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Abstract Background Melanin in the black-bone chicken’s body is considered the material basis for its medicinal effects and is an economically important trait. Therefore, improving the melanin content is a crucial focus in the breeding process of black-bone chickens. Luning chickens are black-bone chickens, with black beaks, skin, and meat. To investigate the genetic diversity and molecular mechanisms of melanin deposition in Luning chickens, we conducted whole-genome resequencing to analyze their breeding history and identify candidate genes influencing their black phenotype, along with transcriptome sequencing of dorsal skin tissues of male Luning chickens. Results Population structure analysis revealed that Luning chickens tend to cluster independently and are closely related to Tibetan chickens. Runs of homozygosity analysis suggested potential inbreeding in the Luning chicken and Tibetan chicken population. By combining genetic differentiation index (Fst) and nucleotide diversity (θπ) ratios, we pinpointed selected regions associated with melanin deposition. Gene annotation identified 540 genes with the highest Fst value in LOC101750371 and LOC121108313, located on the 68.24–68.58 Mb interval of chromosome Z. Combining genomic and transcriptomic data, we identified ATP5E, EDN3, and LOC101750371 as candidate genes influencing skin color traits in black-bone chickens. Conclusions This study characterized the evolutionary history of Luning chickens and preliminarily excavated candidate genes influencing the genetic mechanism of pigmentation in black-bone chickens, providing valuable insights for the study of animal melanin deposition.

Abstract Introduction The Ilizarov bone transport technique is widely recognised as an effective method for treating large segment bone defects in clinical practice. However, axial deviation is a common complication in the treatment of tibial large segment bone defects, which can have a serious impact on the clinical efficacy of bone transport. Our study aims to construct and validate a nomogram for predicting axial deviation of tibial bone transport. Method This study retrospectively collected data from 363 patients who underwent the tibial Ilizarov technique for bone transport. Univariate and multivariate logistic regression analyses were performed to determine the independent risk factors for axial deviation, which were later used to construct a nomogram. The nomogram was evaluated using the decision curve analysis (DCA), the calibration curve, and the area under the receiver operating characteristic curve (AUC). Results Of the 363 patients who underwent Ilizarov tibial bone transport, 31.7% (115/363) experienced axial deviation. Multivariate logistic regression analysis showed that gender, height, defect site, and external fixation index were important risk factors for axial deviation. The AUC value of the nomogram model was 0.705. The calibration curve and the decision curve analysis showed a good consistency between the actual axial deviation and the predicted probability. Conclusion The model assigns a quantitative risk score to each variable, which can be used to predict the risk of axial deviation during tibial bone transport.

Abstract Background Recent Convolutional Neural Networks (CNNs) perform low-error reconstruction in fast Magnetic Resonance Imaging (MRI). Most of them convolve the image with kernels and successfully explore the local information. Nonetheless, the non-local image information, which is embedded among image patches relatively far from each other, may be lost due to the limitation of the receptive field of the convolution kernel. We aim to incorporate a graph to represent non-local information and improve the reconstructed images by using the Graph Convolutional Enhanced Self-Similarity (GCESS) network. Methods First, the image is reconstructed into the graph to extract the non-local self-similarity in the image. Second, GCESS uses spatial convolution and graph convolution to process the information in the image, so that local and non-local information can be effectively utilized. The network strengthens the non-local similarity between similar image patches while reconstructing images, making the reconstruction of structure more reliable. Results Experimental results on in vivo knee and brain data demonstrate that the proposed method achieves better artifact suppression and detail preservation than state-of-the-art methods, both visually and quantitatively. Under 1D Cartesian sampling with 4 × acceleration (AF = 4), the PSNR of knee data reached 34.19 dB, 1.05 dB higher than that of the compared methods; the SSIM achieved 0.8994, 2% higher than the compared methods. Similar results were obtained for the reconstructed images under other sampling templates as demonstrated in our experiment. Conclusions The proposed method successfully constructs a hybrid graph convolution and spatial convolution network to reconstruct images. This method, through its training process, amplifies the non-local self-similarities, significantly benefiting the structural integrity of the reconstructed images. Experiments demonstrate that the proposed method outperforms the state-of-the-art reconstruction method in suppressing artifacts, as well as in preserving image details.

Abstract Background Drug addiction is a serious problem worldwide and is influenced by genetic factors. The present study aimed to investigate the association between genetics and drug addiction among Han Chinese. Methods A total of 1000 Chinese users of illicit drugs and 9693 healthy controls were enrolled and underwent single nucleotide polymorphism (SNP)-based and haplotype-based association analyses via whole-genome genotyping. Results Both single-SNP and haplotype tests revealed associations between illicit drug use and several immune-related genes in the major histocompatibility complex (MHC) region (SNP association: log10BF = 15.135, p = 1.054e-18; haplotype association: log10BF = 20.925, p = 2.065e-24). These genes may affect the risk of drug addiction via modulation of the neuroimmune system. The single-SNP test exclusively reported genome-wide significant associations between rs3782886 (SNP association: log10BF = 8.726, p = 4.842e-11) in BRAP and rs671 (SNP association: log10BF = 7.406, p = 9.333e-10) in ALDH2 and drug addiction. The haplotype test exclusively reported a genome-wide significant association (haplotype association: log10BF = 7.607, p = 3.342e-11) between a region with allelic heterogeneity on chromosome 22 and drug addiction, which may be involved in the pathway of vitamin B12 transport and metabolism, indicating a causal link between lower vitamin B12 levels and methamphetamine addiction. Conclusions These findings provide new insights into risk-modeling and the prevention and treatment of methamphetamine and heroin dependence, which may further contribute to potential novel therapeutic approaches.

Abstract Background It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity. Methods Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data. Results Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan. Conclusion This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.

