complementary correlation is relatively simple, but the multiplicative empirical coefficient in the Priestley-Taylor formula, which is used to calculate evapotranspiration in wet environment, is greatly affected by terrain, and the use of same value across the region will have a significant impact on the results.

Abstract Background Efficient mobilization of hematopoietic stem cells (HSCs) from bone marrow niche into circulation is the key to successful collection and transplantation in patients with hematological malignancies. The efficacy of various HSCs mobilization regimens has been widely investigated, but the results are inconsistent. Methods We performed comprehensive databases searching for eligible randomized controlled trials (RCTs) that comparing the efficacy of HSCs mobilization regimens in patients with hematological malignancies. Bayesian network meta-analyses were performed with WinBUGS. Standard dose of granulocyte colony-stimulating factor (G-CSF SD) was chosen as the common comparator. Estimates of relative treatment effects for other regimens were reported as mean differences (MD) or odds ratio (OR) with associated 95% credibility interval (95% CrI). The surface under the cumulative ranking curve (SUCRA) were obtained to present rank probabilities of all included regimens. Results Databases searching and study selection identified 44 eligible RCTs, of which the mobilization results are summarized. Then we compared the efficacy of mobilization regimens separately for patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) by including 13 eligible trials for network meta-analysis, involving 638 patients with MM and 592 patients with NHL. For patients with MM, data are pooled from 8 trials for 6 regimens, including G-CSF in standard dose (SD) or reduced dose (RD) combined with cyclophosphamide (CY), intermediate-dose cytarabine (ID-AraC) or plerixafor. The results show that compared with G-CSF SD alone, 3 regimens including ID-AraC + G-CSF SD (MD 14.29, 95% CrI 9.99–18.53; SUCRA 1.00), G-CSF SD + Plerixafor SD (MD 4.15, 95% CrI 2.92–5.39; SUCRA 0.80), and CY + G-CSF RD (MD 1.18, 95% CrI 0.29–2.07; SUCRA 0.60) are associated with significantly increased total number of collected CD34+ cells (× 106/kg), among which ID-AraC + G-CSF SD ranked first with a probability of being best regimen of 100%. Moreover, ID-AraC + G-CSF SD and G-CSF SD + Plerixafor SD are associated with significantly higher successful rate of achieving optimal target (collecting ≥ 4–6 × 106 CD34+ cells/kg). For patients with NHL, data are pooled from 5 trials for 4 regimens, the results show that compared with G-CSF SD alone, G-CSF SD + Plerixafor SD (MD 3.62, 95% CrI 2.86–4.38; SUCRA 0.81) and G-CSF SD plus the new CXC chemokine receptor-4 (CXCR-4) antagonist YF-H-2015005 (MD 3.43, 95% CrI 2.51–4.35; SUCRA 0.69) are associated with significantly higher number of total CD34+ cells collected. These 2 regimens are also associated with significantly higher successful rate of achieving optimal target. There are no significant differences in rate of achieving optimal target between G-CSF SD + Plerixafor SD and G-CSF + YF-H-2015005. Conclusions In conclusion, ID-AraC plus G-CSF is associated with the highest probability of being best mobilization regimen in patients with MM. For patients with NHL, G-CSF in combination with plerixafor or YF-H-2015005 showed similar improvements in HSCs mobilization efficacy. The relative effects of other chemotherapy-based mobilization regimens still require to be determined with further investigations.

