Overall survival of patients with low-grade glioma (LGG) has shown no significant improvement over the past 30 years, with survival averaging approximately 7 years. This study aimed to identify novel Show more
Overall survival of patients with low-grade glioma (LGG) has shown no significant improvement over the past 30 years, with survival averaging approximately 7 years. This study aimed to identify novel promising biomarkers of LGG and reveal its potential molecular mechanisms by integrated bioinformatics analysis. The microarray datasets of GSE68848 and GSE4290 were selected from GEO database for integrated analysis. In total, 293 overlapping differentially expressed genes (DEGs) were detected using the limma package. One hundred and eighty-eight nodes with 603 interactions were obtained from the establishment of protein-protein interaction (PPI) network. Functional and signaling pathway enriched were significantly correlated with the synapse and calcium signaling pathway, respectively. Module analysis revealed eight hub genes with high connectivity, which included CHRM1, DLG2, GABRD, GRIN1, HTR2A, KCNJ3, KCNJ9, and NUSAP1, and they were markedly correlated with patients' prognosis. The mining of the Gene Expression Profiling Interactive Analysis database and qPCR further confirmed the abnormal expression of these key genes with their prognostic value in LGG. We eventually predicted the 20 most vital small molecule drugs, which potentially reverse the carcinogenic state of LGG, as per the CMap (connectivity map) database and these DEGs, and MS-275 (enrichment score = -0.939) was considered as the most promising small molecule to treat LGG. In conclusion, our study provided eight reliable novel molecular biomarkers for diagnosis, prognosis prediction, and treatment targets for LGG. These conclusions will contribute to a better comprehension of molecular mechanisms fundamental to LGG occurrence and progression, and providing new insights for future development of genomic individualized treatment in LGG. Show less
Growth and fat deposition are important economic traits due to the influence on production in pigs. In this study, a dataset of 1200 pigs with 345,570 SNPs genotyped by sequencing (GBS) was used to co Show more
Growth and fat deposition are important economic traits due to the influence on production in pigs. In this study, a dataset of 1200 pigs with 345,570 SNPs genotyped by sequencing (GBS) was used to conduct a GWAS with single-marker regression method to identify SNPs associated with body weight and backfat thickness (BFT) and to search for candidate genes in Landrace and Yorkshire pigs. A total of 27 and 13 significant SNPs were associated with body weight and BFT, respectively. In the region of 149.85-149.89 Mb on SSC6, the SNP (SSC6: 149876737) for body weight and the SNP (SSC6: 149876507) for BFT were in the same locus region (a gap of 230 bp). Two SNPs were located in the DOCK7 gene, which is a protein-coding gene that plays an important role in pigmentation. Two SNPs located on SSC8: 54567459 and SSC11: 33043081 were found to overlap weight and BFT; however, no candidate gene was found in these regions. In addition, based on other significant SNPs, two positional candidate genes, NSRP1 and CADPS, were proposed to influence weight. In conclusion, this is the first study report using GBS data to identify the significant SNPs for weight and BFT. A total of four particularly interesting SNPs and one potential candidate genes (DOCK7) were found for these traits in domestic pigs. This study improves our knowledge to better understand the complex genetic architecture of weight and BFT, but further validation studies of these candidate loci and genes are recommended in pigs. Show less
Tripartite Motif Containing 11 (TRIM11), an E3 ubiquitin ligase, is identified as a carcinogen causing certain human cancers. However, the specific role of TRIM11 is still uncovered in human osteosarc Show more
Tripartite Motif Containing 11 (TRIM11), an E3 ubiquitin ligase, is identified as a carcinogen causing certain human cancers. However, the specific role of TRIM11 is still uncovered in human osteosarcoma (OS) cells. To explore the role of TRIM11 in OS cells, TRIM11 was induced by silencing and overexpression in OS cells using RNA interference (RNAi) and lentiviral vector, respectively. qRT-PCR and western blot were used to examine the transcription and translation levels of the target gene. Cell count kit-8 (CCK-8) assays were established to analyze cell proliferation. Cell apoptosis ratio was determined via flow cytometry. In our analyses, TRIM11 was suggested to be upregulated, and it functioned as a pro-proliferation and antiapoptosis factor in OS cells. Moreover, the extracellular-signal-regulated kinase 1/2 (ERK1/2) inhibitor PD98059 was used to examine the relationship between TRIM11 and ERK1/2 in OS cells. Results demonstrated that the role of TRIM11 was significantly disrupted by the ERK1/2 inhibitor PD98059. Interestingly, we found TRIM11 overexpression did not affect dual-specificity phosphatase 6 (DUSP6) transcription, but improved its translation in OS cells. Co-immunoprecipitation (Co-IP) analyses revealed that TRIM11 interacted with DUSP6. Importantly, overexpression of TRIM11 enhanced DUSP6 ubiquitination in OS cells. Therefore, TRIM11 might suppress the translation of DUSP6 via improving its ubiquitination. Additionally, TRIM11 silencing in OS cells significantly reduced its tumorigenicity Show less
