5’tiRNA-Pro-TGG,a novel tRNA halve,promotes oncogenesis in sessile serrated lesions and serrated pathway of colorectal cancer

BACKGROUND Transfer RNA(tRNA)-derived small RNAs(tsRNAs)are small fragments that form when tRNAs severe.tRNA halves(tiRNAs),a subcategory of tsRNA,are involved in the oncogenic processes of many tumors.However,their specific role in sessile serrated lesions(SSLs),a precancerous lesion often observed in the colon,has not yet been elucidated.AIM To identify SSL-related tiRNAs and their potential role in the development of SSLs and serrated pathway of colorectal cancer(CRC).METHODS Small-RNA sequencing was conducted in paired SSLs and their adjacent normal control(NC)tissues.The expression levels of five SSL-related tiRNAs were validated by q-polymerase chain reaction.Cell counting kit-8 and wound healing assays were performed to detect cell proliferation and migration.The target genes and sites of tiRNA-1:33-Pro-TGG-1(5′tiRNA-Pro-TGG)were predicted by TargetScan and miRanda algorithms.Metabolism-associated and immune-related pathways were analyzed by single-sample gene set enrichment analysis.Functional analyses were performed to establish the roles of 5′tiRNA-Pro-TGG based on the target genes.RESULTS In total,we found 52 upregulated tsRNAs and 28 downregulated tsRNAs in SSLs compared to NC.The expression levels of tiRNA-1:33-Gly-CCC-2,tiRNA-1:33-Pro-TGG-1,and tiRNA-1:34-Thr-TGT-4-M25′tiRNAs were higher in SSLs than those in NC,while that of 5′tiRNA-Pro-TGG was associated with the size of SSLs.It was demonstrated that 5′tiRNAPro-TGG promoted cell proliferation and migration of RKO cell in vitro.Then,heparanase 2(HPSE2)was identified as a potential target gene of 5′tiRNA-Pro-TGG.Its lower expression was associated with a worse prognosis in CRC.Further,lower expression of HPSE2 was observed in SSLs compared to normal controls or conventional adenomas and in BRAF-mutant CRC compared to BRAF-wild CRC.Bioinformatics analyses revealed that its low expression was associated with a low interferonγresponse and also with many metabolic pathways such as riboflavin,retinol,and cytochrome p450 drug metabolism pathways.CONCLUSION tiRNAs may profoundly impact the development of SSLs.5′tiRNA-Pro-TGG potentially promotes the progression of serrated pathway CRC through metabolic and immune pathways by interacting with HPSE2 and regulating its expression in SSLs and BRAF-mutant CRC.In the future,it may be possible to use tiRNAs as novel biomarkers for early diagnosis of SSLs and as potential therapeutic targets in serrated pathway of CRC.

Novel aspects of tRNA-derived small RNAs with potential impact in infectious diseases

The complete understanding of the growing catalog of regulatory non-coding RNAs is going to shed light in different aspects of a wide range of pathogenic mechanisms in human diseases. This review was aimed to highlight recent advances in the small non- coding RNA world that could have implications in the development of new strategies in medical sciences. Among the diverse group of small non-coding RNAs, we highlight the group of tRNA-derived fragments as molecules known for a long time which have recently emerged as novel regulators influencing several aspects of cell biology. We describe here recent advances in the field of tRNA-derived fragments playing key roles in the biology of some infectious agents, including E. coli, A. fumigatus, G. lamblia, Ascaris, T. cruzi, Virus, Prions and a brief overview linking them to cancer biology. Additionally, we focus on the potential implications of these molecules in future biotechnological applications in the development of new biomarkers and as new therapeutic targets.

The biogenesis and biological roles of tRNA-derived short RNAs

In recent years, next-generation sequencing (NGS) technologies targeting the microRNA (miRNA)transcriptome revealed the existence of tRNA-derived short RNAs: tRNA halves (tiRNAs) and tRNA-derived fragments (tRFs). These small RNAs represent a novel type of small non-coding RNAs (sncRNAs), which are heterogeneous in size, nucleotide composition and biogenesis, and have been suggested to be involved in translation, cell proliferation, priming of viral reverse transcriptases, regulation of gene expression, modulation of the DNA damage response, tumor suppression and neurological disorders. Herein, we review the mechanism of their biogenesis and discuss in detail the regulatory roles they play in cell physiology. We also point out that the biological function of tRNA-derived short RNAs will be understood better as research moves forward, and that this knowledge will find its way into clinical application in the near future.

