Long non-coding RNAs (lncRNAs) have emerged as critical regulators of genes at epigenetic, transcriptional and post-transcriptional levels, yet what genes are regulated by a specific lncRNA remains to be characterized. To assess the effects of the lncRNA on gene expression, an increasing number of researchers profiled the genome-wide or individual gene expression level change after knocking down or overexpressing the lncRNA. Herein, we describe a curated database named LncRNA2Target, which stores lncRNA-to-target genes and is publicly accessible at http://www.lncrna2target.org. A gene was considered as a target of a lncRNA if it is differentially expressed after the lncRNA knockdown or overexpression. LncRNA2Target provides a web interface through which its users can search for the targets of a particular lncRNA or for the lncRNAs that target a particular gene. Both search types are performed either by browsing a provided catalog of lncRNA names or by inserting lncRNA/target gene IDs/names in a search box.
Fas signaling promotes metastasis of gastrointestinal (GI) cancer cells by inducing epithelial-mesenchymal transition (EMT), and EMT acquisition has been found to cause cancer chemoresistance. Here, we demonstrated that the response to chemotherapy of GI cancer patients with higher expression of FasL was significantly worse than patients with lower expression. Fas-induced activation of the ERK1/2-MAPK pathway decreased the sensitivity of GI cancer cells to chemotherapeutic agents and promoted the expression of P-glycoprotein (P-gp). FasL promoted chemoresistance of GI cancer cell via upregulation of P-gp by increasing ?-catenin and decreasing miR-145. ?-catenin promoted P-gp gene transcription by binding with P-gp promoter while miR-145 suppressed P-gp expression by interacting with the mRNA 3'UTR of P-gp. Immunostaining and qRT-PCR analysis of human GI cancer samples revealed a positive association among FasL, ?-catenin, and P-gp, but a negative correlation between miR-145 and FasL or P-gp. Altogether, our results showed Fas signaling could promote chemoresistance in GI cancer through modulation of P-gp expression by ?-catenin and miR-145. Our findings suggest that Fas signaling-based cancer therapies should be administered cautiously, as activation of this pathway may not only lead to apoptosis but also induce chemoresistance.
Previous studies have shown that the Hippo pathway effector yes-associated protein (YAP) plays an important role in maintaining stem cell proliferation. However, the precise molecular mechanism of YAP in regulating murine embryonic neural stem cells (NSCs) remains largely unknown. Here, we show that bone morphogenetic protein-2 (BMP2) treatment inhibited the proliferation of mouse embryonic NSCs, that YAP was critical for mouse NSC proliferation, and that BMP2 treatment-induced inhibition of mouse NSC proliferation was abrogated by YAP knockdown, indicating that the YAP protein mediates the inhibitory effect of BMP2 signaling. Additionally, we found that BMP2 treatment reduced YAP nuclear translocation, YAP-TEAD interaction, and YAP-mediated transactivation. BMP2 treatment inhibited YAP/TEAD-mediated Cyclin D1 (ccnd1) expression, and knockdown of ccnd1 abrogated the BMP2-mediated inhibition of mouse NSC proliferation. Mechanistically, we found that Smad1/4, effectors of BMP2 signaling, competed with YAP for the interaction with TAED1 and inhibited YAP's cotranscriptional activity. Our data reveal mechanistic cross talk between BMP2 signaling and the Hippo-YAP pathway in murine NSC proliferation, which may be exploited as a therapeutic target in neurodegenerative diseases and aging.
Sufficient vascularization is critical to sustaining viable tissue-engineered (TE) constructs after implantation. Despite significant progress, current approaches lack suturability, porosity, and biodegradability, which hinders rapid perfusion and remodeling in vivo. Consequently, TE vascular networks capable of direct anastomosis to host vasculature and immediate perfusion upon implantation still remain elusive. Here, a hybrid fabrication method is presented for micropatterning fibrous scaffolds that are suturable, porous, and biodegradable. Fused deposition modeling offers an inexpensive and automated approach to creating sacrificial templates with vascular-like branching. By electrospinning around these poly(vinyl alcohol) templates and dissolving them in water, microvascular patterns were transferred to fibrous scaffolds. Results indicated that these scaffolds have sufficient suture retention strength to permit direct anastomosis in future studies. Vascularization of these scaffolds is demonstrated by in vitro endothelialization and perfusion.
Coacervates represent an exciting new class of drug delivery vehicles, developed in the past decade as carriers of small molecule drugs and proteins. This review summarizes several well-described coacervate systems, including: i) elastin-like peptides for delivery of anticancer therapeutics; ii) heparin-based coacervates with synthetic polycations for controlled growth factor delivery; iii) carboxymethyl chitosan aggregates for oral drug delivery; iv) Mussel adhesive protein and hyaluronic acid coacervates. Coacervates present advantages in their simple assembly and easy incorporation into tissue engineering scaffolds or as adjuncts to cell therapies. They are also amenable to functionalization such as for targeting or for enhancing the bioactivity of their cargo. These new drug carriers are anticipated to have broad applications and noteworthy impact in the near future.
Human globin gene expression during development is modulated by transcription factors in a stage-dependent manner. However, the mechanisms controlling the process are still largely unknown. In this study, we found that a nuclear protein, LYAR (human homologue of mouse Ly-1 antibody reactive clone) directly interacted with the methyltransferase PRMT5 which triggers the histone H4 Arg3 symmetric dimethylation (H4R3me2s) mark. We found that PRMT5 binding on the proximal ?-promoter was LYAR-dependent. The LYAR DNA-binding motif (GGTTAT) was identified by performing CASTing (cyclic amplification and selection of targets) experiments. Results of EMSA and ChIP assays confirmed that LYAR bound to a DNA region corresponding to the 5'-untranslated region of the ?-globin gene. We also found that LYAR repressed human fetal globin gene expression in both K562 cells and primary human adult erythroid progenitor cells. Thus, these data indicate that LYAR acts as a novel transcription factor that binds the ?-globin gene, and is essential for silencing the ?-globin gene.
Recently identified molecular tumor markers have numerous potential applications in the diagnosis, therapy and prognostic prediction of renal cell carcinoma (RCC). Through bioinformatics?based screening approaches together with validation of western blot and immunohistochemical data, the present study identified a novel renal cancer?associated gene, preliminarily named Renal Cancer Differentiation Gene 1 (RCDG1), originally known as chromosome 4 open reading frame 46 (C4orf46). RCDG1 expression was evaluated by western blot analysis of RCC and adjacent normal tissues, renal cancer cell lines and normal kidney HEK293T cells. Additionally, RCDG1 expression was assessed in 124 RCC paraffin sections, including 92 paired adjacent normal tissues, by immunohistochemistry. The results showed that RCDG1 was significantly downregulated in RCC tissues as compared with normal adjacent tissues (P<0.001), and the expression of RCDG1 in clear cell (cc) RCC tissues was significantly lower as compared with that of non?ccRCC tissues (P=0.005). Furthermore, statistical analysis revealed RCDG1 expression was negatively correlated with the Fuhrman grade in ccRCC (P=0.008). A reduction in RCDG1 expression may be associated with the oncogenesis of RCC and the differentiation of ccRCC. Further studies may provide more information about the function of RCDG1 gene in RCC.