In this study, a validated quality evaluation method with peony flower fingerprint chromatogram combined with simultaneous determination of sixteen bioactive constituents was established using UPLC-DAD-MS/MS. The results demonstrated that the method was stable, reliable, and accurate. The UPLC chemical fingerprints of 12 different varieties of peonies were established and comprehensively evaluated by similarity evaluation (SE), hierarchical cluster analysis (HCA), principal component analysis (PCA), and quantification analysis. The results of SE indicated that similar chemical components were present in these samples regardless of variety, but there were significant differences in the content of chemical components and material basis characteristics. The results of HCA and PCA showed that 12 varieties of samples were divided into two groups. Four flavonoids (11, 12, 13, and 16), five monoterpenes and their glycosides (3, 4, 6, 14, and 15), three tannins (7, 9, and 10), three phenolic acids (1, 2, and 5), and one aromatic acid (8) were identified from sixteen common peaks by standards and liquid chromatography–mass spectrometry (LC–MS). The simultaneous quantification of six types of components was conducted with the 12 samples, it was found that the sum contents of analytes varied obviously for peony flower samples from different varieties. The content of flavonoids, tannins, and monoterpenes (≥19.34 mg/g) was the highest, accounting for more than 78.45% of the total compounds. The results showed that the flavonoids, tannins, and monoterpenes were considered to be the key indexes in the classification and quality assessment of peony flower. The UPLC-DAD-MS/MS method coupled with multiple compounds determination and fingerprint analysis can be effectively applied as a feature distinguishing method to evaluate the compounds in peony flower raw material for product quality assurance in the food, pharmaceutical, and cosmetic industries. Moreover, this study provides ideas for future research and the improvement of products by these industries.

Abstract As one of the most promising formulations for poorly water-soluble drugs, nanocrystals have been attracting increasing attention in recent years. Isoliquiritigenin (ISL) is a flavonoid with a chalcone structure, and possesses many biological activities. However, its clinical application is significantly limited mainly due to its low oral bioavailability caused by poor hydrophilicity. To address this, ISL nanocrystals were developed in this study to improve its oral bioavailability. Three types of nanocrystals with differing particle size; R1, R2, and R3, were prepared by anti- solvent precipitation or anti-solvent precipitation combined with sonication, which was optimized by single-factor experiments. These nanocrystals were characterized based on their physical properties, in vitro release, and in vivo absorption performance. The mean particle size of R1, R2, and R3 was 555.7, 271.0, and 46.2, respectively. The dissolution ratio of ISL in the nanocrystals was significantly improved, with the quickest rate recorded in R2. Peak concentration and area under the concentration-time curve of R2 after oral administration in rats was 5.83- and 2.72-fold higher than that of the ISL solution, respectively. These findings indicate that the dissolution and absorption of ISL can be significantly enhanced by nanocrystals, and the dissolution behavior and pharmacokinetic properties of nanocrystals is significantly influenced by particle size.

Abstract Background Cellular RNA-binding proteins (RBPs) have multiple roles in post-transcriptional control, and some are shown to bind DNA. However, the global localization and the general chromatin-binding ability of RBPs are not well-characterized and remain undefined in hematopoietic cells. Results We first provide a full view of RBPs’ distribution pattern in the nucleus and screen for chromatin-enriched RBPs (Che-RBPs) in different human cells. Subsequently, by generating ChIP-seq, CLIP-seq, and RNA-seq datasets and conducting combined analysis, the transcriptional regulatory potentials of certain hematopoietic Che-RBPs are predicted. From this analysis, quaking (QKI5) emerges as a potential transcriptional activator during monocytic differentiation. QKI5 is over-represented in gene promoter regions, independent of RNA or transcription factors. Furthermore, DNA-bound QKI5 activates the transcription of several critical monocytic differentiation-associated genes, including CXCL2, IL16, and PTPN6. Finally, we show that the differentiation-promoting activity of QKI5 is largely dependent on CXCL2, irrespective of its RNA-binding capacity. Conclusions Our study indicates that Che-RBPs are versatile factors that orchestrate gene expression in different cellular contexts, and identifies QKI5, a classic RBP regulating RNA processing, as a novel transcriptional activator during monocytic differentiation.

Although the use of detergents in thermal proteome profiling (TPP) has become a common practice to identify membrane protein targets in complex biological samples, surprisingly, there is no proteome-wide investigation into the impacts of detergent introduction on the target identification performance of TPP. In this study, we assessed the target identification performance of TPP in the presence of a commonly used non-ionic detergent or a zwitterionic detergent using a pan-kinase inhibitor staurosporine, our results showed that the addition of either of these detergents significantly impaired the identification performance of TPP at the optimal temperature for soluble target protein identification. Further investigation showed that detergents destabilized the proteome and increased protein precipitation. By lowering the applied temperature point, the target identification performance of TPP with detergents is significantly improved and is comparable to that in the absence of detergents. Our findings provide valuable insight into how to select the appropriate temperature range when detergents are used in TPP. In addition, our results also suggest that the combination of detergent and heat may serve as a novel precipitation-inducing force that can be applied for target protein identification.

