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Acknowledgment The research of Ming Zheng was supported by the National Natural Science Foundation of China Grants (11771095). ...arXiv:2110.10393v1 fatcat:7o2zmgxlsjednpsxnlojjjp24q
Increasing numbers of proteins, nucleic acids and other molecular entities have been explored as therapeutic targets, hundreds of which are targets of approved and clinical trial drugs. Knowledge of these targets and corresponding drugs, particularly those in clinical uses and trials, is highly useful for facilitating drug discovery. Therapeutic Target Database (TTD) has been developed to provide information about therapeutic targets and corresponding drugs. In order to accommodate increasingdoi:10.1093/nar/gkp1014 pmid:19933260 pmcid:PMC2808971 fatcat:6jd6zs7sfvau7ji6zrl6mocaa4
more »... mand for comprehensive knowledge about the primary targets of the approved, clinical trial and experimental drugs, numerous improvements and updates have been made to TTD. These updates include information about 348 successful, 292 clinical trial and 1254 research targets, 1514 approved, 1212 clinical trial and 2302 experimental drugs linked to their primary targets (3382 small molecule and 649 antisense drugs with available structure and sequence), new ways to access data by drug mode of action, recursive search of related targets or drugs, similarity target and drug searching, customized and whole data download, standardized target ID, and significant increase of data (1894 targets, 560 diseases and 5028 drugs compared with the 433 targets, 125 diseases and 809 drugs in the original release described in previous paper). This database can be accessed at
Misspecification of the designing parameters in the planning of a controlled clinical trial may yield an underpowered or an overpowered study. Internal pilot study, a kind of adaptive design, has gained increased attention for its allowing for sample size adjustment, especially blinded sample size adjustment that do not affect the type I error rate. Several methods were proposed to implement internal pilot design in recent years and some software emerges to simulate or implement it. But most ofdoi:10.1016/j.jbi.2008.08.005 pmid:18775797 fatcat:4hy3x6mhf5hzplw74smsfyszaq
more »... the software is only running on a stand-alone terminal or Client/Server(C/S) mode. We develop a system to simulate it based on Browser/Server(B/S) mode and realized on web. It allows the web users to input corresponding parameters from the web browser such as Internet Explorer to make simulations. The system was constructed with generic database schema design method and coded with Microsoft Visual Basic and Active Server Pages (ASP) programming languages. Web users on internet can use the system to make blinded variance estimate, sample size adjustment and randomization test for internal pilot study. The application of the simulation is demonstrated through an example. Not only blinded sample size adjustment is implemented but also a randomization test is performed. With applications of blinding one-sample variance for sample size recalculation and randomization test, the type I error rate is also controlled successfully.
Evolutionary pressure drives gut microbiota-host coevolution and results in complex interactions between gut microbiota and neural development; however, the molecular mechanisms by which the microbiota governs host behavior remain obscure. Here, we report that colonization early in life is crucial for the microbiota to modulate brain development and behavior; later colonization or deletion of microbiota cannot completely reverse the behaviors. Microarray analysis revealed an association betweendoi:10.1038/srep29998 pmid:27444685 pmcid:PMC4956747 fatcat:vtniag4tzbgsdhpu6rbel3n45m
more »... absence of gut microbiota and expression in cAMP responding element-binding protein (CREB) regulated genes in the hippocampus. The absence of gut microbiota from birth was shown to be associated with decreased CREB expression, followed by decreases of protein kinase C beta (PRKCB) and AMPA receptors expression, and an increase of phosphorylation CREB (pCREB) expression. Microbiota colonization in adolescence restored CREB and pCREB expression, but did not alter PRKCB and AMPARs expression. The removal of the gut microbiota from SPF mice using antibiotics only reduced pCREB expression. These findings suggest that (i) colonization of the gut microbiota early in life might facilitate neurodevelopment via PKC-CREB signaling and (ii) although GF mice and ABX mice display reduced anxiety-related behaviors, the molecular mechanisms behind this might differ.