A photoassisted oxygen reduction reaction (ORR) through I(-)/I3(-) redox couple was investigated for proton exchange membrane (PEM) fuel cell cathode reaction. The I(-)/I3(-)-based liquid cathode was used to replace conventional oxygen cathode, and its discharge product I(-) was regenerated to I3(-) by photocatalytic oxidation with the participation of oxygen. This new and innovative approach may provide a strategy to eliminate the usage of challenging ORR electrocatalysts, resulting in an avenue for developing low-cost and high-efficiency PEM fuel cells.
Budd-Chiari syndrome (BCS) is a rare and life-threatening disorder secondary to hepatic venous outflow obstruction. How to manage this complex disease has haunted many surgeons. The aim of this study is to investigate the treatment of Budd-Chiari syndrome in our hospital.
Laparoscopic Roux-en-Y gastric bypass (LRYGB) is one of the most widely used bariatric procedures for the treatment of morbid obesity. Laparoscopic sleeve gastrectomy (LSG) is a relatively innovative procedure which has been increasingly accepted as a sole bariatric procedure in the Asian-Pacific region. This study aims to compare mid-term outcomes in morbid obesity patients undergoing LRYGB and LSG.
Little is known about the endoscopic manifestations of primary colorectal lymphoma. The study was designed to describe the features of colonoscopy and endoscopic ultrasonography of primary colorectal lymphoma.
Lipase-catalyzed hydrolysis of linseed oil was investigated. Four commercially available microbial lipases of Lipase AY, Lipozyme RMIM, Lipozyme TLIM, and Novozym 435 were used. Among these tested lipases, Lipase AY exhibited the best hydrolysis effeciency to linseed oil. The effect of reaction variables was also evaluated and optimized using response surface methodology. A second-order regression for the Box-Behken design was used to study the effect of five independent variables, such as, temperature, pH, oil-aqueous phase ratio, enzyme load, and reaction time, on the hydrolysis of linseed oil. The optimal conditions were as follows: temperature 33°C, pH 5.80, oil-aqueous phase ratio 0.90 (w/w), enzyme load 1.20% (relative to the weight of total substrates), and reaction time 3.33 h. Under these conditions, the hydrolysis ratio of linseed oil was 93.92±0.54%.
Benzo(a)pyrene (BaP) is one of the strongest carcinogens in cigarette smoke, which is an established human carcinogen. Twist, a transcription factor of the basic helix-loop-helix class, is reported to regulate lung cancer metastasis. Evidence has shown that BaP could induce Twist mRNA expression in non-small cell lung cancer (NSCLC) cell line A549 and promote lung adenocarcinoma cell invasion. However, it is unclear whether BaP promotes the migration and invasion of NSCLC cells by Twist modulation. A549 cell was exposed to BaP for different time. MTT assay was applied to assess cell proliferation. Silencing of Twist was done by small interfering RNA. Wound-healing assay was used to evaluate the capability of cell migration. Transwell assay was used to detect the capability of cell invasion. Western blotting and quantitative polymerase chain reaction were used to detect Twist expression. The levels of Twist protein expression and mRNA expression were increased with the treatment of BaP, compared with solvent control. The capability of wound healing of A549 cells was increased in BaP-treated group, compared with solvent control. BaP enhanced the capability of invasion of A549 cells. Twist knockdown could block the migration and invasion of A549 cells induced by BaP treatment. The mRNA levels of Twist were higher in metastatic NSCLC tissue samples than in primary NSCLC tissue samples, and higher levels of Twist mRNA were observed in metastatic NSCLC tissue samples with smoking history than in those with nonsmoking history. BaP treatment could promote the migration and invasion of NSCLC cells by up-regulating Twist expression.
Advances in high-throughput sequencing technologies have brought us into the individual genome era. Projects such as the 1000 Genomes Project have led the individual genome sequencing to become more and more popular. How to visualize, analyse and annotate individual genomes with knowledge bases to support genome studies and personalized healthcare is still a big challenge. The Personal Genome Browser (PGB) is developed to provide comprehensive functional annotation and visualization for individual genomes based on the genetic-molecular-phenotypic model. Investigators can easily view individual genetic variants, such as single nucleotide variants (SNVs), INDELs and structural variations (SVs), as well as genomic features and phenotypes associated to the individual genetic variants. The PGB especially highlights potential functional variants using the PGB built-in method or SIFT/PolyPhen2 scores. Moreover, the functional risks of genes could be evaluated by scanning individual genetic variants on the whole genome, a chromosome, or a cytoband based on functional implications of the variants. Investigators can then navigate to high risk genes on the scanned individual genome. The PGB accepts Variant Call Format (VCF) and Genetic Variation Format (GVF) files as the input. The functional annotation of input individual genome variants can be visualized in real time by well-defined symbols and shapes. The PGB is available at http://www.pgbrowser.org/.
The efficacy of protein-based therapies for treating injured nervous tissue is limited by the short half-life of free proteins in the body. Affinity-based biomaterial delivery systems provide sustained release of proteins, thereby extending the efficacy of such therapies. Here, we investigated the biocompatibility of a novel coacervate delivery system based on poly(ethylene argininylaspartate diglyceride) (PEAD) and heparin in the damaged spinal cord. We found that the presence of the [PEAD:heparin] coacervate did not affect the macrophage response, glial scarring or nervous tissue loss, which are hallmarks of spinal cord injury. Moreover, the density of axons, including serotonergic axons, at the injury site and the recovery of motor and sensorimotor function were comparable in rats with and without the coacervate. These results revealed the biocompatibility of our delivery system and supported its potential to deliver therapeutic proteins to the injured nervous system.
Zinc finger protein 703 (ZNF703), identified as an oncogene in luminal B breast cancer, is a member of the NET/NlZ family of zinc finger transcription factors. However, the role of ZNF703 in colorectal cancer (CRC) is unknown. We investigated the expression of ZNF703 in paired tumor and corresponding normal tissues using reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot analysis. Immunohistochemistry (IHC) was applied on paraffin-embedded specimens, including 138 CRC tissues, 58 matched normal tissues and 30 paired metastatic lymph node samples. Levels of mRNA (72.72%, 16/22) and ZNF703 protein expression (65.38%, 17/26, respectively) were upregulated in CRC tissues. IHC staining revealed higher expression of ZNF703 in the CRC tissues (68/138, 49.3%) compared with that in the adjacent normal mucosal tissues (4/58, 6.9%) (p<0.001). Moreover, high ZNF703 expression was significantly correlated with tumor size, pathological grading, serosal invasion, lymph node metastasis and AJCC stage. CRC patients with relatively low ZNF703 expression had higher survival rates than those with high ZNF703 expression. In addition, we investigated ZNF703 expression in eight CRC cell lines (LS174T, SW480, HT29, SW620, DLD1, SW1116, LoVo and CaCo-2) in vitro. The highest ZNF703 expression was detected in the LoVo cell line. RNA interference was used to assess the effects of ZNF703 knockdown in LoVo cells. Knockdown of ZNF703 expression inhibited CRC cell proliferation and migration. Collectively, these results reveal that ZNF703 may act as an oncogene in CRC and could be considered as a potential therapeutic target for metastatic CRC.
