Objective:To explore the differentially expressed tRNA-derived RNA fragment(tRF)and tRNA halves(tiRNA)in plasma of collagen-induced arthritis(CIA)rats,analyze the biological functions and related pathways of the tRF and tiRNAs target genes in order to identify new targets for diagnosis and therapy of rheumatoid arthritis(RA).Methods:Rat model of RA was estab-lished by injecting typeⅡ collagen.Arthritis index(AI)score and HE staining were conducted to evaluate the successfully establishment model.Illumina platform was used to obtain the tRF and tiRNA expression profiles.RT-qPCR was performed to validate expressions of tRF and tiRNA.Combining miRanda and TargetScan databases,the target genes of differentially expressed tRF and tiRNA were ob-tained.GO and KEGG enrichment analysis were used to annotate the functions of target genes.Results:A total of 25 tRFs and tiRNAs were significantly differentially expressed in plasma in rats after modeling,of which 23 were up-regulated and 2 were down-regulated.Besides,six specifically expressed tRFs and tiRNAs induced by CIA rats were screened,including Other-36:73-tRNA-Arg-CCT-4,Other-57:70-tRNA-Glu-CTC-1-M3,tRF-1:32-Gly-CCC-1-M2,tRF-1:31-Gly-CCC-1-M2,tRF-1:32-Pro-AGG-1-M4 and tRF-1:32-Glu-TTC-2-M2.GO analysis of target genes mainly involved organelle-associated items.What's more,KEGG analysis enriched multi-ple classical signal pathways associated with RA.Conclusion:Target genes of differentially expressed tRFs and tiRNAs in CIA rats may be involved in regulating important pathophysiological processes of RA and drug therapy targets.

Objective:To explore the differentially expressed tRNA-derived RNA fragment(tRF)and tRNA halves(tiRNA)in plasma of collagen-induced arthritis(CIA)rats,analyze the biological functions and related pathways of the tRF and tiRNAs target genes in order to identify new targets for diagnosis and therapy of rheumatoid arthritis(RA).Methods:Rat model of RA was estab-lished by injecting typeⅡ collagen.Arthritis index(AI)score and HE staining were conducted to evaluate the successfully establishment model.Illumina platform was used to obtain the tRF and tiRNA expression profiles.RT-qPCR was performed to validate expressions of tRF and tiRNA.Combining miRanda and TargetScan databases,the target genes of differentially expressed tRF and tiRNA were ob-tained.GO and KEGG enrichment analysis were used to annotate the functions of target genes.Results:A total of 25 tRFs and tiRNAs were significantly differentially expressed in plasma in rats after modeling,of which 23 were up-regulated and 2 were down-regulated.Besides,six specifically expressed tRFs and tiRNAs induced by CIA rats were screened,including Other-36:73-tRNA-Arg-CCT-4,Other-57:70-tRNA-Glu-CTC-1-M3,tRF-1:32-Gly-CCC-1-M2,tRF-1:31-Gly-CCC-1-M2,tRF-1:32-Pro-AGG-1-M4 and tRF-1:32-Glu-TTC-2-M2.GO analysis of target genes mainly involved organelle-associated items.What's more,KEGG analysis enriched multi-ple classical signal pathways associated with RA.Conclusion:Target genes of differentially expressed tRFs and tiRNAs in CIA rats may be involved in regulating important pathophysiological processes of RA and drug therapy targets.

Non-syndromic oral cleft (NSOC), a common birth defect, remains to be a critical public health problem in China. In the context of adjustment of childbearing policy for two times in China and the increase of pregnancy at older childbearing age, NSOC risk prediction will provide evidence for high-risk population identification and prenatal counseling. Genome-wide association study and second generation sequencing have identified multiple loci associated with NSOC, facilitating the development of genetic risk prediction of NSOC. Despite the marked progress, risk prediction models of NSOC still faces multiple challenges. This paper summarizes the recent progress in research of NSOC risk prediction models based on the results of extensive literature retrieval to provide some insights for the model development regarding research design, variable selection, model-build strategy and evaluation methods.
Humans ; Cleft Palate/genetics* ; Cleft Lip/genetics* ; Genome-Wide Association Study ; Genetic Predisposition to Disease ; Risk Factors ; Polymorphism, Single Nucleotide

Next-generation sequencing has revolutionized family-based association tests for rare variants. As the lower power of genome wide association study for detecting casual rare variants, methods aggregating effects of multiple variants have been proposed, such as burden tests and variance component tests. This paper summarizes the methods of rare variants association test that can be applied for family data, introduces their principles, characteristics and applicable conditions and discusses the shortcomings and the improvement of the present methods.
Computer Simulation ; Family Relations ; Genetic Association Studies ; Genetic Variation ; Genome-Wide Association Study/methods* ; Humans

Child ; Consensus ; Drugs, Chinese Herbal ; Humans ; Medicine, Chinese Traditional ; Respiratory System

OBJECTIVE: To explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design. METHODS: Whole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database. RESULTS: A total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes. CONCLUSION Our study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.
Asians ; Case-Control Studies ; Cleft Lip/genetics* ; Cleft Palate/genetics* ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Humans ; Mutation ; Parents ; Polymorphism, Single Nucleotide ; Whole Exome Sequencing

Animals ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Disulfides ; Male ; Mice ; Mice, Inbred BALB C ; Phosphatidylinositol 3-Kinases ; Stomach Neoplasms/drug therapy* ; Sulfoxides