Abstract Background Bifid nose is a rare congenital deformity and the etiology is unknown. The purpose of this study was to report genetic variation in family of patients with bifid nose. Methods Twenty-three consecutive patients who were diagnosed with mild bifid nose were operated with z-plasty from 2009 to 2021. Three underage patients (a pair of twins and a girl) from two family lines, who came to our hospital for surgical treatment, were enrolled. Whole exome sequencing and Sanger sequencing were conducted. Z-shaped flaps were created and the cartilago alaris major were re-stitched. Photographs and CT scan before and after surgery were obtained. Clinical outcomes, complications and patients’ satisfaction were evaluated and analyzed. The follow-up time ranges from 2 to 3 years (2.4 ± 1.2 years). Results Most patients were satisfied with the outcome (96.2%). The nasal deformities were corrected successfully with z-plasty technique in one-stage. FREM1 c.870_876del and c.2 T > C were detected with Whole exome sequencing, which have not been reported before. The results of Sanger sequencing were consistent with those of Whole exome sequencing. Conclusions The newly detected mutations of FREM1 have a certain heritability, and are helpful to make an accurate diagnosis and provide a better understanding of bifid nose mechanism. Z-plasty technique can be an effective technical approach for correcting mild bifid nose deformity.

Abstract Background Since diagnosis of mood disorder heavily depends on signs and symptoms, emerging researches have been studying biomarkers with the attempt to improve diagnostic accuracy, but none of the findings have been broadly accepted. The purpose of the present study was to construct a preliminary diagnostic model to distinguish major depressive disorder (MDD) and bipolar disorder (BD) using potential commonly tested blood biomarkers. Methods Information of 721 inpatients with an ICD-10 diagnosis of MDD or BD were collected from the electronic medical record system. Variables in the nomogram were selected by best subset selection method after a prior univariable screening, and then constructed using logistic regression with inclusion of the psychotropic medication use. The discrimination, calibration and internal validation of the nomogram were evaluated by the receiver operating characteristic curve (ROC), the calibration curve, cross validation and subset validation method. Results The nomogram consisted of five variables, including age, eosinophil count, plasma concentrations of prolactin, total cholesterol, and low-density lipoprotein cholesterol. The model could discriminate between MDD and BD with an area under the ROC curve (AUC) of 0.858, with a sensitivity of 0.716 and a specificity of 0.890. Conclusion The comprehensive nomogram constructed by the present study can be convenient to distinguish MDD and BD since the incorporating variables were common indicators in clinical practice. It could help avoid misdiagnoses and improve prognosis of the patients.

Abstract Grainyhead like 2 (GRHL2) is an essential transcription factor for development and function of epithelial tissues. It has dual roles in cancer by supporting tumor growth while suppressing epithelial to mesenchymal transitions (EMT). GRHL2 cooperates with androgen and estrogen receptors (ER) to regulate gene expression. We explore genome wide GRHL2 binding sites conserved in three ER⍺/GRHL2 positive luminal breast cancer cell lines by ChIP-Seq. Interaction with the ER⍺/FOXA1/GATA3 complex is observed, however, only for a minor fraction of conserved GRHL2 peaks. We determine genome wide transcriptional dynamics in response to loss of GRHL2 by nascent RNA Bru-seq using an MCF7 conditional knockout model. Integration of ChIP- and Bru-seq pinpoints candidate direct GRHL2 target genes in luminal breast cancer. Multiple connections between GRHL2 and proliferation are uncovered, including transcriptional activation of ETS and E2F transcription factors. Among EMT-related genes, direct regulation of CLDN4 is corroborated but several targets identified in other cells (including CDH1 and ZEB1) are ruled out by both ChIP- and Bru-seq as being directly controlled by GRHL2 in luminal breast cancer cells. Gene clusters correlating positively (including known GRHL2 targets such as ErbB3, CLDN4/7) or negatively (including TGFB1 and TGFBR2) with GRHL2 in the MCF7 knockout model, display similar correlation with GRHL2 in ER positive as well as ER negative breast cancer patients. Altogether, this study uncovers gene sets regulated directly or indirectly by GRHL2 in luminal breast cancer, identifies novel GRHL2-regulated genes, and points to distinct GRHL2 regulation of EMT in luminal breast cancer cells. Video Abstract

Abstract Background Guided bone self-generation with periosteum-preserved has successfully regenerated mandibular, temporomandibular and interphalangeal joint. The aim of this study was to investigate the dynamic changes of gene expression of periosteum which was involved in the guided bone self-generation. Methods Rib defects of critical size were created in mature swine with periosteum-preserved. The periosteum was sutured into a sealed sheath that closed the bone defect. The periosteum of trauma and control sites were harvested at postoperative 9 time points, and total RNA was extracted. Microarray analysis was conducted to identify the differences in the transcriptome of different time points between two groups. Results The differentially expressed genes (DEGs) between control and trauma group were different at postoperative different time points. The dynamic changes of the number of DEGs fluctuated a lot. There were 3 volatility peaks, and we chose 3 time points of DEG number peak (1 week, 5 weeks and 6 months) to study the functions of DEGs. Oxidoreductase activity, oxidation–reduction process and mitochondrion are the most enriched terms of Go analysis. The major signaling pathways of DEGs enrichment include oxidative phosphorylation, PI3K-Akt signaling pathway, osteoclast differentiation pathway and Wnt signaling. Conclusions The oxidoreductase reaction was activated during this bone regeneration process. The oxidative phosphorylation, PI3K-Akt signaling pathway, osteoclast differentiation pathway and Wnt signaling may play important roles in the guided bone self-generation with periosteum-preserved. This study can provide a reference for how to improve the application of this concept of bone regeneration.