Whole-genome and -exome sequencing on parent-offspring trios is a powerful approach to identifying disease-associated genes by detecting de novo mutations in patients. Accurate detection of de novo mutations from sequencing data is a critical step in trio-based genetic studies. Existing bioinformatic approaches usually yield high error rates due to sequencing artifacts and alignment issues, which may either miss true de novo mutations or call too many false ones, making downstream validation and analysis difficult. In particular, current approaches have much worse specificity than sensitivity, and developing effective filters to discriminate genuine from spurious de novo mutations remains an unsolved challenge.
Androgen signaling plays a crucial role in spermatogenesis, yet few downstream targets for this signaling pathway have been identified. In the current study, we found that the expression of heat-shock transcription factor 1 (Hsf1) was increased in the testes of Sertoli cell-selective androgen receptor knockout (S-AR(-/y) ) mice compared with wild-type mice by quantitative real-time PCR, and the expression of HSF1 in the S-AR(-/y) Sertoli cells was significantly increased, based on immunofluorescence analysis. In vitro cell-culture studies showed that testosterone repressed the expression of Hsf1 in TM4 cells, a mouse Sertoli cell line. Moreover, a luciferase assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay showed that testosterone repressed Hsf1 expression by facilitating the binding of androgen receptor to the Hsf1 promoter. Our experiments also demonstrated that testosterone-mediated inhibition of Hsf1 transcription down-regulated the expression of heat-shock proteins HSP105 and HSP60. Taken together, these results reveal that Hsf1 is a novel target of androgen receptor in mouse Sertoli cells, and testosterone and its receptor regulate the process of spermatogenesis partially by inhibiting Hsf1 expression.
Copy number variation (CNV) has been found to play an important role in human disease. Next-generation sequencing technology, including whole-genome sequencing (WGS) and whole-exome sequencing (WES), has become a primary strategy for studying the genetic basis of human disease. Several CNV calling tools have recently been developed on the basis of WES data. However, the comparative performance of these tools using real data remains unclear. An objective evaluation study of these tools in practical research situations would be beneficial. Here, we evaluated four well-known WES-based CNV detection tools (XHMM, CoNIFER, ExomeDepth, and CONTRA) using real data generated in house. After evaluation using six metrics, we found that the sensitive and accurate detection of CNVs in WES data remains challenging despite the many algorithms available. Each algorithm has its own strengths and weaknesses. None of the exome-based CNV calling methods performed well in all situations; in particular, compared with CNVs identified from high coverage WGS data from the same samples, all tools suffered from limited power. Our evaluation provides a comprehensive and objective comparison of several well-known detection tools designed for WES data, which will assist researchers in choosing the most suitable tools for their research needs.
Adenosquamous carcinoma (ASC) and sarcomatoid carcinoma (SC) of the prostate are rare, but highly aggressive tumors. The occurrence of mixed carcinomas in the prostate is even more rarely reported. The present study reports the case of a 62-year-old male who was diagnosed with prostatic adenocarcinoma accompanied by multiple bone metastases, as shown by a needle biopsy and skeletal computed tomography scan. The patient was treated with hormonal therapy, but thereafter, specimens from a transurethral resection of the prostate (TURP) were found to be composed of three histologically distinct elements: ASC, SC and adenocarcinoma. The level of p53 was evaluated by immunohistochemistry in detail, and it was found that this was significantly increased in the TURP samples compared with the needle biopsy samples. The abnormal level of p53 was likely associated with the prognosis of the patient; the patient succumbed to prostate carcinoma two months after the confirmation of the diagnosis.
MicroRNAs (miRNAs) are an important class of small, non?coding RNA molecules that regulate gene expression at the transcriptional or post?transcriptional level. They are involved in apoptosis, proliferation and migration and are known to have an important role in many types of cancer. Aberrant expression of miRNA?451a (miR?451a) has previously been reported in tumors, however its role in renal cell carcinoma (RCC) is currently unknown. The aim of the present study was to investigate the role of miR?451a in RCC. The expression of miR?451a was analyzed in 50 paired RCC and normal tissues by quantitative polymerase chain reaction. Furthermore, the effects of miR?451a on cell migration, proliferation and apoptosis were evaluated, using migration scratch, MTT and flow cytometric assays. The present study demonstrated that miR?451a was upregulated in RCC, as compared with paired normal tissues (P<0.05). Downregulation of miR?451a using a synthesized inhibitor, significantly suppressed cell migration and proliferation, and induced apoptosis of renal cancer cells in vitro, as compared with a negative control (P<0.05). In the present study, it was determined that miR?451a may have an important role as a tumor enhancer in RCC. These results imply that miR?451a may be a promising therapeutic target for the treatment of RCC.
Wnt signaling plays an important role in colorectal cancer (CRC). Although the mechanisms of ?-catenin degradation have been well studied, the mechanism by which ?-catenin activates transcription is still not fully understood. While screening a panel of DNA demethylases, we found that thymine DNA glycosylase (TDG) up-regulated Wnt signaling. TDG interacts with the transcription factor TCF4 and coactivator CREB-binding protein/p300 in the Wnt pathway. Knocking down TDG by shRNAs inhibited the proliferation of CRC cells in vitro and in vivo. In CRC patients, TDG levels were significantly higher in tumor tissues than in the adjacent normal tissues. These results suggest that TDG warrants consideration as a potential biomarker for CRC and as a target for CRC treatment.
Si has been considered as a promising alternative anode for next-generation lithium ion batteries (LIBs), but the commercial application of Si anodes is still limited due to their poor cyclability. In this paper, we propose a new strategy to enhance the long-term cyclability of Si anode by embedding nano-Si particles into a Li(+)-conductive polymer to form a Si/polymer composite with core-shell structure, in which nano-Si cores act as active Li-storage phase and the polymeric matrix serves not only as a strong buffer to accommodate the volume change, but also as a protection barrier to prevent the direct contact of Si surface with electrolyte, so as to maintain the mechanical integrity of Si anode and suppress the repeated destruction and construction of solid electrolyte interphase (SEI) on the Si surface. To realize this strategy, we synthesize a Si/PPP (polyparaphenylene) composite simply by ball-milling the Si nanoparticles with PPP polymer that has n-doping activity. Our experimental results demonstrate that the thus-prepared Si/PPP composite exhibits a high capacity of 3184 mA h g(-1) with an initial coulombic efficiency of 78%, an excellent rate capability with a considerably high capacity of 1670 mA h g(-1) even at a very high rate of 16 A g(-1), and a long-term cyclability with 60% capacity retention over 400 cycles, showing a great prospect for battery application. In addition, this structural design could be adopted to other Li-storable metals or alloys for developing cycle-stable anode materials for Li-ion batteries.
Ti nanowire arrays (NAs) prepared by a facile and template-free hydrothermal method were used as three-dimensional (3D) current collectors for the electrodeposition of MnO2. The resulting Ti@MnO2 NAs exhibit remarkable electrochemical behavior with high specific capacitance, good rate performance and desired cycling stability.