BMC Medical Genetics
Background Peri-implantitis is an inflammation that occurs around the implant, resulting in varying degrees of inflammatory damage to the soft and hard tissues. The characteristic criterion is the loss of the supporting bone in an inflammatory environment. However, the specific mechanisms and biomarkers involved in peri-implantitis remain to be further studied. Recently, competing endogenous RNAs (ceRNA) and immune microenvironment have been found to play a more important role in thedoi:10.1186/s12881-020-01145-4 pmid:33081707 fatcat:ylcgnhpn3zcuhafbkao2hkxnza
more »... y process. In our study, we analyzed the expression of immune related microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and message RNAs (mRNAs) in peri-implantitis by analyzing GSE33774 and GSE57631. Methods In this study, we explored the expression profile data of immune-related lncRNAs, miRNAs and mRNAs, and constructed immune-related ceRNA network involved in the pathogenesis of peri-implantitis. In addition, the CIBERSORT was used to evaluate the content of immune cells in normal tissues and peri-implantitis to detect the immune microenvironment of peri-implantitis. Results In the analysis, 14 DElncRNAs, 16 DEmiRNAs, and 18 DEmRNAs were used to establish an immune related ceRNA network and the immune infiltration patterns associated with peri-implantitis was discovered. Through the mutual verification of the two datasets, we found that GSK3B and miR-1297 may have important significance in the immune microenvironment and pathogenesis of peri-implantitis and GSK3B was closely related to four types of immune cells, especially with the highest correlation with resting mast cells (P = 0.0003). Conclusions Through immune-related ceRNA network, immune-related genes (IRGs) and immune cell infiltration can further comprehensively understand the pathogenesis of peri-implantitis, which built up an immunogenomic landscape with clinical significance for peri-implantitis.
Zheng et al. first reduced the carbonyl groups in the diaryl ketone moiety of PEEK to hydroxyl groups and formed a silanization layer on the hydroxylation-pretreated PEEK surface. ...doi:10.3390/coatings12060868 fatcat:edchlwwcdbd5hdjtbqilqoxyii
Background Glucose metabolism in cancer associated fibroblasts (CAFs) within the tumor microenvironment is a material and energy source for tumorigenesis and tumor development. However, the characteristics and important regulatory mechanisms of glucose metabolism in fibroblasts associated with oral squamous cell carcinoma (OSCC) are still unknown. Methods We successfully isolated, cultured, purified and identified CAFs and normal fibroblasts (NFs). Cell culture, immunohistochemistry (IHC) anddoi:10.1186/s12885-021-09049-z pmid:34906113 pmcid:PMC8670112 fatcat:zi7mlqehwfewnotyziuvy54yfm
more »... K8, flow cytometry, Seahorse XF Analyzer, MitoTracker assay, western blotting (WB), transmission electron microscope, Quantitative real-time PCR (qPCR), immunofluorescence (IF), and Label-free quantitative proteomics assay, animal xenograft model studies and statistical analysis were applied in this study. Results We demonstrated that the proliferation activity of CAFs was significantly enhanced as compared to NFs, while the apoptosis rate was significantly decreased. CAFs in OSCC preferentially use oxidative phosphorylation (OXPHOS) rather than glycolysis. Moreover, CAFs showed stronger maximal respiration, a larger substantial mitochondrial spare respiratory capacity (SRC) and higher adenosine triphosphate (ATP) production capacity than NFs. The results of mitotracker green fluorescence staining showed that compared with NFs, CAFs exhibited stronger green fluorescence. The results of WB showed the expression level of Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) obviously increased in CAFs compared to NFs. These results confirmed that CAFs have greater mitochondrial activity and function than NFs. Furthermore, Label-free quantitative proteomics assays showed that both ATP synthase subunit O (ATP5O) and tumor necrosis factor receptor-associated protein 1 (TRAP1) are important differentially expressed proteins in the mitochondria of CAFs/NFs. Overexpression of TRAP1 in CAFs increased basal oxygen consumption rate (OCR), maximal respiration, ATP production and SRC. In vivo, overexpression TRAP1 expression in CAFs suppress tumor growth. Conclusion Taken together, the results indicated that TRAP1 is an important regulatory molecule of CAFs glucose metabolism and promotes OSCC progression by regulating the OXPHOS of CAFs.