Abstract Mantle cell lymphoma (MCL) is highly aggressive and its treatment remains challenging, understanding its pathogenesis is critical for future targeted therapy. SUMO specific proteases 1 (SENP1) is an important protein that regulates the balance between SUMOylation and deSUMOylation. We found that SENP1 was upregulated in MCL patient samples and cell lines. Knockdown of SENP1 could inhibit the proliferation and promote the apoptosis of MCL cells. We also found that SENP1 knockdown caused inhibition of the JAK-STAT5 pathway and upregulation of tumor suppressor cytokine signaling 2 (SOCS2). Moreover, MCL tumor growth in vivo was significantly suppressed after SENP1 knockdown in a xenograft nude mouse model. In summary, our results showed that SENP1 is involved in the pathogenesis of MCL and may be a potential therapeutic target.

Abstract Background Mobilization failure may occur when the conventional hematopoietic stem cells (HSCs) mobilization agent granulocyte colony-stimulating factor (G-CSF) is used alone, new regimens were developed to improve mobilization efficacy. Multiple studies have been performed to investigate the efficacy of these regimens via animal models, but the results are inconsistent. We aim to compare the efficacy of different HSC mobilization regimens and identify new promising regimens with a network meta-analysis of preclinical studies. Methods We searched Medline and Embase databases for the eligible animal studies that compared the efficacy of different HSC mobilization regimens. Primary outcome is the number of total colony-forming cells (CFCs) in per milliliter of peripheral blood (/ml PB), and the secondary outcome is the number of Lin− Sca1+ Kit+ (LSK) cells/ml PB. Bayesian network meta-analyses were performed following the guidelines of the National Institute for Health and Care Excellence Decision Support Unit (NICE DSU) with WinBUGS version 1.4.3. G-CSF-based regimens were classified into the SD (standard dose, 200–250 μg/kg/day) group and the LD (low dose, 100–150 μg/kg/day) group based on doses, and were classified into the short-term (2–3 days) group and the long-term (4–5 days) group based on administration duration. Long-term SD G-CSF was chosen as the reference treatment. Results are presented as the mean differences (MD) with the associated 95% credibility interval (95% CrI) for each regimen. Results We included 95 eligible studies and reviewed the efficacy of 94 mobilization agents. Then 21 studies using the poor mobilizer mice model (C57BL/6 mice) to investigate the efficacy of different mobilization regimens were included for network meta-analysis. Network meta-analyses indicated that compared with long-term SD G-CSF alone, 14 regimens including long-term SD G-CSF + Me6, long-term SD G-CSF + AMD3100 + EP80031, long-term SD G-CSF + AMD3100 + FG-4497, long-term SD G-CSF + ML141, long-term SD G-CSF + desipramine, AMD3100 + meloxicam, long-term SD G-CSF + reboxetine, AMD3100 + VPC01091, long-term SD G-CSF + FG-4497, Me6, long-term SD G-CSF + EP80031, POL5551, long-term SD G-CSF + AMD3100, AMD1300 + EP80031 and long-term LD G-CSF + meloxicam significantly increased the collections of total CFCs. G-CSF + Me6 ranked first among these regimens in consideration of the number of harvested CFCs/ml PB (MD 2168.0, 95% CrI 2062.0−2272.0). In addition, 7 regimens including long-term SD G-CSF + AMD3100, AMD3100 + EP80031, long-term SD G-CSF + EP80031, short-term SD G-CSF + AMD3100 + IL-33, long-term SD G-CSF + ML141, short-term LD G-CSF + ARL67156, and long-term LD G-CSF + meloxicam significantly increased the collections of LSK cells compared with G-CSF alone. Long-term SD G-CSF + AMD3100 ranked first among these regimens in consideration of the number of harvested LSK cells/ml PB (MD 2577.0, 95% CrI 2422.0–2733.0). Conclusions Considering the number of CFC and LSK cells in PB as outcomes, G-CSF plus AMD3100, Me6, EP80031, ML141, FG-4497, IL-33, ARL67156, meloxicam, desipramine, and reboxetine are all promising mobilizing regimens for future investigation.