For bone engineering, the optimal scaffolding material and composition has yet to be elucidated. In this study, we investigated poly (glycerol sebacate) (PGS), an elastomer known primarily for its soft tissue regeneration ability, as a suitable substrate to support osteo-precursor cell attachment and function. We synthesized PGS in the form of sheets where MC3T3-E1 cells were seeded in three different densities of 25,000, 50,000 and 100,000 cells mm(-3) and we investigated the cells/scaffold constructs for their cellular proliferation, matrix deposition, maturation, mineralization and their mechanical compression strength at 24 h and two and four weeks. MC3T3-E1 cells proliferated, synthesized a collagenous matrix and expressed osteogenic markers Runx2, bone sialoprotein and osteocalcin according to their initial seeding density on PGS. We conclude that PGS can support the osteoblastic phenotype in vitro and is a promising osteoconductive substrate for bone regeneration research and for future clinical translation.
Bizarre leiomyomas of the scrotum are rare benign tumors that are often misdiagnosed. In this study, we present a case of bizarre leiomyoma of the scrotum in a 53-year-old male. The patient presented with a painless scrotal mass that was insidious in the right side of the scrotum with no sudden increase in size. Definitive preoperative diagnosis could not be established; however, following surgical resection of the tumor, a diagnosis of bizarre leiomyoma of the scrotum was determined by pathological examination. The patient was followed up six months following resection and no problems were reported. This is the first reported case of bizarre leiomyoma of the scrotum in China. A supplementary review of previously published cases and literature is also presented.
In Gene Ontology, the "Molecular Function" (MF) categorization is a widely used knowledge framework for gene function comparison and prediction. Its structure and annotation provide a convenient way to compare gene functional similarities at the molecular level. The existing gene similarity measures, however, solely rely on one or few aspects of MF without utilizing all the rich information available including structure, annotation, common terms, lowest common parents.
Although endocrine therapy impedes estrogen-ER signaling pathway and thus reduces breast cancer mortality, patients remain at continued risk of relapse after tamoxifen or other endocrine therapies. Understanding the mechanisms of endocrine resistance, particularly the role of transcriptional regulation is very important and necessary.
Controlled delivery of multiple growth factors (GFs) holds great potential for the clinical treatment of ischemic diseases and might be more therapeutically effective to reestablish vasculature than the provision of a single GF. Vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) are two potent angiogenic factors. However, due to rapid degradation and dilution in the body, their clinical potential will rely on an effective mode of delivery. A coacervate, composed of heparin and a biodegradable polycation, which protects GFs from proteolysis and potentiates their bioactivities, is developed. Here, the coacervate incorporates VEGF and HGF and sustains their release for at least three weeks. Their strong angiogenic effects on endothelial cell proliferation and tube formation in vitro are confirmed. Furthermore, it is demonstrated that coacervate-based delivery of these factors has stronger effects than free application of both factors and to coacervate delivery of each GF separately.
High-throughput genomic technologies like lncRNA microarray and RNA-Seq often generate a set of lncRNAs of interest, yet little is known about the transcriptional regulation of the set of lncRNA genes. Here, based on ChIP-Seq peak lists of transcription factors (TFs) from ENCODE and annotated human lncRNAs from GENCODE, we developed a web-based interface titled "TF2lncRNA," where TF peaks from each ChIP-Seq experiment are crossed with the genomic coordinates of a set of input lncRNAs, to identify which TFs present a statistically significant number of binding sites (peaks) within the regulatory region of the input lncRNA genes. The input can be a set of coexpressed lncRNA genes or any other cluster of lncRNA genes. Users can thus infer which TFs are likely to be common transcription regulators of the set of lncRNAs. In addition, users can retrieve all lncRNAs potentially regulated by a specific TF in a specific cell line of interest or retrieve all TFs that have one or more binding sites in the regulatory region of a given lncRNA in the specific cell line. TF2LncRNA is an efficient and easy-to-use web-based tool.
Functional groups can control biointerfaces and provide a simple way to make therapeutic materials. We recently reported the design and synthesis of poly(sebacoyl diglyceride) (PSeD) carrying a free hydroxyl group in its repeating unit. This paper examines the use of this polymer to promote biomineralization for application in bone tissue engineering. PSeD promoted more mineralization of extracellular matrix secreted by human mesenchymal stem cells and rat osteoblasts than poly(lactic-co-glycolic acid) (PLGA), which is currently widely used in bone tissue engineering. PSeD showed in vitro osteocompatibility and in vivo biocompatibility that matched or surpassed that of PLGA, as well as supported the attachment, proliferation and differentiation of rat osteoblasts and human mesenchymal stem cells. This demonstrates the potential of PSeD for use in bone regeneration.
Peutz-Jeghers syndrome (PJS) is a rare hereditary disorder resulting from mutations in serine/threonine kinase 11 (STK11) and characterized by gastrointestinal (GI) hamartomatous polyps, mucocutaneous pigmentation, and an increased risk for specific cancers. Little is known about the genetic implications of specific STK11 mutations with regard to their role in dysplastic and malignant transformation of GI polyps. Peripheral blood genomic DNA samples from 116 Chinese PJS patients from 52 unrelated families were investigated for STK11 mutations. Genotype-phenotype correlations were investigated. The mutation detection rate was 67.3% (51.9% point mutations, 15.4% large deletions). Fourteen out of the 25 point mutations identified were novel. Nearly one-third of all mutations, 8/27 (29.6%), were in exon 7, the shortest out of the nine exons. Strikingly, mutations affecting protein kinase domain XI, encoded in part by exon 7, correlated with a 90% (9/10) incidence of GI polyp dysplasia. In contrast, only two out of 17 (11.8%) nondomain XI mutations were linked to polyp dysplasia (P = 0.0001). The extent of the association between dysplasia and the development of GI-related cancers is currently unknown but our results highlight a novel STK11 genotype-phenotype association as the basis for future genetic counseling and basic research studies.
Chronic hepatitis B (CHB) is an immune-mediated infectious disease caused by the hepatitis B virus (HBV). No ideal immunological markers are available at present. In this study, the expression level of interferon-gamma inducible protein 10 kD (IP-10) in chronic asymptomatic HBV carriers (AsC), patients with CHB, and patients with HBV-related acute-on-chronic liver failure (ACLF) was detected. Serum IP-10 level changes were evaluated during the pre-, on- and post-treatment periods for CHB patients receiving Peg IFN-? therapy. The correlation between the IP-10 level and the inflammation activity (IA) score, alanine aminotransferase (ALT) level, HBV DNA load, and hepatitis B surface antigen (HBsAg) quantification were also evaluated. The IP-10 expression gradually increased from AsC to patients with CHB and was highest in patients with ACLF. Serum IP-10 levels were positively correlated with the hepatic IA score and ALT level, but negatively with the HBV DNA load and HBsAg quantification. The CHB patients achieved hepatitis B e antigen (HBeAg) clearance or HBsAg decline >1 log10 IU/ml had higher pre-treatment IP-10 levels and more obvious on-treatment reduction of the IP-10 level than did patients with HBeAg persistent-positive or HBsAg decline <1 log10 IU/ml. Multivariate logistic-regression analysis revealed that the serum IP-10 level was an independent predictor of HBeAg clearance and HBsAg decline. In conclusion, IP-10 expression distinctly varies at different clinical stages of HBV infection. Higher pre-treatment serum IP-10 expression and dynamic down-regulation might be associated with an increased probability of HBeAg clearance and HBsAg decline in CHB patients during Peg IFN-? therapy.