Abstract Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of paratuberculosis. As a potential zoonotic pathogen, MAP also seriously threatens human health and social security. At present, long non-coding RNA (lncRNA) has attracted wide attention as an useful biomarker in various diseases. Therefore, our study analyzed the lncRNA expression profiles and lncRNA-mRNA regulatory network of MAP infected bovine monocytes-macrophages and uninfected bovine cells by high-throughput sequencing. A total of 4641 differentially expressed lncRNAs genes were identified, including 3111 up-regulated genes and 1530 down-regulated genes. In addition, lncRNA-mRNA interaction analysis was performed to predict the target genes of lncRNA. Among them, after MAP infection, 86 lncRNAs targeted to mRNA, of which only 6 genes were significantly different. The results of Gene Ontology (GO) enrichment analysis showed that the differentially expressed genes significantly enriched in functional groups were related to immune regulation. Multiple signal pathways including NF-κB, NOD-like receptor, Cytokine-cytokine receptor, Toll-like receptor signaling pathway, Chemokine signaling pathway, and other important biochemical, metabolic and signal transduction pathways were enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG). In this study, analysis of macrophage transcriptomes in response to MAP infection is expected to provide key information to deeply understand role of the pathogen in initiating an inappropriate and persistent infection in susceptible hosts and molecular mechanisms that might underlie the early phases of paratuberculosis.

Abstract Objective To investigate the dynamic expression of NFAT family of periosteum in guided bone regeneration process. Material and methods The swine ribs on one side were used as the trauma group and the contralateral side as the control group. After rib segment was removed, periosteum was sutured to form a closed cavity mimicking guided bone regeneration. The periosteum and regenerated bone tissue were collected at nine time points for gene sequencing and hematoxylin–eosin staining. The expression data of each member were extracted for analysis. Expression correlations among various members were analyzed. Results Staining showed the guided bone regeneration was almost completed 1 month after the operation with later stage for bone remodeling. The expression levels of each member in both groups changed greatly, especially within postoperative 1.5 months. The expression of NFATc1 and NFATC2IP in trauma group was significantly correlated with those of control group. The foldchange of each member also had large fluctuations especially within 1.5 months. In the trauma group, NFATc2 and NFATc4 were significantly upregulated, and there was a significant aggregation correlation of NFAT family expression between the various time points within one month, similar to the “pattern-block” phenomenon. Conclusion This study revealed the dynamic expression of NFAT family in guided bone regeneration, and provided a reference for the specific mechanism. The first 1.5 months is a critical period and should be paid attention to. The significant high-expression of NFATc2 and NFATc4 may role importantly in this process, which needs further research to verify it.

Abstract Background IgA nephropathy is the most common glomerular disease and is a common cause of progression to end-stage renal disease in patients with kidney diseases. Proteinuria levels are critical for the prognosis of patients with IgA nephropathy, but many patients are still unable to effectively control their proteinuria levels after receiving RAAS blockers. Antimalarial drugs have shown good efficacy in the treatment of kidney disease in previous studies; however, there have been no strictly designed randomized controlled trials to confirm the clinical efficacy of artesunate for treating IgA nephropathy patients. Therefore, we designed this clinical trial to compare the effect of artesunate versus placebo in patients with IgA nephropathy. Methods This study is a randomized, double-blind, three-group-parallel, placebo-controlled clinical trial. One hundred and twenty eligible IgA nephropathy patients at risk of progression will be randomly divided into the artesunate 100-mg group, artesunate 50-mg group, and placebo group. Changes in proteinuria and renal function will be measured 6 months after the intervention. The levels of Gd-IgA1 and anti-Gd-IgA1 in the patient’s blood will also be tested to explore the possible immune mechanisms. Discussion Clinical evidence supporting artesunate treatment of IgA nephropathy is currently lacking, and we expect that the results of this trial will provide high-quality clinical evidence for artesunate as a treatment option for IgA nephropathy in the future. Trial registration Chinese Clinical Trial Registry ChiCTR2000038104 . Registered on 10 September 2020

Abstract Background Glioblastoma multiforme (GBM) is the most common aggressive malignant brain tumor. However, the molecular mechanism of glioblastoma formation is still poorly understood. To identify candidate genes that may be connected to glioma growth and development, weighted gene co-expression network analysis (WGCNA) was performed to construct a gene co-expression network between gene sets and clinical characteristics. We also explored the function of the key candidate gene. Methods Two GBM datasets were selected from GEO Datasets. The R language was used to identify differentially expressed genes. WGCNA was performed to construct a gene co-expression network in the GEO glioblastoma samples. A custom Venn diagram website was used to find the intersecting genes. The GEPIA website was applied for survival analysis to determine the significant gene, FUBP3. OS, DSS, and PFI analyses, based on the UCSC Cancer Genomics Browser, were performed to verify the significance of FUBP3. Immunohistochemistry was performed to evaluate the expression of FUBP3 in glioblastoma and adjacent normal tissue. KEGG and GO enrichment analyses were used to reveal possible functions of FUBP3. Microenvironment analysis was used to explore the relationship between FUBP3 and immune infiltration. Immunohistochemistry was performed to verify the results of the microenvironment analysis. Results GSE70231 and GSE108474 were selected from GEO Datasets, then 715 and 694 differentially expressed genes (DEGs) from GSE70231 and GSE108474, respectively, were identified. We then performed weighted gene co-expression network analysis (WGCNA) and identified the most downregulated gene modules of GSE70231 and GSE108474, and 659 and 3915 module genes from GSE70231 and GSE108474, respectively, were selected. Five intersection genes (FUBP3, DAD1, CLIC1, ABR, and DNM1) were calculated by Venn diagram. FUBP3 was then identified as the only significant gene by survival analysis using the GEPIA website. OS, DSS, and PFI analyses verified the significance of FUBP3. Immunohistochemical analysis revealed FUBP3 expression in GBM and adjacent normal tissue. KEGG and GO analyses uncovered the possible function of FUBP3 in GBM. Tumor microenvironment analysis showed that FUBP3 may be connected to immune infiltration, and immunohistochemistry identified a positive correlation between immune cells (CD4 + T cells, CD8 + T cells, and macrophages) and FUBP3. Conclusion FUBP3 is associated with immune surveillance in GBM, indicating that it has a great impact on GBM development and progression. Therefore, interventions involving FUBP3 and its regulatory pathway may be a new approach for GBM treatment.