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is primarily caused by cigarette smoke (CS)-induced chronic inflammation. In this study, we investigated the function an Show more
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that is primarily caused by cigarette smoke (CS)-induced chronic inflammation. In this study, we investigated the function and mechanism of action of the long non-coding RNA (lncRNA) taurine-up-regulated gene 1 (TUG1) in CS-induced COPD. We found that the expression of TUG1 was significantly higher in the sputum cells and lung tissues of patients with COPD as compared to that in non-smokers, and negatively correlated with the percentage of predicted forced expiratory volume in 1 second. In addition, up-regulation of TUG1 was observed in CS-exposed mice, and knockdown of TUG1 attenuated inflammation and airway remodelling in a mouse model. Moreover, TUG1 expression was higher in CS extract (CSE)-treated human bronchial epithelial cells and lung fibroblasts, whereas inhibition of TUG1 reversed CSE-induced inflammation and collagen deposition in vitro. Mechanistically, TUG1 promoted the expression of dual-specificity phosphatase 6 (DUSP6) by sponging miR-145-5p. DUSP6 overexpression reversed TUG1 knockdown-mediated inhibition of inflammation and airway remodelling. These findings suggested an important role of TUG1 in the pathological alterations associated with CS-mediated airway remodelling in COPD. Thus, TUG1 may be a promising therapeutic target in CS-induced airway inflammation and fibroblast activation. Show less
Recent methylome-wide association studies (MWAS) in humans have solidified the concept that aberrant DNA methylation is associated with Alzheimer's disease (AD). We summarize these findings to improve Show more
Recent methylome-wide association studies (MWAS) in humans have solidified the concept that aberrant DNA methylation is associated with Alzheimer's disease (AD). We summarize these findings to improve the understanding of mechanisms governing DNA methylation pertinent to transcriptional regulation, with an emphasis of AD-associated promoter DNA hypermethylation, which establishes an epigenetic barrier for transcriptional activation. By considering brain cell type specific expression profiles that have been published only for non-demented individuals, we detail functional activities of selected neuron, microglia, and astrocyte-enriched genes (AGAP2, DUSP6 and GPR37L1, respectively), which are DNA hypermethylated at promoters in AD. We highlight future directions in MWAS including experimental confirmation, functional relevance to AD, cell type-specific temporal characterization, and mechanism investigation. Show less
Romi Gupta, Suresh Bugide, Biao Wang+3 more · 2019 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Acquired resistance to BRAF kinase inhibitors (BRAFi) is the primary cause for their limited clinical benefit. Although several mechanisms of acquired BRAFi resistance have been identified, the basis Show more
Acquired resistance to BRAF kinase inhibitors (BRAFi) is the primary cause for their limited clinical benefit. Although several mechanisms of acquired BRAFi resistance have been identified, the basis for acquired resistance remains unknown in over 40% of melanomas. We performed a large-scale short-hairpin RNA screen, targeting 363 epigenetic regulators and identified Block of Proliferation 1 (BOP1) as a factor the loss of which results in resistance to BRAFi both in cell culture and in mice. Show less
Non-planar sensor arrays are used to determine solar orientation based on the orientation matrix formed by orientation vectors of the sensor planes. Solar panels or existing photodiodes can be directl Show more
Non-planar sensor arrays are used to determine solar orientation based on the orientation matrix formed by orientation vectors of the sensor planes. Solar panels or existing photodiodes can be directly used without increasing the size or mass of the spacecraft. However, a limiting factor for the improvement of the accuracy of orientation lies with the lack of an assessment-based approach. A formulation was developed for the supremum (i.e., the least upper bound) of orientation error of an arbitrary orientation matrix in terms of its influencing factors. The new formulation offers a way to evaluate the supremum of orientation error considering interference with finite energy and interference with infinite energy but finite average energy. For a given non-planar sensor array, a sub-matrix of the full orientation matrix would reach the optimal accuracy of orientation if its supremum of orientation error is the least. Principles for designing an optimal sensor array relate to the configuration of the orientation matrix, which can be pre-determined for a given number of sensors. Simulations and field experiment tested and validated the methods, showing that our sensor array optimization method outperforms the existing methods, while providing a way of assessment and optimization. Show less
Non-planar sun sensors can determine solar orientation by existing photodiodes or by reusing solar panels, without increasing the size and mass of spacecraft. However, a limiting factor for the improv Show more