To describe an innovative approach for developing and implementing an in-service curriculum in China for staff of the newly established health emergency response offices (HEROs), and that is generalisable to other settings.
Measuring similarity between diseases plays an important role in disease-related molecular function research. Functional associations between disease-related genes and semantic associations between diseases are often used to identify pairs of similar diseases from different perspectives. Currently, it is still a challenge to exploit both of them to calculate disease similarity. Therefore, a new method (SemFunSim) that integrates semantic and functional association is proposed to address the issue.
Laterally spreading tumor (LST) is a colorectal pre-cancerous lesion. Previous studies have demonstrated distinct LST clinicopathological characteristics in different populations. This study evaluated clinicopathological characteristics of LST in a Chinese population.
Topological entropy is one of the most difficult entropies to be used to analyze the DNA sequences, due to the finite sample and high-dimensionality problems. In order to overcome these problems, a generalized topological entropy is introduced. The relationship between the topological entropy and the generalized topological entropy is compared, which shows the topological entropy is a special case of the generalized entropy. As an application the generalized topological entropy in introns, exons and promoter regions was computed, respectively. The results indicate that the entropy of introns is higher than that of exons, and the entropy of the exons is higher than that of the promoter regions for each chromosome, which suggest that DNA sequence of the promoter regions is more regular than the exons and introns.
Hyperthermia and oxidative stresses are the two central elements contributing to varicocele-related sperm damage. Growing evidence indicates that microRNAs (miRNAs) are involved in the regulation of the heat and oxidative stress responses. In this study, we analyzed the expressions of several stress-related miRNAs in the sperm and found that the expression of miR-15a was significantly decreased in patients with varicocele compared with the control. Furthermore, miR-15a repressed the expression of HSPA1B, which is a typical stress-induced chaperone protein, through directly binding its 3'-UTR. The expressions of miR-15a and HSPA1B exhibited an inverse correlation in sperm. Our results provide a valuable insight into the varicocele-related sperm impairment and male infertility, and may help to develop potential therapeutic targets and novel biomarkers for male infertility.
Heterogeneous III-V/Si integration with a compact optical vertical interconnect access is fabricated and the light coupling efficiency between the III-V/Si waveguide and the silicon nanophotonic waveguide is characterized. The III-V semiconductor material is directly bonded to the silicon-on-insulator (SOI) substrate and etched to form the III-V/Si waveguide for a higher light confinement in the active region. The compact optical vertical interconnect access is formed through tapering a III-V and an SOI layer in the same direction. The measured III-V/Si waveguide has a light coupling efficiency above ?90% to the silicon photonic layer with the tapering structure. This heterogeneous and light coupling structure can provide an efficient platform for photonic systems on chip, including passive and active devices.
The selection criteria for potential bone engineering scaffolds are based chiefly on their relative mechanical comparability to mature bone. In this study, we challenge this notion by obtaining full regeneration of a rabbit ulna critical size defect by employing the elastomeric polymer, poly(glycerol sebacate) (PGS). We tested the regeneration facilitated by PGS alone, PGS in combination with hydroxyapatite particles, or PGS seeded with bone marrow stromal cells. We investigated the quantity and quality of the regenerated bone histologically, by microcomputed tomography and by four-point bending flexural mechanical testing at 8 weeks postimplantation. We conclude that the relatively lower stiffness of this biocompatible elastomer allows a load-transducing milieu in which osteogenesis, matrix deposition, and eventual bone maturation can take place. This studys results suggest that PGS elastomer is an auspicious osteoconductive material for the regeneration of bony defects. These results call for an innovative reassessment of the current art of selection for novel bone scaffold materials.
Cell therapy for nervous tissue repair is limited by low transplant survival. We investigated the effects of a polyurethane-based reverse thermal gel, poly(ethylene glycol)-poly(serinol hexamethylene urethane) (ESHU) on bone marrow stromal cell (BMSC) transplant survival and repair using a rat model of spinal cord contusion. Transplantation of BMSCs in ESHU at three days post-contusion resulted in a 3.5-fold increase in BMSC survival at one week post-injury and a 66% increase in spared nervous tissue volume at four weeks post-injury. These improvements were accompanied by enhanced hindlimb motor and sensorimotor recovery. In vitro, we found that ESHU protected BMSCs from hydrogen peroxide-mediated death, resulting in a four-fold increase in BMSC survival with two-fold fewer BMSCs expressing the apoptosis marker, caspase 3 and the DNA oxidation marker, 8-oxo-deoxyguanosine. We argue that ESHU protected BMSCs transplanted is a spinal cord contusion from death thereby augmenting their effects on neuroprotection leading to improved behavioral restoration. The data show that the repair effects of intraneural BMSC transplants depend on the degree of their survival and may have a widespread impact on cell-based regenerative medicine.
There are few cases of prostatic schistosomiasis. Here we report a case of Schistosoma japonicum of the prostate, in which the immunophenotyping of individual glandular tubes was atypical. Whether the S. japonicum infection contributed to the lesion or not is unknown. We suspect the lesion was a sign of early precancerous hyperplasia. Follow-up of this patient may give clues about the relationship between schistosomiasis and prostate cancer. This is the first case report of prostatic S. japonicum in the English literatures. A review of the literature is carried out.
With the widely use in portable electronic devices and electric vehicles, the safety of lithium-ion battery has raised serious concerns, in which the thermal stability of separator plays an essential role in preventing thermal runaway reactions. The novelty of this work is to coat commercialized polyethylene (PE) separator and trilayer polypropylene/polyethylene/polypropylene (PP/PE/PP) separator with ethylcellulose (EC), a thermally stable and renewable biomass. The formation of the EC layer with high porosity is through a simple dipping and extracting process. The effects of the EC layer on thermal shrinkage, electrolyte wettability and cell performance are investigated. After coating, the thermal shrinkage of PE separator at shutdown and meltdown point is reduced from 20% to 9% and 42% to 23% respectively, while the drop of OCV under increasing temperature is also postponed from 130°C to 160°C. The electrolyte wettability of pristine trilayer PP/PE/PP separator is greatly improved, leading to increased capacity retention from 28% to 99% of the cell.
The objective of this study was to evaluate the long-term performance of cell-free vascular grafts made from a fast-degrading elastic polymer. We fabricated small arterial grafts from microporous tubes of poly(glycerol sebacate) (PGS) reinforced with polycaprolactone (PCL) nanofibers on the outer surface. Grafts were interpositioned in rat abdominal aortas and characterized at 1 year post-implant. Grafts remodeled into "neoarteries" (regenerated arteries) with similar gross appearance to native rat aortas. Neoarteries mimic arterial tissue architecture with a confluent endothelium and media and adventita-like layers. Patent vessels (80%) showed no significant stenosis, dilation, or calcification. Neoarteries contain nerves and have the same amount of mature elastin as native arteries. Despite some differences in matrix organization, regenerated arteries had similar dynamic mechanical compliance to native arteries in vivo. Neoarteries responded to vasomotor agents, albeit with different magnitude than native aortas. These data suggest that an elastic vascular graft that resorbs quickly has potential to improve the performance of vascular grafts used in small arteries. This design may also promote constructive remodeling in other soft tissues.