Abstract Chronic inflammatory systemic diseases are the result of the body's immune imbalance, with a long course and recurring episodes. Immunosuppressants are the main treatment, but not all patients respond well to it. Being capable of both self-renewal and differentiation into multiple tissue cells and low immunogenicity, mesenchymal stem cell is a promising treatment for chronic inflammatory systemic diseases. In this article, we describe the research progress and clinical application of mesenchymal stem cells in chronic inflammatory systemic diseases and look for influencing factors and biomarkers that can predict the outcome of patient with mesenchymal stem cell transplantation.

Abstract Background Diagnosing seronegative rheumatoid arthritis (RA) can be challenging due to complex diagnostic criteria. We sought to discover diagnostic biomarkers for seronegative RA cases by studying metabolomic and lipidomic changes in RA patient serum. Methods We performed comprehensive metabolomic and lipidomic profiling in serum of 225 RA patients and 100 normal controls. These samples were divided into a discovery set (n = 243) and a validation set (n = 82). A machine-learning-based multivariate classification model was constructed using distinctive metabolites and lipids signals. Results Twenty-six metabolites and lipids were identified from the discovery cohort to construct a RA diagnosis model. The model was subsequently tested on a validation set and achieved accuracy of 90.2%, with sensitivity of 89.7% and specificity of 90.6%. Both seropositive and seronegative patients were identified using this model. A co-occurrence network using serum omics profiles was built and parsed into six modules, showing significant association between the inflammation and immune activity markers and aberrant metabolism of energy metabolism, lipids metabolism and amino acid metabolism. Acyl carnitines (20:3), aspartyl-phenylalanine, pipecolic acid, phosphatidylethanolamine PE (18:1) and lysophosphatidylethanolamine LPE (20:3) were positively correlated with the RA disease activity, while histidine and phosphatidic acid PA (28:0) were negatively correlated with the RA disease activity. Conclusions A panel of 26 serum markers were selected from omics profiles to build a machine-learning-based prediction model that could aid in diagnosing seronegative RA patients. Potential markers were also identified in stratifying RA cases based on disease activity.

Abstract Background Magnetic resonance imaging (MRI) is an effective auxiliary diagnostic method in clinical medicine, but it has always suffered from the problem of long acquisition time. Compressed sensing and parallel imaging are two common techniques to accelerate MRI reconstruction. Recently, deep learning provides a new direction for MRI, while most of them require a large number of data pairs for training. However, there are many scenarios where fully sampled k-space data cannot be obtained, which will seriously hinder the application of supervised learning. Therefore, deep learning without fully sampled data is indispensable. Main text In this review, we first introduce the forward model of MRI as a classic inverse problem, and briefly discuss the connection of traditional iterative methods to deep learning. Next, we will explain how to train reconstruction network without fully sampled data from the perspective of obtaining prior information. Conclusion Although the reviewed methods are used for MRI reconstruction, they can also be extended to other areas where ground-truth is not available. Furthermore, we may anticipate that the combination of traditional methods and deep learning will produce better reconstruction results.

Abstract Disordered chromatin remodeling regulation has emerged as an essential driving factor for cancers. Imitation switch (ISWI) family are evolutionarily conserved ATP-dependent chromatin remodeling complexes, which are essential for cellular survival and function through multiple genetic and epigenetic mechanisms. Omics sequencing and a growing number of basic and clinical studies found that ISWI family members displayed widespread gene expression and genetic status abnormalities in human cancer. Their aberrant expression is closely linked to patient outcome and drug response. Functional or componential alteration in ISWI-containing complexes is critical for tumor initiation and development. Furthermore, ISWI-non-coding RNA regulatory networks and some non-coding RNAs derived from exons of ISWI member genes play important roles in tumor progression. Therefore, unveiling the transcriptional regulation mechanism underlying ISWI family sparked a booming interest in finding ISWI-based therapies in cancer. This review aims at describing the current state-of-the-art in the role of ISWI subunits and complexes in tumorigenesis, tumor progression, immunity and drug response, and presenting deep insight into the physiological and pathological implications of the ISWI transcription machinery in cancers.

Abstract Background Colorectal cancer (CRC) is one of the most common cancers of the gastrointestinal tract and ranks third in cancer-related deaths worldwide. This study was conducted to identify novel biomarkers related to the pathogenesis of CRC based upon a bioinformatics analysis, and further verify the biomarkers in clinical tumor samples and CRC cell lines. Methods A series of bioinformatics analyses were performed using datasets from NCBI-GEO and constructed a protein–protein interaction (PPI) network. This analysis enabled the identification of Hub genes, for which the mRNA expression and overall survival of CRC patients data distribution was explored in The Cancer Genome Atlas (TCGA) colon cancer and rectal cancer (COADREAD) database. Furthermore, the differential expression of HCAR3 and INLS5 was validated in clinical tumor samples by Real-time quantitative PCR analysis, western blotting analysis, and immunohistochemistry analysis. Finally, CRC cells over-expressing INSL5 were constructed and used for CCK8, cell cycle, and cell apoptosis validation assays in vitro. Results A total of 286 differentially expressed genes (DEGs) were screened, including 64 genes with increased expression and 143 genes with decreased expression in 2 CRC database, from which 10 key genes were identified: CXCL1, HCAR3, CXCL6, CXCL8, CXCL2, CXCL5, PPY, SST, INSL5, and NPY1R. Among these genes, HCAR3 and INSL5 had not previously been explored and were further verified in vitro. Conclusions HCAR3 expression was higher in CRC tissues and associated with better overall survival of CRC patients. INSL5 expression in normal tissue was higher than that in tumor tissue and its high expression was associated with a better prognosis for CRC. The overexpression of INSL5 significantly inhibited the proliferation and promoted the shearing of PARP of CRC cells. This integrated bioinformatics study presented 10 key hub genes associated with CRC. HCAR3 and INSL5 were expressed in tumor tissue and these were associated with poor survival and warrant further studies as potential therapeutic targets.