Abstract Background “Loss-of-only-child family” refers to the family in which the only child died and the mother has passed her child-bearing age. The parents who are unable to reproduce or do not foster other children are known as “shidu parents” in China. This study aimed to estimate the quality of life (QOL) and the mediating role of social support between perceived stress and QOL in Chinese shidu parents. Methods 502 shidu parents were recruited in Shenyang city. Shidu parents were asked to complete a questionnaire including the MOS item short from health survey (SF-36), the perceived stress scale-10 (PSS-10) and the functional social support questionnaire (FSSQ). Hierarchical linear regression was performed to assess the associations among perceived stress, social support and QOL. Asymptotic and resampling strategies were used to explore the mediating role of social support. Results The mean score of PCS and MCS was 64.83 ± 22.66 and 59.36 ± 21.83, respectively. Perceived stress was found to be negatively associated with both PCS (β = − 0.21, p

Abstract Rituximab combined with chemotherapy is the first-line induction therapy of CD20 positive B-cell non-Hodgkin lymphomas (CD20+ B-NHL). Recently new anti-CD20 monoclonal antibodies (mAbs) have been developed, but their efficacy and safety compared with rituximab are still controversial. We searched MEDLINE, Embase, and Cochrane Library for eligible randomized controlled trials (RCTs) that compared new anti-CD20 mAbs with rituximab in induction therapy of B-NHL. The primary outcomes are progression-free survival (PFS) and overall survival (OS), additional outcomes include event-free survival (EFS), disease-free survival (DFS), overall response rate (ORR), complete response rate (CRR) and incidences of adverse events (AEs). Time-to-event data were pooled as hazard ratios (HRs) using the generic inverse-variance method and dichotomous outcomes were pooled as odds ratios (ORs) using the Mantel–Haenszel method with their respective 95% confidence interval (CI). Eleven RCTs comprising 5261 patients with CD20+ B-NHL were included. Compared with rituximab, obinutuzumab significantly prolonged PFS (HR 0.84, 95% CI 0.73–0.96, P = 0.01), had no improvement on OS, ORR, and CRR, but increased the incidences of serious AEs (OR 1.29, 95% CI 1.13–1.48, P

Abstract In situ consolidation is the most common treatment to conserve cultural relics, but materials for preserving fragile organic cultural relics in humid archaeological excavation sites are scarce. To solve the problem, a moisture-curable polyurethane (MCPU) prepolymer was synthesized by reacting isophorone diisocyanate with polyethylene glycol 600. The standard acetone–dibutylamine method, Fourier transform infrared spectroscopy, gel chromatography and thermogravimetric analysis were utilized to determine the change in isocyanate groups before and after the reaction, the prepolymer molecular weight, the thermal decomposition kinetic parameters and the MCPU film lifetime. The results showed that the number-average molecular weight of the prepolymer was 749, and the weight average molecular weight was 1684. Isophorone groups in the prepolymer react with moisture in the air to form colorless, transparent, flexible films. The thermal decomposition of the MCPU films was a first-order reaction, and the decomposition process consisted of two stages. The Dakin equation was used to obtain the thermal aging equation lg t = 4600.82/T − 8.07, meaning that at 15 °C, the sample has an approximately 150-year lifetime. A new conservation material was developed, and its thermal decomposition kinetics were studied, which are significant for the conservation of fragile organic cultural relics in humid environments.