Three dimensional (3D) conduits facilitate nerve regeneration. Parallel microfibers have been shown to guide axon extension and Schwann cell migration on flat sheets via topographical cues. However, incorporation of aligned microfibers into 3D conduits to accelerate nerve regeneration has proven challenging. We report an electrospinning technique to incorporate parallel microfibers into 3D constructs at high surface areas while retaining an open architecture. The nerve guide consists of many microchannels lined with a thin layer of longitudinally-aligned microfibers. This design aims to maximize benefits of topographical cues without inhibiting cellular infiltration. We support this hypothesis by demonstrating efficient cell infiltration in vitro. Additionally, this new technique reduces wall thickness compared to our previous design, providing a greater total area for tissue growth. This approach results in an architecture that very closely mimics the structure of decellularized nerve but with larger microchannel diameters to encourage cell infiltration. We believe that reproducing the native architecture is the first step toward matching autograph efficacy. Furthermore, this design can be combined with other biochemical cues to promote nerve regeneration.
Fas signaling has been shown to induce the epithelial-mesenchymal transition (EMT) to promote gastrointestinal (GI) cancer metastasis, but the involvement of microRNA in this mechanism remains unknown. We found that Fas ligand (FasL) treatment inhibited E-cadherin expression and promoted cell invasion by upregulation of miR-23a, but overexpression of the miR-23a inhibitor could partially block this activity. FasL-induced extracellular signal-regulated kinase/mitogen-activated protein kinase signaling activated the activator protein 1 (AP-1) complex and repressed glycogen synthase kinase-3? activity, which contributed to nuclear translocation of AP-1 and nuclear factor of activated T cells (NFAT4). Nuclear accumulation and interaction of AP-1 and NFAT4 and subsequent binding to the miR-23a promoter led to increased miR-23a expression. Inhibition of Fas signaling by downregulation of the Fas receptor led to a decrease in miR-23a expression and cell invasion ability in vivo and in vitro, as well as an increase in E-cadherin. Evaluation of human GI precancerous and cancer specimens showed that the expression of FasL and miR-23a increased, whereas the expression of E-cadherin decreased during GI cancer progression. A significant correlation was noted between any two of these three molecules. An EMT phenotype was shown to correlate with an advanced cancer stage and worse prognosis. Taken together, our results show that miR-23a participates in the mechanism of the FasL-induced EMT process and may serve as a potential therapeutic target for cancer metastasis.
Muscle-derived stem cells (MDSCs) isolated from mouse skeletal muscle by a modified preplate technique exhibit long-term proliferation, high self-renewal, and multipotent differentiation capabilities in vitro. MDSCs retrovirally transduced to express bone morphogenetic proteins (BMPs) can differentiate into osteocytes and chondrocytes and enhance bone and articular cartilage repair in vivo, a feature that is not observed with nontransduced MDSCs. These results emphasize that MDSCs require prolonged exposure to BMPs to undergo osteogenic and chondrogenic differentiation. A sustained BMP protein delivery approach provides a viable and potentially more clinically translatable alternative to genetic manipulation of the cells. A unique growth factor delivery platform comprised of native heparin and a synthetic polycation, poly(ethylene argininylaspartate diglyceride) (PEAD), was used to bind, protect, and sustain the release of bone morphogenetic protein-2 (BMP2) in a temporally and spatially controlled manner. Prolonged exposure to BMP2 released by the PEAD:heparin delivery system promoted the differentiation of MDSCs to an osteogenic lineage in vitro and induced the formation of viable bone at an ectopic site in vivo. This new strategy represents an alternative approach for bone repair mediated by MDSCs while bypassing the need for gene therapy.
Host cell recruitment is crucial for vascular graft remodeling and integration into the native blood vessel; it is especially important for cell-free strategies which rely on host remodeling. Controlled release of growth factors from vascular grafts may enhance host cell recruitment. Stromal cell-derived factor (SDF)-1? has been shown to induce host progenitor cell migration and recruitment; however, its potential in regenerative therapies is often limited due to its short half-life in vivo. This report describes a coacervate drug delivery system for enhancing progenitor cell recruitment into an elastomeric vascular graft by conferring protection of SDF-1?. Heparin and a synthetic polycation are used to form a coacervate, which is incorporated into poly(glycerol sebacate) (PGS) scaffolds. In addition to protecting SDF-1?, the coacervate facilitates uniform scaffold coating. Coacervate-laden scaffolds have high SDF-1? loading efficiency and provide sustained release under static and physiologically-relevant flow conditions with minimal initial burst release. In vitro assays showed that coacervate-laden scaffolds enhance migration and infiltration of human endothelial and mesenchymal progenitor cells by maintaining a stable SDF-1? gradient. These results suggest that SDF-1? coacervate-laden scaffolds show great promise for in situ vascular regeneration.
Polycations have good potential as carriers of proteins and genetic material. However, poor control over the release rate and safety issues currently limit their use as delivery vehicles. Here we introduce a new lysine-based polycation, poly(ethylene lysinylaspartate diglyceride) (PELD), which exhibits high cytocompatibility. PELD self-assembles with the biological polyanion heparin into a coacervate that incorporates proteins with high loading efficiency. Coacervates of varying surface charge were obtained by simple alteration of the PELD:heparin ratio and resulted in diverse release profiles of the model protein bovine serum albumin. Therefore, coacervate charge represents a direct means of control over release rate and duration. The PELD coacervate also rapidly adsorbed onto a porous polymeric scaffold, demonstrating potential use in tissue engineering applications. This coacervate represents a safe and tunable protein delivery system for biomedical applications.
Oxidative stress and inflammation play major roles in the pathogenesis of coronary heart disease including myocardial infarction (MI). The pathological progression following MI is very complex and involves a number of cell populations including cells localized within the heart, as well as cells recruited from the circulation and other tissues that participate in inflammatory and reparative processes. These cells, with their secretory factors, have pleiotropic effects that depend on the stage of inflammation and regeneration. Excessive inflammation leads to enlargement of the infarction site, pathological remodeling and eventually, heart dysfunction. Stem cell therapy represents a unique and innovative approach to ameliorate oxidative stress and inflammation caused by ischemic heart disease. Consequently, it is crucial to understand the crosstalk between stem cells and other cells involved in post-MI cardiac tissue repair, especially immune cells, in order to harness the beneficial effects of the immune response following MI and further improve stem cell-mediated cardiac regeneration. This paper reviews the recent findings on the role of antioxidation and immunomodulation in postnatal multipotent stem cell-mediated cardiac repair following ischemic heart disease, particularly acute MI and focuses specifically on mesenchymal, muscle and blood-vessel-derived stem cells due to their antioxidant and immunomodulatory properties.
The analysis of allele-specific gene expression (ASE) is essential for the mapping of genetic variants that affect gene regulation, and for the identification of alleles that modify disease risk. Although RNA sequencing offers the opportunity to measure expression at allele levels, the availability of powerful statistical methods for mapping ASE in single or multiple individuals is limited. We developed a maximum likelihood model to characterize ASE in the human genome. Approximately 17% of genes displayed an allele-specific effect on gene expression in a single individual. Simulations using our model gave a better performance and improved robustness when compared with the binomial test, with different coverage levels, allelic expression fractions and random noise. In addition, our method can identify ASE in multiple individuals, with enhanced performance. This is helpful in understanding the mechanism of genetic regulation leading to expression changes, alternative splicing variants and even disease susceptibility.