Abstract Background Sufficient vascular network plays an important role in the repair of bone defects. Bone morphogenetic protein 2 (BMP2) being a key regulator of angiogenesis has attracted the attention of researchers. In addition, evidence has suggested that BMP2 coordinates with microRNAs (miRNAs) to form intracellular networks regulating mesenchymal stem cells (MSCs) angiogenesis. Elucidating the underlying mechanisms that are regulating adipose-derived mesenchymal stem cells (ADSCs) angiogenesis might provide more effective method to enhance bone regeneration. Methods We identified the specific miRNA in rat ADSCs during BMP2-induced angiogenesis and chose the most significant differentially expressed miRNA, miR-672. Three lentiviral system named Lenti-miR-672, Lenti-as-miR-672, and Lenti-miR-NC were transduced into the ADSCs individually. Then, the quantitative real-time polymerase chain reaction (qPCR), western blotting, and blood vessel formation analysis were performed to investigate the effects of miR-672 on ADSCs angiogenesis. Bioinformation platforms were used to screen the potential target of miR-672. Small interfering RNA (siRNA) against TIMP2 (si-TIMP2) mRNA were obtained from GenePharma, and then si-TIMP2 miRNA and miR-672 were co-transfected into ADSCs to detect the effects of TIMP2 on angiogenesis. Calcium phosphate cement (CPC) scaffolds that seeded the lentiviral-modified ADSCs were constructed to test the vascularized bone regeneration in vivo. Results Our data showed that after the angiogenesis of ADSCs induced by BMP2, miR-672 was the most significantly upregulated miRNA. Overexpression of miR-672 promoted the angiogenesis of ADSCs, while knockdown of miR-672 repressed the angiogenesis of ADSCs. The bioinformation prediction showed that TIMP2 might be the one of miR-672′ potential targets. TIMP2 protein expression was gradually decreased in ADSCs with overexpressed miR-672. And the angiogenic factors were upregulated in the ADSCs which were transduced with si-TIMP2. Then, the CPC scaffolds coupled the miR-672-modified ADSCs and showed the good potential in vascularized bone regeneration. The overexpressed miR-672 could greatly enhance the blood vessel volume and Microfil-labeled blood vessel numbers in newly formed bone. Conclusion BMP2 could promote the angiogenesis of ADSCs through stimulating the expression of miR-672 in ADSCs. miR-672 acted as a positive regulator on the angiogenesis of ADSCs, and incorporating the miR-672-modified ADSCs in the CPC could significantly promote the vascularization and the bone regeneration.

Abstract Background Older age and elevated d-dimer are reported risk factors for coronavirus disease 2019 (COVID-19). However, whether early radiographic change is a predictor of fatality remains unknown. Methods We retrospectively reviewed records of all laboratory-confirmed patients admitted to a quarantine unit at Tongji Hospital, a large regional hospital in Wuhan, China, between January 31 and March 5, 2020. Confirmed cases were defined by positive RT-PCR detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in throat-swab specimens. Chest CT images were reviewed independently by two radiologists. The Tongji Hospital ethics committee approved this study. Results A total of 102 patients were confirmed to have SARS-CoV-2 infection. As of March 25, 85 confirmed patients were discharged, 15 died, and 2 remained hospitalized. When compared with survivors, non-survivors were older (median age, 69 [interquartile range, 58–77] vs. 55 [44–66], p = 0.003), and more likely to have decreased lymphocyte count (0.5 vs. 0.9 × 109/L, p = 0.006), elevated lactate dehydrogenase (LDH) (569.0 vs. 272.0 U/L, p 1 μg/mL, 86% vs. 37%, p = 0.002) on admission. Older age and elevated LDH were independent risk factors for fatality in a multivariate regression model included the above variables. In a subset of patients with CT images within the first week, higher total severity score, and more involved lung lobes (5 involved lobes) in CT images within the first week were significantly associated with fatality. Moreover, in this subset of patients, higher total severity score was the only independent risk factor in a multivariate analysis incorporating the above mentioned variables. Conclusions Older age, elevated LDH on admission, and higher severity score of CT images within the first week are potential predictors of fatality in adults with COVID-19. These predictors may help clinicians identify patients with a poor prognosis at an early stage.

Abstract Background Eosinophilic peritonitis is a relatively rare entity. Kimura’s disease is a rare chronic inflammatory disorder of unknown etiology, characterized by subcutaneous nodules mainly in the head and neck region, regional lymphadenopathy and occasional involvement of kidney. There is currently no report of eosinophilic peritonitis in Kimura’s disease. Case presentation A 44-year-old Chinese man presented with abdominal distention, nausea, vomiting and edema in lower limbs for 1 month. Laboratory data showed elevated eosinophils in peripheral blood and ascites, nephrotic syndrome with progressively renal dysfunction, and elevated IgE. Ultrasonography of lymph nodes showed multiple lymphadenopathy in bilateral inguinal regions. Surgical excision was performed for one of the enlarged lymph nodes and histopathology revealed diagnosis of Kimura’s disease. Renal biopsy indicated focal segmental glomerulosclerosis (FSGS) and acute tubulointerstitial nephritis with infiltration of eosinophils in renal interstitium. The patient was prescribed with oral prednisolone therapy (30 mg/day), and underwent continuous ambulatory peritoneal dialysis (CAPD). The peripheral and peritoneal eosinophil count decreased rapidly and normalized within 2 days. Forty-five days after prednisolone therapy, partial remission of nephrotic syndrome and decrease of serum creatinine were achieved while peritoneal dialysis dosage had decreased. Inguinal lymph nodes gradually shrunk in size. The overall conditions remain stable afterwards. Conclusions This rare case highlighted the clinical conundrum of a patient presenting with eosinophilic peritonitis, lymphadenopathy, nephrotic syndrome and renal failure associated with Kimura’s disease. The remarkable eosinophilia, pathology of lymph node and kidney, as well as significant response to steroids should guide towards the diagnosis.