ObjectivesTo investigate superiority of a telerehabilitation programme for COVID-19 (TERECO) over no rehabilitation with regard to exercise capacity, lower limb muscle strength (LMS), pulmonary function, health-related quality of life (HRQOL) and dyspnoea.DesignParallel-group randomised controlled trial with 1:1 block randomisation.SettingThree major hospitals from Jiangsu and Hubei provinces, China.Participants120 formerly hospitalised COVID-19 survivors with remaining dyspnoea complaints weredoi:10.1136/thoraxjnl-2021-217382 pmid:34312316 pmcid:PMC8318721 fatcat:rsfflqtqobdfnb2pgpqwtie7d4
more »... randomised with 61 allocated to control and 59 to TERECO.InterventionUnsupervised home-based 6-week exercise programme comprising breathing control and thoracic expansion, aerobic exercise and LMS exercise, delivered via smartphone, and remotely monitored with heart rate telemetry.OutcomesPrimary outcome was 6 min walking distance (6MWD) in metres. Secondary outcomes were squat time in seconds; pulmonary function assessed by spirometry; HRQOL measured with Short Form Health Survey-12 (SF-12) and mMRC-dyspnoea. Outcomes were assessed at 6 weeks (post-treatment) and 28 weeks (follow-up).ResultsAdjusted between-group difference in change in 6MWD was 65.45 m (95% CI 43.8 to 87.1; p<0.001) at post-treatment and 68.62 m (95% CI 46.39 to 90.85; p<0.001) at follow-up. Treatment effects for LMS were 20.12 s (95% CI 12.34 to 27.9; p<0.001) post-treatment and 22.23 s (95% CI 14.24 to 30.21; p<0.001) at follow-up. No group differences were found for lung function except post-treatment maximum voluntary ventilation. Increase in SF-12 physical component was greater in the TERECO group with treatment effects estimated as 3.79 (95% CI 1.24 to 6.35; p=0.004) at post-treatment and 2.69 (95% CI 0.06 to 5.32; p=0.045) at follow-up.ConclusionsThis trial demonstrated superiority of TERECO over no rehabilitation for 6MWD, LMS, and physical HRQOL.Trial registration numberChiCTR2000031834.
Rice (Oryza sativa L.) is an important food crop species in China. Cultivating high-yielding rice varieties that have a high photosynthetic efficiency is an important goal of rice breeding in China. In recent years, due to the continual innovation of molecular breeding methods, many excellent genes have been applied in rice breeding, which is highly important for increasing rice yields. In this paper, the hexokinase gene OsHXK1 was knocked out via the CRISPR/Cas9 gene-editing method in thedoi:10.3390/ijms22179554 pmid:34502462 fatcat:f3qzzjdekjd6fhebzrnqtstiai
more »... a rice varieties Huanghuazhan, Meixiangzhan, and Wushansimiao, and OsHXK1-CRISPR/Cas9 lines were obtained. According to the results of a phenotypic analysis and agronomic trait statistics, the OsHXK1-CRISPR/Cas9 plants presented increased light saturation points, stomatal conductance, light tolerance, photosynthetic products, and rice yields. Moreover, transcriptome analysis showed that the expression of photosynthesis-related genes significantly increased. Taken together, our results revealed that knocking out OsHXK1 via the CRISPR/Cas9 gene-editing method could effectively lead to the cultivation of high-photosynthetic efficiency and high-yielding rice varieties. They also revealed the important roles of OsHXK1 in the regulation of rice yield and photosynthesis.
Gut microbiota has an important role in the immune system, metabolism, and digestion, and has a significant effect on the nervous system. Recent studies have revealed that abnormal gut microbiota induces abnormal behaviors, which may be associated with the hypothalamic-pituitary-adrenal (HPA) axis. Therefore, we investigated the behavioral changes in germ-free (GF) mice by behavioral tests, quantified the basal serum cortisol levels, and examined glucocorticoid receptor pathway genes indoi:10.1038/s41398-018-0240-5 pmid:30194287 pmcid:PMC6128920 fatcat:5d5pzovj2rdltekzsfvkqhw5bi
more »... pus using microarray analysis followed by real-time PCR validation, to explore the molecular mechanisms by which the gut microbiota influences the host's behaviors and brain function. Moreover, we quantified the basal serum cortisol levels and validated the differential genes in an Escherichia coli-derived lipopolysaccharide (LPS) treatment mouse model and fecal "depression microbiota" transplantation mouse model by real-time PCR. We found that GF mice showed antianxiety-and antidepressant-like behaviors, whereas E. coli LPS-treated mice showed antidepressant-like behavior, but did not show antianxiety-like behavior. However, "depression microbiota" recipient mice exhibited anxiety-and depressive-like behaviors. In addition, six glucocorticoid receptor pathway genes (Slc22a5, Aqp1, Stat5a, Ampd3, Plekhf1, and Cyb561) were upregulated in GF mice, and of these only two (Stat5a and Ampd3) were upregulated in LPS-treated mice, whereas the shared gene, Stat5a, was downregulated in "depression microbiota" recipient mice. Furthermore, basal serum cortisol levels were decreased in E. coli LPS-treated mice but not in GF mice and "depression microbiota" recipient mice. These results indicated that the gut microbiota may lead to behavioral abnormalities in mice through the downstream pathway of the glucocorticoid receptor. Herein, we proposed a new insight into the molecular mechanisms by which gut microbiota influence depressive-like behavior.