Non-planar sun sensors can determine solar orientation by existing photodiodes or by reusing solar panels, without increasing the size and mass of spacecraft. However, a limiting factor for the improvement of the accuracy of orientation lies in the lack of a detailed performance assessment on interference suppression. In this paper, a new method that determines solar orientation in the frequency domain is developed for regular pyramid sun sensors, which are formed by regular pyramid arrays. Furthermore, two formulations are established to evaluate the errors of the solar azimuth and elevation angle in solar orientation determination based on the newly proposed frequency-domain method. With these formulations of performance evaluation, we discover the mathematical relationship between the interference spectrum, array geometry, solar irradiance, solar azimuth or elevation angle, and the error in solar orientation determination for the first time. This reveals that the internal interference from the detection system can be completely suppressed in solar orientation determination, and the constant interference can be eliminated in the estimation of solar azimuth angle. Simulation and field experiments validated the effectiveness of the new orientation method, error formulations and performance of each interference source. Show less
Both mandibular condylar hyperplasia and condylar osteochondroma can lead to maxillofacial skeletal asymmetry and malocclusion, although they exhibit different biological behavior. This study attempte Show more
Both mandibular condylar hyperplasia and condylar osteochondroma can lead to maxillofacial skeletal asymmetry and malocclusion, although they exhibit different biological behavior. This study attempted to compare the histological features of mandibular condylar hyperplasia and condylar osteochondroma using hematoxylin-and-eosin (H&E) staining, and immunohistochemistry staining of PCNA and EXT1 with quantitative analysis method. The H&E staining showed that condylar hyperplasia and condylar osteochondroma could be divided into four histological types and exhibited features of different endochondral ossification stages. There was evidence of a thicker cartilage cap in condylar osteochondroma as compared condylar hyperplasia (P = 0.018). The percentage of bone formation in condylar osteochondroma was larger than was found in condylar hyperplasia (P = 0.04). Immunohistochemical staining showed that PCNA was mainly located in the undifferentiated mesenchymal layer and the hypertrophic cartilage layer, and there were more PCNA positive cells in the condylar osteochondroma (P = 0.007). EXT1 was mainly expressed in the cartilage layer, and there was also a higher positive rate of EXT1 in condylar osteochondroma (P = 0.0366). The thicker cartilage cap, higher bone formation rate and higher PCNA positive rate indicated a higher rate of proliferative activity in condylar osteochondroma. The more significant positive rate of EXT1 in condylar osteochondroma implied differential biological characteristic as compared to condylar hyperplasia. These features might be useful in histopathologically distinguishing condylar hyperplasia and osteochondroma. Show less
Exostosin-1 (Ext1) encodes a glycosyltransferase required for heparan sulfate (HS) chain elongation in HS-proteoglycan biosynthesis. HS chains serve as binding partners for signaling proteins, affecti Show more
Exostosin-1 (Ext1) encodes a glycosyltransferase required for heparan sulfate (HS) chain elongation in HS-proteoglycan biosynthesis. HS chains serve as binding partners for signaling proteins, affecting their distribution and activity. The Wnt/β-catenin pathway emerged as critical regulator of chondrogenesis. Yet, how EXT1 and HS affect Wnt/β-catenin signaling during chondrogenesis remains unexplored. Ext1 was stably knocked-down or overexpressed in ATDC5 chondrogenic cells cultured as micromasses. HS content was determined using ELISA. Chondrogenic markers Sox9, Col2a1, Aggrecan, and Wnt direct target gene Axin2 were measured by RT-qPCR. Proteoglycan content was evaluated by Alcian blue and DMMB assay, canonical Wnt signaling activation by β-catenin Western blot and TOP/FOP assay. ATDC5 cells and human articular chondrocytes were treated with Wnt activators CHIR99021 and recombinant WNT3A. Ext1 knock-down reduced HS, and increased chondrogenic markers and proteoglycan accumulation. Ext1 knock-down reduced active Wnt/β-catenin signaling. Conversely, Ext1 overexpressing cells, with higher HS content, showed decreased chondrogenic differentiation and enhanced Wnt/β-catenin signaling. Wnt/β-catenin signaling activation led to a down-regulation of Ext1 expression in ATDC5 cells and in human articular chondrocytes. EXT1 affects chondrogenic differentiation of precursor cells, in part via changes in the activity of Wnt/β-catenin signaling. Wnt/β-catenin signaling controls Ext1 expression, suggesting a regulatory loop between EXT1 and Wnt/β-catenin signaling during chondrogenesis. Show less
Osteochondroma is a benign autosomal dominant hereditary disease characterized by abnormal proliferation of cartilage in the long bone. It is divided into solitary osteochondroma and hereditary multip Show more