Abstract Normal hematopoiesis requires the accurate orchestration of lineage-specific patterns of gene expression at each stage of development, and epigenetic regulators play a vital role. Disordered epigenetic regulation has emerged as a key mechanism contributing to hematological malignancies. Histone deacetylases (HDACs) are a series of key transcriptional cofactors that regulate gene expression by deacetylation of lysine residues on histone and nonhistone proteins. In normal hematopoiesis, HDACs are widely involved in the development of various lineages. Their functions involve stemness maintenance, lineage commitment determination, cell differentiation and proliferation, etc. Deregulation of HDACs by abnormal expression or activity and oncogenic HDAC-containing transcriptional complexes are involved in hematological malignancies. Currently, HDAC family members are attractive targets for drug design, and a variety of HDAC-based combination strategies have been developed for the treatment of hematological malignancies. Drug resistance and limited therapeutic efficacy are key issues that hinder the clinical applications of HDAC inhibitors (HDACis). In this review, we summarize the current knowledge of how HDACs and HDAC-containing complexes function in normal hematopoiesis and highlight the etiology of HDACs in hematological malignancies. Moreover, the implication and drug resistance of HDACis are also discussed. This review presents an overview of the physiology and pathology of HDACs in the blood system.

Abstract Background X-ray micro-CT has increasingly been used for 3D imaging of plant structures. At the micrometer resolution however, limitations in X-ray contrast often lead to datasets with poor qualitative and quantitative measures, especially within dense cell clusters of plant tissue specimens. The current study developed protocols for delivering a cesium based contrast enhancing solution to varying plant tissue specimens for the purpose of improving 3D tissue structure characterization within plant specimens, accompanied by new image processing workflows to extract the additional data generated by the contrast enhanced scans. Results Following passive delivery of a 10% cesium iodide contrast solution, significant increases of 85.4 and 38.0% in analyzable cell volumes were observed in pear fruit hypanthium and tomato fruit outer mesocarp samples. A significant increase of 139.6% in the number of analyzable cells was observed in the pear fruit samples along the added ability to locate and isolate better brachysclereids and vasculature in the sample volume. Furthermore, contrast enhancement resulted in significant improvement in the definition of collenchyma and parenchyma in the petiolule of tomato leaflets, from which both qualitative and quantitative data can be extracted with respect to cell measures. However, contrast enhancement was not achieved in leaf vasculature and mesophyll tissue due to fundamental limitations. Active contrast delivery to apple fruit hypanthium samples did yield a small but insignificant increase in analyzable volume and cells, but data on vasculature can now be extracted better in correspondence to the pear hypanthium samples. Contrast delivery thus improved visualization and analysis the most in dense tissue types. Conclusions The cesium based contrast enhancing protocols and workflows can be utilized to obtain detailed 3D data on the internal microstructure of plant samples, and can be adapted to additional samples of interest with minimal effort. The resulting datasets can therefore be utilized for more accurate downstream studies that requires 3D data.

Abstract Background Surgeries are inevitable for treating primary congenital glaucoma (PCG) and risk factors of surgical failure play a key role in surgical decision making. The aim of this study was to investigate the influence of delay of surgery and preoperative speed of progression (SP) on the surgical outcomes in these patients. Methods Medical records of 83 eyes of 51 PCG patients with trabeculotomy within 3 years were retrospectively observed. Surgical outcomes, demographic and clinical data were compared after separating the eyes into two groups based on the interval (between onset of PCG and trabeculotomy) and SP index (SPI) respectively. Student’s t-test, Wilcoxon rank-sum test, Pearson’s chi-square test and Kaplan-Meier survival analysis were used in the statistical analysis. Results Comparative analysis showed better outcomes in the group with longer interval and lower SPIs. Better intraocular pressure (IOP) control was found in patients with lower SPI at 1, 3, 6, 12 and 24 months postoperatively (19.54 ± 4.84 mmHg vs. 24.75 ± 8.87 mmHg, p = 0.004; 19.88 ± 7.78 mmHg vs. 23.19 ± 6.74 mmHg, p = 0.089; 17.45 ± 6.23 mmHg vs. 21.31 ± 7.28 mmHg, p = 0.031; 15.09 ± 6.21 mmHg vs. 19.18 ± 6.66 mmHg, p = 0.008; 14.95 ± 2.95 mmHg vs. 18.10 ± 3.96 mmHg, p = 0.004). The correlation between SPI and IOP at 1, 3, 6, 12 and 24 months postoperatively was 0.328 (CI = 0.105 to 0.529, p = 0.005), 0.192 (CI = −0.070 to 0.429, p = 0.149), 0.261 (CI = 0.010 to 0.481, p = 0.042), 0.046 (CI = −0.183 to 0.270, p = 0.70), and 0.230 (CI = −0.072 to 0.493, p = 0.134), respectively. Patients with lower SPI were less likely to fail (χ2 = 22.71, p = 0.000, OR: 0.174; 95%CI: 0.059–0.510). Kaplan-Meier analysis showed a much slower decline of success rate in patients with lower SPI (χ2 = 25.52, p = 0.000). Conclusions In PCG patients, lower preoperative SPI was associated with better short-term IOP control and success rate. Evaluation of preoperative SPI may help with surgical decision. However, early detection and treatment are important given the same SPI.