Chanjuan Zheng: Literature research, clinical studies, and data acquisition. Suiqiang Zhu: Conception, clinical studies, and manuscript editing. Zhouping Tang: Data analysis and statistical analysis. ...doi:10.1177/0269215515578698 pmid:25819076 pmcid:PMC4767143 fatcat:hkdgtnk5knhrrjpetkgrs4umlm
Dilated cardiomyopathy (DCM) is the most common cardiomyopathy with a common presentation of heart failure. It has been reported that CASZ1 loss-of-function mutation contributes to familial DCM and congenital ventricular septal defect (VSD). To date, only two pathogenic variants in CASZ1 have been previously reported worldwide.doi:10.1002/mgg3.828 pmid:31268246 pmcid:PMC6687865 fatcat:o4sger73mreujk3vflrwhydesu
Programmed cell death (PCD) plays crucial roles in plant development and defence response. Reactive oxygen species (ROS) are produced during normal plant growth, and high ROS concentrations can change the antioxidant status of cells, leading to spontaneous cell death. In addition, ROS function as signalling molecules to improve plant stress tolerance, and they induce PCD under different conditions. This review describes the mechanisms underlying plant PCD, the key functions of mitochondria anddoi:10.3390/ijms222312942 pmid:34884747 pmcid:PMC8657872 fatcat:tflexmfzuzfshbq7g3l3ichijq
more »... hloroplasts in PCD, and the relationship between mitochondria and chloroplasts during PCD. Additionally, the review discusses the factors that regulate PCD. Most importantly, in this review, we summarise the sites of production of ROS and discuss the roles of ROS that not only trigger multiple signalling pathways leading to PCD but also participate in the execution of PCD, highlighting the importance of ROS in PCD.
Journal of Cancer
Effective treatment modality for triple-negative breast cancer (TNBC) is currently lacking due to the absence of defined receptor targets. Recently, we have demonstrated that lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor and a lipid-lowering drug, can selectively inhibit TNBC by targeting cancer stem cells in vivo and in vitro. Interestingly, we found that lovastatin induced the reappearance of human epidermal growth factor receptor 2 (HER2), one of the tripledoi:10.7150/jca.39265 pmid:32328175 pmcid:PMC7171481 fatcat:jimfm2wzaff6tcinnecmxlatz4
more »... that are missing in TNBC. This prompted us to explore the possibility of regaining sensitivity of TNBC cancer stem cells to receptor tyrosine kinase-targeting drugs. We found that while the combination of lovastatin with a HER2 inhibitor was not sufficient to show synergism, addition of an epidermal growth factor receptor (EGFR/HER1) inhibitor to this combination resulted in significant synergistic inhibitory effect on cell viability. Our findings provide a potential novel strategy of designing a cocktail composed of a lipid-lowering drug and two receptor tyrosine kinase inhibitors for the treatment of TNBC.
Bacillus nematocida B16 is able to dominate in the intestines of the worm Caenorhabditis elegans in 'Trojan horse' pathogenic mechanism. The adp is one candidate gene which potentially play a vital role in the colonization from our previous random mutagenesis screening results. To analyse the functional role of this gene, we constructed the adp knockout mutant through customized transcription activator-like effectors nucleases (TALEN), which has been successfully used in yeasts, nematodes,doi:10.1111/1751-7915.12282 pmid:25912819 pmcid:PMC4476823 fatcat:3n6whs62yjcx5duh4mzf3nhueu
more »... fish and human pluripotent cells. Here, we first time report this knockout method in bacteria on this paper. Bioassay experiments demonstrated that the adp knockout mutant of B16 showed considerably lower colonization activity, reduced numbers of intestines and less than 80% nematocidal activity compared with the wild-type strain when infected for 48 h. However, no obvious change on proteolytic activity was observed in the mutant. Conversely, the complementation of adp gene restored most of the above deficient phenotypes. These results indicated that the adp gene was involved in surface adhesion and played a comparatively important role in colonizing host nematodes. Moreover, TALENs successfully disrupt target genes in bacteria.
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