This study aimed to increase the solubility of glycyrrhetinic acid (GA) in water and enhance its liver-targeting ability using self-assembling nanomicelles (NMs) based on stearic acid-modified fenugreek gum (FG-C18). The GA/FG-C18 NMs were prepared by an ultrasonication dispersion method. The nanomicelles were spherical particles with a particle size of 198.61 ± 1.58 nm and a zeta potential of −30.12 ± 0.28 mV. The drug loading and encapsulation efficiency were 13.34 ± 0.24% and 80.07 ± 1.44%, respectively. The results of differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD) indicated that GA was successfully encapsulated into the nanomicelles in a molecularly dispersed state. An in vitro release test showed that GA/FG-C18 NMs possessed a slow drug release profile in PBS (pH 7.4) over 200 h. The cytotoxicity assay indicated that GA/FG-C18 NMs showed much higher inhibitory efficacy in HepG2 cells than in MCF-7 cells. Tissue section studies indicated that the accumulation of DiR-loaded FG-C18 nanomicelles in the liver of mice was higher than that of the DiR solution, and the fluorescence intensity decreased over time. GA/FG-C18 NMs showed a larger area under the curve (AUC) and mean residence time (MRT) compared with free GA after intravenous administration in mice. The in vivo studies showed that GA mainly accumulated in the liver after encapsulation by FG-C18 NMs, and the drug concentration was higher than that of free GA. These results suggested that FG-C18 NMs could serve as a potential drug delivery system for targeting GA to liver tissue.

The objective of this study was to hydrophobically modify fenugreek gum (FG) and to further evaluate the potential application of the obtained derivative in liver-targeted drug delivery system. Stearic acid (C18) was conjugated with FG (FG-C18) by a simple esterification reaction. The obtained FG-C18 was then characterized on its chemical structure by Fourier transform infrared spectroscopy and 1H-nuclear magnetic resonance. The self-assembled nanomicelles (NMs) of FG-C18 in water were prepared by an ultrasonication method. The average diameter and zeta potential of FG-C18 NMs were 196.70 ± 6.12 nm and −31.79 ± 1.58 mV, respectively. FG-C18 NMs appeared as spherical particles under transmission electron microscopy and possessed a critical micellar concentration of 0.042 mg/ml by pyrene fluorescence probe method. A low toxicity of FG-C18 was revealed on both HepG2 and MCF-7 cells at 0.1–100 mg/ml. Haemolysis of FG-C18 was less than 5%. Cellular uptake of coumarin-6 into HepG2 cells was enhanced by treating with C6-loaded FG-C18 NMs compared to free coumarin-6. These results suggest that FG-C18 have a potential application for a liver targeted drug delivery.

Mucosal melanoma (MM) is a rare melanoma subtype that originates from melanocytes within sun-protected mucous membranes. Compared with cutaneous melanoma (CM), MM has worse prognosis and lacks effective treatment options. Moreover, the endogenous or exogenous risk factors that influence mucosal melanocyte transformation, as well as the identity of MM precursor lesions, are ambiguous. Consequently, there remains a lack of molecular markers that can be used for early diagnosis, and therefore better management, of MM. In this review, we first summarize the main functions of mucosal melanocytes. Then, using oral mucosal melanoma (OMM) as a model, we discuss the distinct pathologic stages from benign mucosal melanocytes to metastatic MM, mapping the possible evolutionary trajectories that correspond to MM initiation and progression. We highlight key areas of ambiguity during the genetic evolution of MM from its benign lesions, and the resolution of which could aid in the discovery of new biomarkers for MM detection and diagnosis. We outline the key pathways that are altered in MM, including the MAPK pathway, the PI3K/AKT pathway, cell cycle regulation, telomere maintenance, and the RNA maturation process, and discuss targeted therapy strategies for MM currently in use or under investigation.

Functional miRNAs derived from the 5p or 3p arm of some miRNA duplexes have opposite roles in cancer progression. Here, the authors show that oncogenic miR-574-5p has greater preference in aggressive gastric cancer as compared with miR-574-3p and this arm preference is partly dependent on complementary targets mediated miRNA decay.

The 5p and 3p arms of microRNA (miRNA) are typically generated from the same precursor, and one arm influences protein output, while the other has a short half‐life. However, a few miR‐5p/3p pairs have been reported to co‐exist in cancer cells. Here, we performed a genome‐wide analysis of miRNA expression in gastric cancer (GC) cells to systematically investigate the co‐expression profile of miR‐5p/3p in gastric tumorigenesis. We discovered that only 41 miR‐5p/3p pairs out of 1749 analyzed miRNA were co‐expressed. Specifically, abnormal expression of miR‐369‐5p and miR‐369‐3p was correlated with GC progression. Importantly, both in vitro and in vivo assays revealed that miR‐369‐5p and miR‐369‐3p exhibited tumor‐suppressive roles by regulating jun proto‐oncogene and v‐akt murine thymoma viral oncogene homolog 1 function in GC cells, respectively. Moreover, we observed that miR‐369 was inactivated in GC tissues due to DNA methylation. We also showed that inhibition of miR‐369‐5p/3p attenuated the effect of azacitidine (AZA) treatment on suppressing cell growth and invasion. These results suggest that the therapeutic efficacy of AZA in GC is at least partly attributable to miR‐369 activation. Overall, our findings provide convincing evidence that both the 5p and 3p arms of miRNA co‐expressed in GC and DNA methylation‐induced miR‐369 signaling contribute to GC progression.