Improved efforts are necessary to define the functional product of cancer mutations currently being revealed through large-scale sequencing efforts. Using genome-scale pooled shRNA screening technology, we mapped negative genetic interactions across a set of isogenic cancer cell lines and confirmed hundreds of these interactions in orthogonal co-culture competition assays to generate a high-confidence genetic interaction network of differentially essential or differential essentiality (DiE) genes. The network uncovered examples of conserved genetic interactions, densely connected functional modules derived from comparative genomics with model systems data, functions for uncharacterized genes in the human genome and targetable vulnerabilities. Finally, we demonstrate a general applicability of DiE gene signatures in determining genetic dependencies of other non-isogenic cancer cell lines. For example, the PTEN(-/-) DiE genes reveal a signature that can preferentially classify PTEN-dependent genotypes across a series of non-isogenic cell lines derived from the breast, pancreas and ovarian cancers. Our reference network suggests that many cancer vulnerabilities remain to be discovered through systematic derivation of a network of differentially essential genes in an isogenic cancer cell model.
This paper describes the design and implementation of a radiosonde which can measure the meteorological temperature, humidity, pressure, and other atmospheric data. The system is composed of a CPU, microwave module, temperature sensor, pressure sensor and humidity sensor array. In order to effectively solve the humidity sensor condensation problem due to the low temperatures in the high altitude environment, a capacitive humidity sensor including four humidity sensors to collect meteorological humidity and a platinum resistance heater was developed using micro-electro-mechanical-system (MEMS) technology. A platinum resistance wire with 99.999% purity and 0.023 mm in diameter was used to obtain the meteorological temperature. A multi-sensor data fusion technique was applied to process the atmospheric data. Static and dynamic experimental results show that the designed humidity sensor with platinum resistance heater can effectively tackle the sensor condensation problem, shorten response times and enhance sensitivity. The humidity sensor array can improve measurement accuracy and obtain a reliable initial meteorological humidity data, while the multi-sensor data fusion technique eliminates the uncertainty in the measurement. The radiosonde can accurately reflect the meteorological changes.
Epidemiological studies have evaluated the association between transforming growth factor-?1 (TGF-?1) -509C/T polymorphisms and breast cancer risk. However, the results remain conflicting rather than conclusive. The aim of this study was to comprehensively clarify the association between TGF-?1 -509C/T polymorphisms and breast cancer risk. All relevant studies were searched in the electronic databases. The potential sources of heterogeneity were detected with the chi-square-based Q test. The strength of associations between TGF-?1 -509C/T polymorphisms and breast cancer risk was measured by odds ratio (OR) and 95 % confidence intervals (CI). Publication bias was tested by Beggs test and Eggers test. A total of 10 studies including 10,913 cases and 14,187 controls were included in the meta-analysis. Overall, there was no evidence of significant association of TGF-?1 -509C/T polymorphisms with breast cancer risk (TT vs. CC [OR?=?0.97, 95 % CI?=?0.83-1.14]; CT vs. CC [OR?=?1.05, 95 % CI?=?0.90-1.22]; TT?+?CT vs. CC [OR?=?0.99, 95 % CI?=?0.91-1.08]; T allele vs. C allele [OR?=?0.99, 95 % CI?=?0.93-1.06]). Similar results were also found in the subgroup analyses by ethnicity and source of control. When stratified by estrogen receptor (ER) status, TT genotype and T allele were associated with a decreased ER-positive breast cancer risk (OR?=?0.66, 95 % CI?=?0.49-0.90 and OR?=?0.85, 95 % CI?=?0.75-0.96, respectively). The present meta-analysis results suggest that TGF-?1 -509C/T variants may not contribute to the risk of breast cancer overall. However, T allele may be a potential protective factor for developing ER-positive breast cancer. Well-designed studies with larger sample size were required to verify our findings further.
MicroRNA-7 (miR-7) has been described as a tumor suppressor in several human cancers, but the results of a study to identify miRNAs associated with metastatic capability in breast cancer suggested that miR-7 may be characterized as an oncogene. The present study was to determine the expression and function of miR-7 in renal cell carcinoma. Quantitative real-time polymerase chain reaction was used to validate the expressions of miR-7 in 48 paired renal cell carcinomas (RCC) and normal tissues, based on the preliminary sequencing results of miRNAs. Furthermore, the impacts of miR-7 on cell migration, proliferation and apoptosis were analyzed using wound scratch assay, MTT and flow cytometry, respectively. The results demonstrated that miR-7 was up-regulated in RCC compared with normal tissues (p = 0.001). Down-regulation of miR-7 with synthesized inhibitor inhibited cell migration in vitro, suppressed cell proliferation and induced renal cancer cell apoptosis, prompting that miR-7 could be characterized as an oncogene in RCC. The present study was the first to reveal that miR-7 was up-regulated in RCC and it played an important role in RCC by affecting cellular migration, proliferation and apoptosis. Further researches should be conducted to explore the roles and target genes of miR-7 in RCC and other cancers.
Fas signalling has been shown to induce the epithelial-mesenchymal transition (EMT) to promote gastrointestinal (GI) cancer metastasis, but its mechanism of action is still unknown. The effects of Fas-ligand (FasL) treatment and inhibition of Fas signalling on GI cancer cells were tested using invasion assay, immunofluorescence, immunoblot, Reverse Transcription Polymerase Chain Reaction (RT-PCR), quantitative Real-time PCR (qRT-PCR), immunoprecipitation and luciferase reporter assay. Immunohistochemistry was used to analyse the EMT-associated molecules in GI cancer specimens. FasL treatment inhibited E-cadherin transcription by upregulation of Snail in GI cancer cells. The nuclear expression and transcriptional activity of Snail and ?-catenin were increased by inhibitory phosphorylation of glycogen synthase kinase-3 beta (GSK-3?) at Ser9 by FasL-induced extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) signalling. Snail associated with ?-catenin in the nucleus and, thus, increased ?-catenin transcriptional activity. Evaluation of human GI cancer specimens showed that the expression of FasL, phospho-GSK-3?, Snail and ?-catenin increase during GI cancer progression. An EMT phenotype was shown to correlate with an advanced cancer stage, and a non-EMT phenotype significantly correlated with a better prognosis. Collectively, these data indicate that GSK-3? regulates Snail and ?-catenin expression during Fas-induced EMT in gastrointestinal cancer.
Mechanical strength is a key design factor in tissue engineering of arteries. Most existing techniques assess the mechanical property of arterial constructs destructively, leading to sacrifice of a large number of animals. We propose an ultrasound-based non-invasive technique for the assessment of the mechanical strength of engineered arterial constructs. Tubular scaffolds made from a biodegradable elastomer and seeded with vascular fibroblasts and smooth muscle cells were cultured in a pulsatile-flow bioreactor. Scaffold distension was computed from ultrasound radiofrequency signals of the pulsating scaffold via 2-D phase-sensitive speckle tracking. Youngs modulus was then calculated by solving the inverse problem from the distension and the recorded pulse pressure. The stiffness thus computed from ultrasound correlated well with direct mechanical testing results. As the scaffolds matured in culture, ultrasound measurements indicated an increase in Youngs modulus, and histology confirmed the growth of cells and collagen fibrils in the constructs. The results indicate that ultrasound elastography can be used to assess and monitor non-invasively the mechanical properties of arterial constructs.
Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key stemness property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term and irreversible impairment of tumor growth. Targeting the BMI-1-related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.
Over 10,000 long intergenic non-coding RNAs (lincRNAs) have been identified in the human genome. Some have been well characterized and known to participate in various stages of gene regulation. In the post-transcriptional process, another class of well-known small non-coding RNA, or microRNA (miRNA), is very active in inhibiting mRNA. Though similar features between mRNA and lincRNA have been revealed in several recent studies, and a few isolated miRNA-lincRNA relationships have been observed. Despite these advances, the comprehensive miRNA regulation pattern of lincRNA has not been clarified.
Bidirectional promoters are shared promoter sequences between divergent gene pair (genes proximal to each other on opposite strands), and can regulate the genes in both directions. In the human genome, > 10% of protein-coding genes are arranged head-to-head on opposite strands, with transcription start sites that are separated by < 1,000 base pairs. Many transcription factor binding sites occur in the bidirectional promoters that influence the expression of 2 opposite genes. Recently, RNA polymerase II (RPol II) ChIP-seq data are used to identify the promoters of coding genes and non-coding RNAs. However, a bidirectional promoter with RPol II ChIP-Seq data has not been found.
Gene Ontology (GO) has been widely used in biological databases, annotation projects, and computational analyses. Although the three GO categories are structured as independent ontologies, the biological relationships across the categories are not negligible for biological reasoning and knowledge integration. However, the existing cross-category ontology term similarity measures are either developed by utilizing the GO data only or based on manually curated term name similarities, ignoring the fact that GO is evolving quickly and the gene annotations are far from complete.
Reverse thermal gels have numerous biomedical implications, as they undergo physical gelation upon temperature increases and can incorporate biomolecules to promote tissue repair. Such a material is developed for the sustained release of bevacizumab (Avastin), a drug used to treat age-related macular degeneration. The polymer, poly(ethylene glycol)-poly(serinol hexamethylene urethane) (ESHU), forms a physical gel when heated to 37?°C and shows good cytocompatibility with ocular cells. ESHU is capable of sustaining bevacizumab release over 17?weeks in vitro, and the release kinetics can be altered by changing the drug dose and the ESHU concentration. These results suggest that ESHU is biologically safe, and suitable for ocular drug delivery.
We have prepared and characterized a new polyurethane-based antimicrobial material, N,N-dodecyl,methyl-polyurethane (Quat-12-PU). It exhibits strong antiviral and antibacterial activities when coated (as an organic solution or an aqueous nanosuspension) onto surfaces and antibacterial activity when electrospun into nanofibers. Quat-12-PU surfaces are able to kill airborne Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli bacteria, as well as inactivate the enveloped influenza virus (but not the non-enveloped poliovirus).
Graphene, one kind of emerging carbon nanomaterial, has attracted increasing attention recently. Due to its fascinating physical and electrochemical properties, graphene as a promising electrode material has been widely used in electrochemical sensing applications. In this review, different approaches for the fabrication of graphene and the preparation of graphene-modified electrodes for electrochemical sensors are introduced. Moreover, recent research results on different graphene-based materials as an electrochemical platform for the detection of various biomolecules and chemicals are reviewed and compared. More electrochemical studies on this novel material should show up in the near future.
The evaluation of candidate materials and designs for soft tissue scaffolds would benefit from the ability to monitor the mechanical remodeling of the implant site without the need for periodic animal sacrifice and explant analysis. Toward this end, the ability of non-invasive ultrasound elasticity imaging (UEI) to assess temporal mechanical property changes in three different types of porous, biodegradable polyurethane scaffolds was evaluated in a rat abdominal wall repair model. The polymers utilized were salt-leached scaffolds of poly(carbonate urethane) urea, poly(ester urethane) urea and poly(ether ester urethane) urea at 85% porosity. A total of 60 scaffolds (20 each type) were implanted in a full thickness muscle wall replacement in the abdomens of 30 rats. The constructs were ultrasonically scanned every 2 weeks and harvested at weeks 4, 8 and 12 for compression testing or histological analysis. UEI demonstrated different temporal stiffness trends among the different scaffold types, while the stiffness of the surrounding native tissue remained unchanged. The changes in average normalized strains developed in the constructs from UEI compared well with the changes of mean compliance from compression tests and histology. The average normalized strains and the compliance for the same sample exhibited a strong linear relationship. The ability of UEI to identify herniation and to characterize the distribution of local tissue in-growth with high resolution was also investigated. In summary, the reported data indicate that UEI may allow tissue engineers to sequentially evaluate the progress of tissue construct mechanical behavior in vivo and in some cases may reduce the need for interim time point animal sacrifice.
To search for genetic regulators influencing miRNA transcript abundance, we performed a genome-wide association study (GWAS) to identify quantitative trait loci associated with primary miRNA transcript abundance (pri-miQTL) using genotype data from HapMap CEU phased data. We detected robust expression for 150 pri-miRNAs out of 1523 interrogated using RNA-seq. We have identified some pri-miRNAs that showed significant evidence for cis- (34%) and trans-pri-miQTLs (3%). Furthermore, we observed that multiple cis-pri-miQTLs, showed allele-specific expression associated with single pri-miRNA expression. Interestingly, a cis-regulatory variation influenced the expression levels of two pri-miRNAs that expressed identical mature sequences. We also observed that a single trans-regulatory variation was associated with multiple unrelated pri-miRNAs: rs292253 was associated with the expression of hsa-mir-3181, hsa-mir-3665 and hsa-mir-762. These findings revealed that the expression of pri-miRNA detected by RNA-seq can be used to identify pri-miQTLs, as an alternative method to dissect the genetic control mechanisms governing pri-miRNA expression.
Nonalcoholic fatty liver disease (NAFLD) is one of the critical public health problems in China. The full spectrum of the disease ranges from simple steatosis and nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma(HCC). The infiltration of inflammatory cells characterizes NASH. This characteristic contributes to the progression of hepatitis, fibrosis, cirrhosis, and HCC. Therefore, distinguishing NASH from NAFLD is crucial.
Epidemiologic studies have reported the association of X-ray repair cross-complementary group 1 (XRCC1) Arg399Gln polymorphisms with susceptibility to squamous cell carcinoma of the head and neck (HNSCC). However, the results were conflictive rather than conclusive. The purpose of this study was to clarify the association of XRCC1 Arg399Gln variants with HNSCC risk.
A number of databases have been developed to collect disease-related molecular, phenotypic and environmental features (DR-MPEs), such as genes, non-coding RNAs, genetic variations, drugs, phenotypes and environmental factors. However, each of current databases focused on only one or two DR-MPEs. There is an urgent demand to develop an integrated database, which can establish semantic associations among disease-related databases and link them to provide a global view of human disease at the biological level. This database, once developed, will facilitate researchers to query various DR-MPEs through disease, and investigate disease mechanisms from different types of data.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.