Osteochondroma is a benign autosomal dominant hereditary disease characterized by abnormal proliferation of cartilage in the long bone. It is divided into solitary osteochondroma and hereditary multiple exostoses (HMEs). The exostosin-1 (EXT-1) and exostosin-2 (EXT-2) gene mutations are well-defined molecular mechanisms in the pathogenesis of HME. EXT-1 and EXT-2 encode glycosyltransferases that are necessary for the synthesis of heparin sulfate. Accumulating evidence suggests that mutations in the EXT family induce changes in isolated hypogonadotropic hypogonadism-parathyroid hormone-related protein, bone morphogenetic protein, and fibroblast growth factor signaling pathways. Studies have also found that a large number of microRNAs (miRNAs) are abnormally expressed in osteochondroma tissues, and some of them also participate in several major signaling pathways. The regulation of miRNA expression could be another breakthrough in the treatment of osteochondroma. Although the pathogenesis of osteochondroma is very complicated, significant progress has been made in recent years. It is hoped that the pathogenesis of osteochondroma will be clearly understood and the most effective methods for the prevention and treatment of osteochondroma will be determined. This review provides an update on the recent progress in the interpretation of the underlying molecular mechanisms of osteochondroma. Show less
Although the prognosis of patients with occult hepatitis B virus (HBV) infection (OBI) is usually benign, a small portion may undergo cirrhosis and subsequently hepatocellular carcinoma (HCC). We stud Show more
Although the prognosis of patients with occult hepatitis B virus (HBV) infection (OBI) is usually benign, a small portion may undergo cirrhosis and subsequently hepatocellular carcinoma (HCC). We studied the mechanism of life-long Integration of virus DNA into OBI host's genome, of which may induce hepatocyte transformation. We applied HBV capture sequencing on single cells from an OBI patient who, developed multiple HCC tumors and underwent liver resection in May 2013 at Tongji Hospital in China. Despite with the undetectable virus DNA in serum, we determined the pattern of viral integration in tumor cells and adjacent non-tumor cells and obtained the details of the viral arrangement in host genome, and furthermore the HBV integrated region in cancer genome. HBV captured sequencing of tissues and individual cells revealed that samples from multiple tumors shared two viral integration sites that could affect three host genes, including CSMD2 on chr1 and MED30/EXT1 on chr8. Whole genome sequencing further indicated one hybrid chromosome formed by HBV integrations between chr1 and chr8 that was shared by multiple tumors. Additional 50 poorly differentiated liver tumors and the paired adjacent non-tumors were evaluated and functional studies suggested up-regulated EXT1 expression promoted HCC growth. We further observed that the most somatic mutations within the tumor cell genome were common among the multiple tumors, suggesting that HBV associated, multifocal HCC is monoclonal in origin. Through analyzing the HBV integration sites in multifocal HCC, our data suggested that the tumor cells were monoclonal in origin and formed in the absence of active viral replication, whereas the affected host genes may subsequently contribute to carcinogenesis. Show less
Fatness traits are important in pigs because of their implications for fattening efficiency, meat quality, reproductive performance and immunity. Songliao black pigs and Landrace pigs show important d Show more
Fatness traits are important in pigs because of their implications for fattening efficiency, meat quality, reproductive performance and immunity. Songliao black pigs and Landrace pigs show important differences in production and meat quality traits, including fatness and muscle growth. Therefore, we used a high-throughput massively parallel RNA-seq approach to identify genes differentially expressed in backfat tissue between these two breeds (six pigs in each). An average of 37.87 million reads were obtained from the 12 samples. After statistical analysis of gene expression data by edgeR, a total of 877 differentially expressed genes were detected between the two pig breeds, 205 with higher expression and 672 with lower expression in Songliao pigs. Candidate genes (LCN2, CES3, DGKB, OLR1, LEP, PGM1, PCK1, ACACB, FADS1, FADS2, MOGAT2, SREBF1, PPARGC1B) with known effects on fatness traits were included among the DEGs. A total of 1071 lncRNAs were identified, and 85 of these lncRNAs were differentially expressed, including 53 up-regulated and 32 down-regulated lncRNAs, respectively. The differentially expressed genes and lncRNAs involved in glucagon signaling pathway, glycolysis/gluconeogenesis, insulin signaling pathway, MAPK signaling pathway and so on. Integrated analysis potential trans-regulating or cis-regulating relation between DEGs and DE lncRNAs, suggested lncRNA MSTRG.2479.1 might regulate the expressed level of VLDLR affecting porcine fat metabolism. These results provide a number of candidate genes and lncRNAs potentially involved in porcine fat deposition and provide a basis for future research on the molecular mechanisms underlying in fat deposition. Show less
To unravel the genetic mechanisms of disease and physiological traits, it requires comprehensive sequencing analysis of large sample size in Chinese populations. Here, we report the primary results of Show more