Abstract Background The SUMO-activating enzyme SAE1 is indispensable for protein SUMOylation. A dysregulation of SAE1 expression involves in progression of several human cancers. However, its biological roles of SAE1 in glioma are unclear by now. Methods The differential proteome between human glioma tissues and para-cancerous brain tissues were identified by LC-MS/MS. SAE1 expression was further assessed by immunohistochemistry. The patient overall survival versus SAE1 expression level was evaluated by Kaplan–Meier method. The glioma cell growth and migration were evaluated under SAE1 overexpression or inhibition by the CCK8, transwell assay and wound healing analysis. The SUMO1 modified target proteins were enriched from total cellular or tissue proteins by incubation with the anti-SUMO1 antibody on protein-A beads overnight, then the SUMOylated proteins were detected by Western blot. Cell apoptosis and cell cycle were analyzed by flow cytometry. The nude mouse xenograft was determined glioma growth and tumorigenicity in vivo. Results SAE1 is identified to increase in glioma tissues by a quantitative proteomic dissection, and SAE1 upregulation indicates a high level of tumor malignancy grade and a poor overall survival for glioma patients. SAE1 overexpression induces an increase of the SUMOylation and Ser473 phosphorylation of AKT, which promotes glioma cell growth in vitro and in nude mouse tumor model. On the contrary, SAE1 silence induces an obvious suppression of the SUMOylation and Ser473 phosphorylation of Akt, which inhibits glioma cell proliferation and the tumor xenograft growth through inducing cell cycle arrest at G2 phase and cell apoptosis driven by serial biochemical molecular events. Conclusion SAE1 promotes glioma cancer progression via enhancing Akt SUMOylation-mediated signaling pathway, which indicates targeting SUMOylation is a promising therapeutic strategy for human glioma.

As an important source of cholinesterase inhibitors, alkaloids in natural products have high potential value in terms of exerting pharmacological activities. In this study, a strategy for targeted preparation of cholinesterase inhibitors in Uncaria rhynchophlly (Miq.) Miq. ex Havil (UR) by high-speed counter-current chromatography was provided. In the method, a two-phase polar solvent system composed of ethyl acetate/n-butanol/water (1:4:5, v/v/v) was used, which isolated five alkaloids from the UR extract for the first time. All alkaloids were identified by HR-ESI-MS and NMR as 7-epi-javaniside (1), vincosamide (2), strictosamide (3), cadambine (4), and 3α-dihydrocadambine (5). The poorly resolved compounds 2 and 3 were separated by preparative HPLC (prep-HPLC). Among them, compounds 1, 4, and 5 were firstly obtained from UR. The purity of these plant isolates was 98.8%, 98.7%, 99.2%, 95.7%, and 98.5%, respectively. Compounds 1–5 exhibited an inhibitory effect on acetyl-cholinesterase and butyryl-cholinesterase with an IC50 from 1.47 to 23.24 µg/mL and 1.01 to 18.24 µg/mL. Molecular docking and inhibitory activities indicated that compound 1 showed stronger inhibitory activity on acetyl-cholinesterase and butyryl-cholinesterase.

RNA-binding proteins (RBPs) regulate RNA activity and are implicated in haematopoietic malignancies, but their role in myeloid cell specification is unclear. Here, the authors show a role for the RBP KSRP in promoting granulocyte fate over monocyte fate through the biogenesis of miR-129 and a decrease in RUNX1.