Abstract Background In recent years, highly frequent swine respiratory diseases have been caused by extraintestinal pathogenic Escherichia coli (ExPEC) in China. Due to this increase in ExPECs, this bacterial pathogen has become a threat to the development of the Chinese swine industry. To investigate ExPEC pathogenesis, we isolated a strain (named SLPE) from lesioned porcine lungs from Changchun in China, reported the draft genome and performed comparative genomic analyses. Results Based on the gross post-mortem examination, bacterial isolation, animal regression test and 16S rRNA gene sequence analysis, the pathogenic bacteria was identified as an ExPEC. The SLPE draft genome was 4.9 Mb with a G + C content of 51.7%. The phylogenomic comparison indicated that the SLPE strain belongs to the B1 monophyletic phylogroups and that its closest relative is Avian Pathogenic Escherichia coli (APEC) O78. However, the distribution diagram of the pan-genome virulence genes demonstrated significant differences between SLPE and APEC078. We also identified a capsular polysaccharide synthesis gene cluster (CPS) in the SLPE strain genomes using blastp. Conclusions We isolated the ExPEC (SLPE) from swine lungs in China, performed the whole genome sequencing and compared the sequence with other Escherichia coli (E. coli). The comparative genomic analysis revealed several genes including several virulence factors that are ExPEC strain-specific, such as fimbrial adhesins (papG II), ireA, pgtP, hlyF, the pix gene cluster and fecR for their further study. We found a CPS in the SLPE strain genomes for the first time, and this CPS is closely related to the CPS from Klebsiella pneumoniae.

After the publication of this work [1], the authors note that there are no figure legends in published paper.

Abstract Objectives Non-suicidal self-injury (NSSI) behavior is a severe public health issue in adolescents. This study investigated the possible impact of the coronavirus disease 2019 (COVID-19) and analyzed psychological risk factors on adolescent NSSI. Methods A one-year follow-up study was conducted in September 2019 (Time 1) and September 2020 (Time 2) among 3588 high school students. The completed follow-up participants (N = 2527) were classified into no NSSI (negative at both time points), emerging NSSI (negative at Time 1 but positive at Time 2), and sustained NSSI (positive at both time points) subgroups according to their NSSI behaviors before and during the COVID-19 pandemic. Perceived family functioning, perceived school climate, negative life events, personality traits (neuroticism, impulsivity, and self-control) were assessed using self-report scales. Results The data indicated an increase (10.3%) in the incidence of NSSI. Compared to no NSSI subjects, the emerging NSSI and sustained NSSI subgroups had lower perceived family functioning, higher neuroticism, higher impulse-system but lower self-control scores, and more negative life events. Logistic regressions revealed that after controlling for demographics, neuroticism and impulse-system levels at Time 1 positively predicted emerging NSSI behavior, and similarly, higher neuroticism and impulsivity and lower self-control at Time 1 predicted sustained NSSI behavior. Conclusions These findings highlighted the aggravated impact of the COVID-19 on NSSI, and suggested that individual neuroticism, impulsivity, and self-control traits might be crucial for the development of NSSI behavior among adolescent students.

Abstract Purpose To investigate the predictive role of pre-thrombolytic high sensitivity C-reactive protein (hs-CRP) on the safety and efficacy of intravenous thrombolysis in patients with acute ischemic stroke (AIS). Methods Patients with AIS who underwent intravenous thrombolysis with recombinant plasminogen activator (rtPA) or urokinase without endovascular therapy from June 2019 to June 2022 were retrospectively analysed. All patients were grouped into two groups (high or low hs-CRP group) according to the median value of hs-CRP before intravenous thrombolysis. The baseline NIHSS, NIHSS changes before and after thrombolysis (ΔNIHSS), the rate of good thrombolysis response (NIHSS decreased ≥ 2 points from baseline), the rate of any intracranial hemorrhage, age, sex, hypertension, diabetes, uric acid and platelet count were compared between the two groups. Logistic regression analysis was performed to identify possible prognostic factors for a good thrombolysis response. Results A total of 212 patients were included in the analysis, with a mean age of 66.3 ± 12.5 years. In total, 145 patients received rtPA, and 67 patients received urokinase. Patients were divided into a high hs-CRP group (> 1.60 mg/L) and a low hs-CRP group (≤ 1.60 mg/L) according to the median hs-CRP level (1.60 mg/L). The ΔNIHSS of the high hs-CRP group was significantly smaller than that of the low hs-CRP group (0 [-1 ~ 0] vs. -1 [-2 ~ 0], P 1.60 mg/L was negatively correlated with a good thrombolysis response rate (OR = 0.496, 95% CI = 0.266–0.927, P = 0.028). Conclusion hs-CRP > 1.6 mg/L may serve as a poor prognosis predictive factor for patients with AIS receiving intravenous thrombolysis. However, due to the small sample size of this study, further studies are needed to verify our results.

Abstract N6-Methyladenosine (m6A) modification is one of the most widely distributed RNA modifications in eukaryotes. It participates in various RNA functions and plays vital roles in tissue development, stem cell formation and differentiation, heat shock response control, and circadian clock controlling, particularly during tumor development. The reversible regulation of m6A modification is affected by the so-called ‘reader’, ‘writer’ and ‘eraser’. As a required component and the largest methyltransferase, vir-like m6A methyltransferase associated (VIRMA) can promote the progression of cancer and is associated with poor survival in multiple types of cancer. The present review investigated the role of VIRMA in various types of cancer. In an m6A-dependent or -independent manner, VIRMA can play an oncogenic role by regulating cancer cell proliferation, migration and invasion, metastasis, apoptosis resistance and tumor growth in different pathways by targeting stem factors, CCAT1/2, ID2, GATA3, CDK1, c-Jun, etc. VIRMA can also predict better prognosis in kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP) and papillary thyroid carcinoma by TCGA analysis. The obvious oncogenic roles of VIRMA observed in different types of cancer and the mechanisms of VIRMA promoting cancers provided the basis for potential therapeutic targeting for cancer treatments.