To unravel the genetic mechanisms of disease and physiological traits, it requires comprehensive sequencing analysis of large sample size in Chinese populations. Here, we report the primary results of the Chinese Academy of Sciences Precision Medicine Initiative (CASPMI) project launched by the Chinese Academy of Sciences, including the de novo assembly of a northern Han reference genome (NH1.0) and whole genome analyses of 597 healthy people coming from most areas in China. Given the two existing reference genomes for Han Chinese (YH and HX1) were both from the south, we constructed NH1.0, a new reference genome from a northern individual, by combining the sequencing strategies of PacBio, 10× Genomics, and Bionano mapping. Using this integrated approach, we obtained an N50 scaffold size of 46.63 Mb for the NH1.0 genome and performed a comparative genome analysis of NH1.0 with YH and HX1. In order to generate a genomic variation map of Chinese populations, we performed the whole-genome sequencing of 597 participants and identified 24.85 million (M) single nucleotide variants (SNVs), 3.85 M small indels, and 106,382 structural variations. In the association analysis with collected phenotypes, we found that the T allele of rs1549293 in KAT8 significantly correlated with the waist circumference in northern Han males. Moreover, significant genetic diversity in MTHFR, TCN2, FADS1, and FADS2, which associate with circulating folate, vitamin B12, or lipid metabolism, was observed between northerners and southerners. Especially, for the homocysteine-increasing allele of rs1801133 (MTHFR 677T), we hypothesize that there exists a "comfort" zone for a high frequency of 677T between latitudes of 35-45 degree North. Taken together, our results provide a high-quality northern Han reference genome and novel population-specific data sets of genetic variants for use in the personalized and precision medicine. Show less
Intervertebral disc degeneration (IVDD)-related disorders are the major causes of low back pain. A previous study suggested that Notch activation serves as a protective mechanism and is a part of the Show more
Intervertebral disc degeneration (IVDD)-related disorders are the major causes of low back pain. A previous study suggested that Notch activation serves as a protective mechanism and is a part of the compensatory response that maintains the necessary resident nucleus pulposus (NP) cell proliferation to replace lost or non-functional cells. However, the exact mechanism remains to be determined. In this study, we aimed to investigate the role of JAG2/Notch2 in NP cell proliferation and apoptosis. Recombinant JAG2 or Notch2, Hes1, and Hey2 siRNAs were used to activate or inhibit Notch signaling. Cell proliferation, apoptosis, cell cycle regulatory factors, and pathways associated with Notch-mediated proliferation were examined. In vivo experiments involving an intradiscal injection of Sprague-Dawley rats were performed. Recombinant JAG2 induced Notch2 and Hes1/Hey2 expression together with NP cell proliferation. Downregulation of Notch2/Hes1/Hey2 induced G0/G1 phase cell cycle arrest in NP cells. Moreover, Notch2 mediated NP cell proliferation by regulating cyclin D1 and by activating PI3K/Akt and Wnt/β-catenin signaling. Furthermore, Notch signaling inhibited TNF-α-promoted NP cell apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Finally, we found that intradiscal injection of JAG2 alleviated IVDD and that sh-Notch2 aggravated IVDD in a rat model. These results indicated that JAG2/Notch2 inhibited IVDD by modulating cell proliferation, apoptosis, and extracellular matrix. The JAG2/Notch2 axis regulated NP cell proliferation via PI3K/Akt and Wnt/β-catenin signaling and inhibited TNF-α-induced apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. The current and previous results shed light on the therapeutic implications of targeting the JAG2/Notch2 axis to inhibit or reverse IVDD. Show less
The HEY2 (hairy and enhancer of split-related with YRPW motif 2) is reported to play potential roles in tumorigenesis. However, the underlying mechanism in tumorigenesis is remain elusive. The present Show more
The HEY2 (hairy and enhancer of split-related with YRPW motif 2) is reported to play potential roles in tumorigenesis. However, the underlying mechanism in tumorigenesis is remain elusive. The present study aims to investigate the molecular mechanism of biological function of HEY2 in hepatocellular carcinoma (HCC). Dysfunction of the transforming growth factor-beta (TGF-β) pathway plays a critical role in HCC pathogenesis. Here, we identified HEY2 as a suppressor for TGF-β biological response. We demonstrated that HEY2 protein in tumor cytoplasm was up-regulated in HCC. Further, HEY2 overexpression inhibited TGF-β-induced growth arrest of HCC cells and inhibited TGF-β-induced downregulation of c-Myc, both in mRNA and in protein levels. While knockdown of HEY2, by small interfering RNA, was shown to enhance the TGF-β-mediated biological response of HCC cells. Moreover, HEY2 could form complexes with Smad3 and Smad4 and repress Smad3/Smad4 transcriptional activity. In conclusion, our findings indicate a novel role of HEY2 in mediating the TGF-β/Smad signaling pathway in HCC tumorigenesis. Show less
Enhancing differentiation of mesenchymal stem cells (MSCs) to endothelial cells may improve their ability to vascularize tissue and promote wound healing. This study describes a novel role for nitric Show more
Enhancing differentiation of mesenchymal stem cells (MSCs) to endothelial cells may improve their ability to vascularize tissue and promote wound healing. This study describes a novel role for nitric oxide (NO) in reprogramming MSCs towards an endothelial lineage and highlights the role of Wnt signaling and epigenetic modification by NO. Rat MSCs were transduced with lentiviral vectors expressing endothelial nitric oxide synthase (pLV-eNOS) and a mutated caveolin gene (pLV-CAV-1 Show less