Background/Aims: Osteopontin (OPN) is an Extracellular Matrix (ECM) molecule and is involved in many physiologic and pathologic processes, including cell adhesion, angiogenesis and tumor metastasis. OPN is a well-known multifunctional factor involved in various aspects of cancer progression, including endometrial cancer. In this study, we examined the significance of OPN in endometrial cancer. Methods: The proliferation, migration and invasion ability of HEC-1A cells were detected by Cell Counting Kit-8 (CCK-8), Wound scratch assay and transwell. Western blots were employed to detect the expression of Matrix metalloproteinase-2 (MMP-2) and epithelial-mesenchymal transition (EMT)-related factors in HEC-1A cells treated with rhOPN. Results: rhOPN promotes cell proliferation, migration and invasion in HEC-1A cells. rhOPN influenced EMT-related factors and MMP-2 expression in HEC-1A cells. rhOPN promoted HEC-1A cells migration, invasion and EMT through protein kinase B (PKB/AKT) and Extracellular regulated protein kinases (ERK1/2) signaling pathway. Conclusions: These results may open up a novel therapeutic strategy for endometrial cancer: namely, rhOPN have important roles in controlling growth of endometrial of cancer cells and suggest a novel target pathway for treatment of this cancer.

BACKGROUND: MicroRNAs act as posttranscriptional regulators of gene expression in many biological processes. Their deregulations occur commonly in gastric cancer (GC). Although DNA methylation constitutes an important mechanism for microRNA deregulation in cancer, this field largely remains unexplored. METHODOLOGY/PRINCIPAL FINDINGS: Total RNA was extracted from the tissues of 100 patients with GC and four gastric cancer cell lines. The expression levels of miR-10a were determined by real-time PCR with specific TaqMan probes. Moreover, a functional analysis of miR-10a in regulating cell proliferation, migration and invasion was performed. Subsequently, quantitative methylation-specific PCR (qMSP) was used to detect the DNA methylation status in the CpG islands upstream of miR-10a. In this study, we found that the expression of miR-10a in GC cells was lower than that in normal cells, which was due to the hypermethylation of the CpG islands upstream of miR-10a. We also validated the slightly lower expression of miR-10a in GC tissues than their adjacent non-neoplastic tissues in 100 GC patients and confirmed the hypermethylation of CpG islands upstream of miR-10a in some patients. Furthermore, re-introduction of miR-10a into GC cells was able to inhibit cell proliferation, migration and invasion. Bioinformatic and immunoblot analysis indicated that the tumor suppressor roles of miR-10a in GC cells were possibly through targeting HOXA1. CONCLUSIONS/SIGNIFICANCE: Our data indicate that miR-10a acts as a tumor suppressor in GC cells and is partially silenced by DNA hypermethylation in GC, suggesting that miR-10a may serve as a potential diagnostic or therapeutic target of GC.

BACKGROUND AIMS: Gastric cancer is the most frequent gastrointestinal tumor in adults and is the most lethal form of human cancer. Despite of the improvements in treatments, the underlying mechanism of gastric carcinogenesis is not well known. To define novel modulators that regulate susceptibility to tumorgenesis, we focused on miR-219-2-3p. METHODS: Quantitative RT-PCR was employed to investigate the level of miR-219-2-3p in gastric cancer (GC) tissues (n = 113) and their matched adjacent normal tissues (n = 113). In vitro cell proliferation, apoptosis assays, cell migration, and invasion assays were performed to elucidate biological effects of miR-219-2-3p. Since silencing of miRNA by promoter CpG island methylation may be an important mechanism in tumorgenesis, GC cells were treated with 5-aza-2'-deoxycytidine and trichostatin A, and expression changes of miR-219-2-3p were subsequently examined by quantitative RT-PCR. Finally, the methylation status of CpG island upstream of miR-219-2-3p was analyzed by methylation-specific PCR in GC tissues (n = 22). RESULTS: miR-219-2-3p was down-regulated in GC and cell lines. In addition, the experiments documented the lower expression of miR-219-2-3p in GC specimens with higher grade and later stage tumors. Meanwhile, miR-219-2-3p exerted antiproliferative, proapoptotic, and antimetastatic roles and reduced levels of p-ERK1/2 in GC cells. Furthermore, 5-aza-2'-deoxycytidine and trichostatin A increased the expression (~2 fold) of miR-219-2-3p in GC cells. By methylation-specific PCR, DNA methylation in the upstream region of miR-219-2-3p was detected in both adjacent normal tissues and cancer tissues. As expected, the methylation level was considerably higher in the miR-219-2-3p down-regulated group than up-regulated group. CONCLUSIONS: miR-219-2-3p is potentially involved in gastric cancer progression and metastasis by regulating ERK1/2-related signal pathways, which may provide a novel therapeutic strategy for treatment of gastric cancer. Methylation mechanism may be involved in modulating the expression level of miR-219-2-3p in gastric cancer.