Objective:To investigate the clinical and pathological features of pediatric NTRK-rearranged tumors.Methods:Four NTRK-rearranged soft tissue tumors and one renal tumor at Shanghai Children′s Medical Center, Shanghai Jiaotong University and Singapore KK Women′s and Children′s Hospital from January 2017 to September 2019 were identified. Pan-TRK immunohistochemistry, and the ALK and ETV6 gene break-apart fluorescence in situ hybridizations (FISH) were performed. NTRK gene rearrangement was detected using sequencing-based methods.Results:There were 3 males and 2 females in this study. The patients were between 3 months and 13 years of age. Histologically, the tumors were infiltrative spindle cell tumors with variable accompanying inflammatory cells. Immunohistochemistry showed positive reactivity for pan-TRK in all tumors, with nuclear staining for NTRK3 fusion, and cytoplasmic staining for NTRK1 fusion. The molecular testing revealed NTRK gene fusions (one each of TPM3-NTRK1, ETV6-NTRK3 and DCTN1-NTRK1, and two cases of LMNA-NTRK1). Two patients were receiving larotrectinib. The others were are well without disease, with follow-up durations of 9 to 29 months.Conclusions:NTRK-rearranged mesenchymal tumors from soft tissue sites and kidney are identified. A novel DCTN1-NTRK1 fusion is described. Pan-TRK immunohistochemistry is useful for diagnosis. NTRK-targeted therapy may be an option for unresectable, recurrent or metastatic cases.

OBJECTIVES: To develop a new Chinese medicine (CM)-based drug and to evaluate its safety and effect for suppressing acute respiratory distress syndrome (ARDS) in COVID-19 patients. METHODS: A putative ARDS-suppressing drug Keguan-1 was first developed and then evaluated by a randomized, controlled two-arm trial. The two arms of the trial consist of a control therapy (alpha interferon inhalation, 50 µg twice daily; and lopinavir/ritonavir, 400 and 100 mg twice daily, respectively) and a testing therapy (control therapy plus Keguan-1 19.4 g twice daily) by random number table at 1:1 ratio with 24 cases each group. After 2-week treatment, adverse events, time to fever resolution, ARDS development, and lung injury on newly diagnosed COVID-19 patients were assessed. RESULTS: An analysis of the data from the first 30 participants showed that the control arm and the testing arm did not exhibit any significant differences in terms of adverse events. Based on this result, the study was expanded to include a total of 48 participants (24 cases each arm). The results show that compared with the control arm, the testing arm exhibited a significant improvement in time to fever resolution (P=0.035), and a significant reduction in the development of ARDS (P=0.048). CONCLUSIONS Keguan-1-based integrative therapy was safe and superior to the standard therapy in suppressing the development of ARDS in COVID-19 patients. (Trial registration No. NCT04251871 at www.clinicaltrials.gov ).
Administration, Inhalation ; Adult ; China ; Coronavirus Infections ; diagnosis ; drug therapy ; mortality ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Follow-Up Studies ; Humans ; Integrative Medicine ; Interferon-alpha ; administration & dosage ; Lopinavir ; administration & dosage ; Male ; Middle Aged ; Pandemics ; Pneumonia, Viral ; diagnosis ; drug therapy ; mortality ; Risk Assessment ; Severe Acute Respiratory Syndrome ; diagnosis ; drug therapy ; mortality ; Severity of Illness Index ; Survival Rate

BACKGROUND:Anti-infective ability determine the success or failure of skin grafting. It is one of the commonly used methods to enhance the anti-infective ability of implants by compounding antibacterial materials with scaffolds. OBJECTIVE:To investigate the effect of porous collagen/silk fibroin scaffolds carrying zinc oxide nanoparticles against infection and inflammation, and to evaluate its effect on wound healing. METHODS:Thirty-two Sprague-Dawley rats with a full-thickness wound on the back skin were randomly divided into two groups. In experimental groiup, porous collagen/silk fibroin scaffolds containing zinc oxide nanoparticles were implanted, while only collagen/silk fibroin scaffolds were implanted in control group. Wound healing was compared between the two groups by measuring residual wound area at 1, 2, 4, 8 weeks post implantation. Hematoxylin-eosin and interleukin 6 immumohistochemical staining were performed at 1, 2, 4 weeks post implantation to observe wound morphology and inflammatory reactions. Meanwhile, expression of interleukin 6 and interleukin 1β was detected by real-time PCR. RESULTS AND CONCLUSION:(1) At 2, 4, 8 weeks post implantation, significantly increased healing rate was observed in the experiment group compared with the control group (P<0.05). (2) Findings from the hematoxylin-eosin staining showed that obvious inflammatory cell infiltration was observed in the control group, but less inflammation with vigorous growth of granulation tissues on the wound surface occurred in the experimental group at 1 week after implantation. Then, the wound repair was basically completed in the experimental group presenting with complete and compact epidermal tissue structure, while scar formation with no skin cover was found in the control group at 4 weeks after implantation. (3) Findings from the interleukin 6 immumohistochemical staining showed that there was interleukin 6 positive expression in both two groups to different extents; at 4 weeks after implantation, the expression of interleukin 6 was remarkably reduced in the control group, but it was still a strong positive expression, while week positive expression of interleukin 6 was observed in the experimental group. (4) Compared with the control group, the mRNA expression of interleukin 6 and interleukin 1β was both lower in the experimental group at 1, 2, 4 weeks after implantation, but there was a significant difference between the two groups at 1 and 2 weeks after implantation (P<0.05). Overall, the porous collagen/silk fibroin scaffold carrying zinc oxide nanoparticles can effectively reduce inflammations following skin injury, and accelerate skin wound healing.