Damage or loss of auditory hair cells leads to irreversible sensorineural hearing loss in human, thus regeneration of these cells to reconstruct auditory sensory epithelium holds the promise for the t Show more
Damage or loss of auditory hair cells leads to irreversible sensorineural hearing loss in human, thus regeneration of these cells to reconstruct auditory sensory epithelium holds the promise for the treatment of deafness. Regulatory factors involved in the development of auditory sensory epithelium play crucial roles in hair cell regeneration and hearing restoration. Here, we first focus on the transcription factor Atoh1 which is critical for hair cell development and regeneration, and comprehensively summarize the current understanding of the protein structure, target binding motif, developmental expression pattern, functional role, and upstream and downstream regulatory mechanism of Atoh1 in the context of controlling the cell fate commitment to hair cells or transdifferentiation from supporting cells. We also discuss cellular context dependency of Atoh1 in hair cell induction which should be taken into consideration when using Atoh1 gene therapy for hair cell regeneration. Next, we review the roles of Gfi1, Pou4f3, and Barhl1 in hair cell maturation and maintenance, and suggest that manipulation of these genes and their downstream targets will be helpful for the generation of functional hair cells with long-term viability. Finally, we provide an overview of the interplay between Notch, Wnt, Shh, and FGF signaling pathways during auditory sensory epithelium development. By analyzing crosstalk between these pathways, we suggest that combination of Wnt signaling activation with Hey1 and Hey2 inhibition will be crucial for hair cell regeneration and hearing restoration. Furthermore, this review highlights the importance of deeper understanding of the cellular context for hair cell development and the interconnection between these key regulators in developing new strategies to treat sensorineural hearing loss. Show less
JMJD1C, a member of the lysine demethylase 3 family, is aberrantly expressed in mixed lineage leukemia (MLL) gene-rearranged (MLLr) leukemias. We have shown previously that JMJD1C is required for self Show more
JMJD1C, a member of the lysine demethylase 3 family, is aberrantly expressed in mixed lineage leukemia (MLL) gene-rearranged (MLLr) leukemias. We have shown previously that JMJD1C is required for self-renewal of acute myeloid leukemia (AML) leukemia stem cells (LSCs) but not normal hematopoietic stem cells. However, the domains within JMJD1C that promote LSC self-renewal are unknown. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease (Cas9) negative-selection screening and identified a requirement for the catalytic Jumonji (JmjC) domain and zinc finger domain for leukemia cell survival in vitro and in vivo. In addition, we found that histone H3 lysine 36 methylation (H3K36me) is a marker for JMJD1C activity at gene loci. Moreover, we performed single cell transcriptome analysis of mouse leukemia cells harboring a single guide RNA (sgRNA) against the JmjC domain and identified increased activation of RAS/MAPK and the JAK-STAT pathway in cells harboring the JmjC sgRNA. We discovered that upregulation of interleukin 3 (IL-3) receptor genes mediates increased activation of IL-3 signaling upon JMJD1C loss or mutation. Along these lines, we observed resistance to JMJD1C loss in MLLr AML bearing activating RAS mutations, suggesting that RAS pathway activation confers resistance to JMJD1C loss. Overall, we discovered the functional importance of the JMJD1C JmjC domain in AML leukemogenesis and a novel interplay between JMJD1C and the IL-3 signaling pathway as a potential resistance mechanism to targeting JMJD1C catalytic activity. Show less
Abnormal metabolism is a fundamental hallmark of cancer and represents a therapeutic opportunity, yet its regulation by oncogenes remains poorly understood. Here, we uncover that JMJD1C, a jumonji C ( Show more
Abnormal metabolism is a fundamental hallmark of cancer and represents a therapeutic opportunity, yet its regulation by oncogenes remains poorly understood. Here, we uncover that JMJD1C, a jumonji C (JmjC)-containing H3K9 demethylase, is a critical regulator of aberrant metabolic processes in homeobox A9 (HOXA9)-dependent acute myeloid leukemia (AML). JMJD1C overexpression increases in vivo cell proliferation and tumorigenicity through demethylase-independent upregulation of a glycolytic and oxidative program, which sustains leukemic cell bioenergetics and contributes to an aggressive AML phenotype in vivo. Targeting JMJD1C-mediated metabolism via pharmacologic inhibition of glycolysis and oxidative phosphorylation led to ATP depletion, induced necrosis/apoptosis and decreased tumor growth in vivo in leukemias co-expressing JMJD1C and HOXA9. The anti-metabolic therapy effectively diminished AML stem/progenitor cells and reduced tumor burden in a primary AML patient-derived xenograft. Our data establish a direct link between drug responses and endogenous expression of JMJD1C and HOXA9 in human AML cell line- and patient-derived xenografts. These findings demonstrate a previously unappreciated role for JMJD1C in counteracting adverse metabolic changes and retaining the metabolic integrity during tumorigenesis, which can be exploited therapeutically. Show less
Jinpeng Liu, Thilakam Murali, Tianxin Yu+19 more · 2019 · Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · added 2026-04-24