Silymarin has been widely used as a hepatoprotective drug in the treatment of various liver diseases, yet its effectiveness is affected by its poor water solubility and low bioavailability after oral administration, and there is a need for the development of intravenous products, especially for liver-targeting purposes. In this study, silymarin was encapsulated in self-assembled nanoparticles of Bletilla striata polysaccharide (BSP) conjugates modified with stearic acid and the physicochemical properties of the obtained nanoparticles were characterized. The silymarin-loaded micelles appeared as spherical particles with a mean diameter of 200 nm under TEM. The encapsulation of drug molecules was confirmed by DSC thermograms and XRD diffractograms, respectively. The nanoparticles exhibited a sustained-release profile for nearly 1 week with no obvious initial burst. Compared to drug solutions, the drug-loaded nanoparticles showed a lower viability and higher uptake intensity on HepG2 cell lines. After intravenous administration of nanoparticle formulation for 30 min to mice, the liver became the most significant organ enriched with the fluorescent probe. These results suggest that BSP derivative nanoparticles possess hepatic targeting capability and are promising nanocarriers for delivering silymarin to the liver.

There are two independent molecules in the asymmetric unit of the title compound, C15H13NO2, in both the six-membered dihydropyridine rings adopt a half-chair conformation. The two benzene rings make dihedral angles of 43.66 (10) and 62.22 (10)° in the two molecules. In the crystal, the two independent molecules are linked alternately by intermolecular O—H...O hydrogen bonds, forming a zigzag chain along the c axis. Furthermore, intermolecular C—H...π interactions link the chains into a three-dimensional network.

In the title hemihydrated salt, C15H13BrN+·NCS−·0.5H2O, the two benzene rings are aligned at a dihedral angle of 46.9 (1)°. The six-membered heterocycle of the dihydroisoquinoline unit adopts a half-chair conformation. The water molecule and thiocyanate ion are linked by O—H...N hydrogen bonds, generating a four-membered ring motif. In addition, C—H...O and C—H...S interactions link the components into a chain along the c axis. π–π interactions [centroid–centroid distance = 3.974 (2) Å] link the chains into sheets and further π—π [centroid–centroid distance = 3.746 (2) Å] and C—H...π interactions give rise to a three-dimensional nework.

In the title compound, C16H13IN2, the benzene ring of the tetrahydroisoquinoline moiety makes a dihedral angle of 45.02 (9)° with the benzene ring of the 4-iodophenyl fragment. The N atom and the adjacent unsubstituted C atom of the tetrahydroisoquinoline unit are displaced by 0.294 (2) and 0.441 (3) Å, respectively, from the plane through the remaining eight C atoms. In the crystal, pairs of adjacent molecules are linked into dimers by weak intermolecular C—H...π interactions.

In the title compound, C16H13IN2, the two benzene rings make a dihedral angle of 67.26 (5)°. The six-membered heterocycle of the tetrahydroisoquinoline unit adopts a half-chair conformation. In the crystal, adjacent molecules are linked by pairs of weak intermolecular C—H...N hydrogen bonds, forming inversion dimers. An intramolecular C—H...I close contact is also observed.

In the title compound, C12H14N4·6H2O, the two pyrimidine rings make a dihedral angle of 5.285 (6)°. Intermolecular O—H...O hydrogen bonds link the six water molecules, generating edge-fused four-, five- or six-membered ring motifs and forming two-dimensional sheets. The sheets are stabilized by the formation of O—H...N hydrogen bonds between the water molecules and the bipyrimidine molecules, resulting in a three-dimensional network.