Abstract Background Although lncRNA CTBP1-AS2 has been functionally analyzed only in cardiomyocyte hypertrophy and diabetes, analysis of TCGA dataset revealed its downregulation in endometrial carcinoma (EC), indicating its involvement in EC. Results In this study we found that CTBP1-AS2 was downregulated in EC and correlated with poor survival. MiR-216a might form base pairs with CTBP1-AS2 based on RNA-RNA interaction, which was confirmed by luciferase activity assay. Interestingly, upregulation of PTEN was observed after CTBP1-AS2 overexpression. Transwell assay showed that CTBP1-AS2 and PTEN overexpression led to decreased cancer cell invasion and migration and reduced enhancing effects of miR-216a on cell invasion and migration. It was known that miR-216a targeted PTEN. Conclusion Therefore, CTBP1-AS2 may sponge miR-216a to upregulate PTEN, thereby suppressing endometrial cancer cell invasion and migration.

Abstract Background Circular RNAs (circRNAs) have received considerable attention in human cancer research. However, many circRNAs remain to be detected. In our study, we determined novel circRNAs and investigated their effects on bladder cancer (BCa). Methods Microarray dataset GSE92675 was downloaded from Gene Expression Omnibus (GEO). Then, we combined computational biology with quantitative real-time polymerase chain reaction (qRT-PCR) to select related circRNAs in BCa. The selected circRNA–microRNA (miRNA)–messenger RNA (mRNA) regulatory subnetwork was determined by Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results The regulatory network constructed from the microarray dataset (GSE92675) contained 49 differentially expressed circRNAs (DECs). GO and KEGG analyses showed that the MAPK and PI3K–AKT signaling pathways were statistically significant. On the basis of qRT-PCR and the degree value calculated by the cytoHubba plugin of Cytoscape, hsa_circ_0011385 was finally confirmed. The subnetwork around hsa_circ_0011385 was constructed. In addition, we created a protein–protein interaction (PPI) network composed of 67 nodes and 274 edges after removing independent nodes. GO and KEGG analyses showed that hubgenes were involved in cell cycle activities. Moreover, they could be regulated by miRNAs and play an eventful role in BCa pathogenesis. Conclusions We proposed a novel circRNA–miRNA–mRNA network related to BCa pathogenesis. This network might be a new molecular biomarker and could be used to develop potential treatment strategies for BCa.

Abstract Background METTL3 is known to be involved in all stages in the life cycle of RNA. It affects the tumor formation by the regulation the m6A modification in the mRNAs of critical oncogenes or tumor suppressors. In bladder cancer, METTL3 could promote the bladder cancer progression via AFF4/NF-κB/MYC signaling network by an m6A dependent manner. Recently, METTL3 was also found to affect the m6A modification in non-coding RNAs including miRNAs, lincRNAs and circRNAs. However, whether this mechanism is related to the proliferation of tumors induced by METTL3 is not reported yet. Methods Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of METTL3 in bladder cancer. The survival analysis was adopted to explore the association between METTL3 expression and the prognosis of bladder cancer. Bladder cancer cells were stably transfected with lentivirus and cell proliferation and cell cycle, as well as tumorigenesis in nude mice were performed to assess the effect of METTL3 in bladder cancer. RNA immunoprecipitation (RIP), co-immunoprecipitations and RNA m6A dot blot assays were conducted to confirm that METTL3 interacted with the microprocessor protein DGCR8 and modulated the pri-miR221/222 process in an m6A-dependent manner. Luciferase reporter assay was employed to identify the direct binding sites of miR221/222 with PTEN. Colony formation assay and CCK8 assays were conducted to confirm the function of miR-221/222 in METTL3-induced cell growth in bladder cancer. Results We confirmed the oncogenic role of METTL3 in bladder cancer by accelerating the maturation of pri-miR221/222, resulting in the reduction of PTEN, which ultimately leads to the proliferation of bladder cancer. Moreover, we found that METTL3 was significantly increased in bladder cancer and correlated with poor prognosis of bladder cancer patients. Conclusions Our findings suggested that METTL3 may have an oncogenic role in bladder cancer through interacting with the microprocessor protein DGCR8 and positively modulating the pri-miR221/222 process in an m6A-dependent manner. To our knowledge, this is the first comprehensive study that METTL3 affected the tumor formation by the regulation the m6A modification in non-coding RNAs, which might provide fresh insights into bladder cancer therapy.

Abstract Background The efficacy of partial nephrectomy (PN) for T1b renal cell carcinoma (RCC) is controversial. The oncological outcomes, the change in postoperative renal function and the perioperative complications are unclear. Methods We searched PUBMED, EMBASE and the Cochrane Central Register for studies from March 1998 to March 2018 for studies comparing PN to radical nephrectomy (RN) for the treatment of T1b RCC. After data extraction and quality assessment, we used RevMan 5.2 to pool the data. Then, we used Stata 12.0 to perform sensitivity analyses and meta-regression. We used the GRADE profiler to evaluate the evidence according to the GRADE approach. Results A total of 16 studies involving 33,117 patients were included in our meta-analysis. No significant difference was found in the 5-year overall survival (OS), 10-year OS, 5-year recurrence-free survival (RFS) and 10-year RFS. The 5-year cancer-special survival (CSS) and 10-year CSS were better in RN compared to PN, respectively, at RR = 1.02, P

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13048-020-00754-0.