Lung cancer is the leading cause of cancer mortality in the United States (U.S.). Squamous cell carcinoma (SQCC) represents 22.6% of all lung cancers nationally, and 26.4% in Appalachian Kentucky (App Show more
Lung cancer is the leading cause of cancer mortality in the United States (U.S.). Squamous cell carcinoma (SQCC) represents 22.6% of all lung cancers nationally, and 26.4% in Appalachian Kentucky (AppKY), where death from lung cancer is exceptionally high. The Cancer Genome Atlas (TCGA) characterized genetic alterations in lung SQCC, but this cohort did not focus on AppKY residents. Whole-exome sequencing was performed on tumor and normal DNA samples from 51 lung SQCC subjects from AppKY. Somatic genomic alterations were compared between the AppKY and TCGA SQCC cohorts. From this AppKY cohort, we identified an average of 237 nonsilent mutations per patient and, in comparison with TCGA, we found that This study has identified an increased percentage of Our study is the first report to characterize genomic alterations in lung SQCC from AppKY. These findings suggest population differences in the genetics of lung SQCC between AppKY and U.S. populations, highlighting the importance of the relevant population when developing personalized treatment approaches for this disease. Show less
Depression is the most common comorbidity among patients with epilepsy. Despite prior assumptions that antiepileptic drugs are to blame, more and more pathological studies have shown that latent neuro Show more
Depression is the most common comorbidity among patients with epilepsy. Despite prior assumptions that antiepileptic drugs are to blame, more and more pathological studies have shown that latent neurological alterations associated with white matter injury and demyelination may underlie this link. However, whether disturbances in cerebral myelination contribute to the initiation of depression in epilepsy remains unclear. In the present study, we investigated the connection between demyelination disorders and the development of depression comorbidity in epilepsy. We first induced spontaneous recurrent epilepticus seizure (SRS) in young rats with pilocarpine. We then established depressive behaviors by recurrent forced swimming test and evaluate the depression state by sucrose preference test. The ratio of depression comorbidity in SRS rats was then calculated. Next, myelination in SRS-Depressed (SRS-D) rats was explored via PCR, western blotting, and immunohistochemistry for the key myelin promotion factor, Olig2 and inhibition factor, LINGO-1. Finally, in situ RNA hybridization of NCX3, one of the dominant Ca Show less
Suture and autologous nerve transplantation are the primary therapeutic measures for completely severed nerves. However, imbalances in the microenvironment and adhesion of surrounding tissues can affe Show more
Suture and autologous nerve transplantation are the primary therapeutic measures for completely severed nerves. However, imbalances in the microenvironment and adhesion of surrounding tissues can affect the quality of nerve regeneration and repair. Previous studies have shown that human amniotic membrane can promote the healing of a variety of tissues. In this study, the right common peroneal nerve underwent a 5-mm transection in rats. Epineural nerve repair was performed using 10/0 non-absorbable surgical suture. The repair site was wrapped with a two-layer amniotic membrane with α-cyanoacrylate rapid medical adhesive after suture. Hindlimb motor function was assessed using footprint analysis. Conduction velocity of the common peroneal nerve was calculated by neural electrical stimulation. The retrograde axoplasmic transport of the common peroneal nerve was observed using fast blue BB salt retrograde fluorescent staining. Hematoxylin-eosin staining was used to detect the pathological changes of the common peroneal nerve sputum. The mRNA expression of axon regeneration-related neurotrophic factors and inhibitors was measured using real-time polymerase chain reaction. The results showed that the amniotic membrane significantly improved the function of the injured nerve; the toe spread function rapidly recovered, the nerve conduction velocity was restored, and the number of fast blue BB salt particles were increased in the spinal cord. The amniotic membrane also increased the recovery rate of the tibialis anterior muscle and improved the tissue structure of the muscle. Meanwhile, mRNA expression of nerve growth factor, growth associated protein-43, collapsin response mediator protein-2, and brain-derived neurotrophic factor recovered to near-normal levels, while Lingo-1 mRNA expression decreased significantly in spinal cord tissues. mRNA expression of glial-derived neurotrophic factor did not change significantly. Changes in mRNA levels were more significant in amniotic-membrane-wrapping-treated rats compared with model and nerve sutured rats. These results demonstrate that fresh amniotic membrane wrapping can promote the functional recovery of sutured common peroneal nerve via regulation of expression levels of neurotrophic factors and inhibitors associated with axonal regeneration. The study was approved by the Committee on Animal Research and Ethics at the Affiliate Hospital of Zunyi Medical University, China (approval No. 112) on December 1, 2017. Show less
Spinal root avulsion typically leads to massive motoneuron death and severe functional deficits of the target muscles. Multiple pathological factors such as severe neuron loss, induction of inhibitory Show more
Spinal root avulsion typically leads to massive motoneuron death and severe functional deficits of the target muscles. Multiple pathological factors such as severe neuron loss, induction of inhibitory molecules, and insufficient regeneration are responsible for the poor functional recovery. Leucine-rich repeat and immunoglobulin-like domain-containing Nogo receptor-interacting protein 1 (LINGO-1), a central nervous system (CNS)-specific transmembrane protein that is selectively expressed on neurons and oligodendrocytes, serves as a potent negative mediator of axonal regeneration and myelination in CNS injuries and diseases. Although accumulating evidence has demonstrated improvement in axonal regeneration and neurological functions by LINGO-1 antagonism in CNS damage, the possible effects of LINGO-1 in spinal root avulsion remain undiscovered. In this study, a LINGO-1 knockdown strategy using lentiviral vectors encoding LINGO-1 short hairpin interfering RNA (shRNA) delivered by the Pluronic F-127 (PF-127) hydrogel was described after brachial plexus avulsion (BPA). We provide evidence that following BPA and immediate reimplantation, transplantation of LINGO-1 shRNA lentiviral vectors encapsulated by PF-127 rescued the injured motoneurons, enhanced axonal outgrowth and myelination, rebuilt motor endplates, facilitated the reinnervation of terminal muscles, improved angiogenesis, and promoted recovery of avulsed forelimbs. Altogether, these data suggest that delivery of LINGO-1 shRNA by a gel scaffold is a potential therapeutic approach for root avulsion. Impact Statement In this study, we attempted transplantation of lentivirus (LV)/leucine-rich repeat and immunoglobulin-like domain-containing Nogo receptor-interacting protein 1 (LINGO-1)-short hairpin interfering RNA (shRNA) encapsulated by the Pluronic F-127 (PF-127) hydrogel into a brachial plexus avulsion (BPA)-reimplantation model. We found that administration of LV/LINGO-1 shRNA facilitates neuron survival and axonal regeneration, attenuates muscle atrophy and motor endplate (MEP) loss, enhances neovascularization, and promotes functional recovery in BPA rats. Co-transplantation of LV/LINGO-1 shRNA and gel reinforces the survival-promoting effect, axonal outgrowth, and angiogenesis in comparison with LV/LINGO-1 shRNA application alone. Our research provides evidence that LV /LINGO-1 shRNA delivered by PF-127 represents a new treatment strategy for BPA repair. Show less
Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a rare and severe disorder characterized by functional obstruction in the urinary and gastrointestinal tract. The molecular basis o Show more
Megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) is a rare and severe disorder characterized by functional obstruction in the urinary and gastrointestinal tract. The molecular basis of this condition has been defined recently. Heterozygous variants in ACTG2, homozygous mutations in LMOD1, MYLK, and MYH9 were related to the pathogenesis of the syndrome, which encodes proteins involved in the process of smooth muscle contraction, supporting a myopathic basis for the disease. Recent studies have identified homozygous or compound heterozygous variants in MYH11 as a candidate gene of MMIHS. In this report, we described a nonconsanguineous Chinese family with three male fetuses affected with megacystis. Trio-targeted exome sequencing identified compound heterozygous variants, c.2051 G > A (p.R684H) and c.3540₃₅₄₁delinsTT (p.(E1180D, Q1181Ter)), in MYH11 (NM₀₀₁₀₄₀₁₁₄₎. The variants were inherited from the parents, respectively. Western blotting showed a marked decrease in MYH11 protein in the proband's umbilical cord tissue compared with the control sample. The study's results confirmed that MYH11 is a candidate gene for MMIHS with autosomal recessive (AR) inheritance and expanded the mutation spectrum for this clinical condition. Combining clinical phenotype with molecular diagnosis may enable the identification of candidate genes for potential monogenic diseases and facilitate accurate genetic counseling, informed decision-making, and prenatal diagnosis. Show less
Intracranial aneurysm (IA) represents a cerebrovascular disorder that featured by dilation or bulging of the weakened blood vessel wall. When it ruptures, an IA leads to subarachnoid hemorrhage with h Show more
Intracranial aneurysm (IA) represents a cerebrovascular disorder that featured by dilation or bulging of the weakened blood vessel wall. When it ruptures, an IA leads to subarachnoid hemorrhage with high disability and mortality rates. Despite the numerous studies focusing on IA ruptures, little research on IA pathogenesis has been reported. In this study, we aimed to reveal key genes related to IA formation. Four datasets from Gene Expression Omnibus data were downloaded, normalized, and separated into the IA group and the normal vessel control group for analyses. We screened for differentially expressed genes (DEGs) between groups and conducted functional enrichment, pathway enrichment, and gene set enrichment analysis analyses among significant DEGs. according to our analyses, significant DEGs majorly associate with smooth muscle system and the complement system. Among all DEGs, 5 down-regulated genes (MYH11, CNN1, MYOCD, ACTA1, and LMOD1) and 3 up-regulated genes (C1QB, C3AR1, and VSIG4) are most relevant in IA formation. Key DEGs identified in this study are related to IA pathogenesis. Among identified DEGs, LMOD1 is the most significant and merits more attention. Show less