Go Halves

Have you ever gone halves? You have if you've ever agreed to share half of something with someone. The thing we most often go halves on is expenses. 'Let's go halves and buy a car.' 'No, I'm not interested in buying a car. I'll go halves on dinner, though.'

The Efficacy of In-Phase and Quadrature Demodulation in Electronic Fetal Heart Rate Monitoring During Labor

Objective:To investigate the efficacy of in-phase and quadrature(IQ)demodulation in electronic fetal heart rate monitoring(EFM)to reduce false reports of fetal heart rate(FHR)doubling or halving.Methods:This is a prospective cohort study.A total of 263 full-term pregnant women who delivered at Peking University Shenzhen Hospital between August 2019 and July 2020 were prospectively enrolled in the study.FHR monitoring began when the cervix was dilated to 2-3 cm and continued until delivery.Raw fetal Doppler audio signals and internal and external cardiotocography curves from internal electrode monitoring,EFM with conventional demodulation(external),and EFM with IQ demodulation(external)were acquired to compare FHR doubling and halving time.In cohort 1,FHR was compared between IQ demodulation and conventional demodulation.In cohort 2,FHR was compared between IQ demodulation,conventional demodulation,and internal FHR monitoring.Count data were statistically analyzed using the Chi-squared test,and measurement data were statistically analyzed usingt-test for correlation coefficients,and Bland-Altman analysis for concordance ranges.Results:To compare IQ demodulation and conventional demodulation,225 pregnant women were monitored for a total of 835,870 seconds.The beat-to-beat interval of FHRs in raw fetal Doppler audio signals was used as the reference.The results showed a doubling time of 3401 seconds(0.407%,3401/835,870)and a halving time of 2918 seconds(0.349%,2918/835,870)with conventional demodulation,compared to 241 seconds(0.029%,241/835,870)and 589 seconds(0.070%,589/835,870),respectively,with IQ demodulation.IQ demodulation reduced FHR doubling by approximately 93%(3160/3401)and FHR halving by approximately 80%(2329/2918)compared to conventional demodulation(P<0.01).Conclusion:EFM with IQ demodulation significantly reduces false FHR doubling and halving,with an efficacy similar to that of internal FHR monitoring.

Sensitivity of UK Covid-19 deaths to the timing of suppression measures and their relaxation

In this paper I examine the sensitivity of total UK Covid-19 deaths and the demand for intensive care and ward beds,to the timing and duration of suppression periods during a 500-day period.This is achieved via a SEIR model.Using an expected latent period of 4.5 days and infectious period of 3.8 days,R0 was first estimated as 3.18 using observed death rates under unmitigated spread and then under the effects of the total lockdown(R0-0.60)beginning 23 March.The case fatality rate given infection is taken as 1%.Parameter values for mean length of stay and conditional probability of death for ICU and non-ICU hospital admissions are guided by Ferguson et al.(2020).Under unmitigated spread the model predicts around 600,000 deaths in the UK.Starting with one exposed person at time zero and a suppression consistent with an R0 of 0.60 on day 72,the model predicts around 39,000 deaths for a first wave,but this reduces to around 11,000 if the intervention takes place one week earlier.If the initial suppression were in place until day 200 and then relaxed to an R0 of 1.5 between days 200 and 300,to be followed by a return to an R0 of 0.60,the model predicts around 43,000 deaths.This would increase to around 64,000 if the release from the first suppression takes place 20 days earlier.The results indicate the extreme sensitivity to timing and the consequences of even small delays to suppression and premature relaxation of such measures.

Extensive profiling of the expressions of tRNAs and tRNA-derived fragments(tRFs)reveals the complexities of tRNA and tRF populations in plants

Evidence is emerging that t RNA-derived fragments(t RFs)are regulatory molecules.Studies of t RFs in plants have been based on conventional small RNA sequencing,and focused on profiling of t RF-5 and t RF-3 species.A more comprehensive and quantitative analysis of the entire t RF population is highly necessary.Here,we employ t RNA-seq and YAMAT-seq,and develop a bioinformatics tool to comprehensively profile the expressions of t RNAs and t RFs in plants.We show that in Arabidopsis,approximately half of t RNA genes are extremely weakly expressed,accounting for only 1%of total t RNA abundance,while~12%of t RNA genes contribute to~80%of t RNA abundance.Our t RNA sequencings in various plants reveal that t RNA expression profiles exhibit a cross-species conserved pattern.By characterizing the composition of a highly heterogeneous t RF population,we show that t RNA halves and previously unnoticed 10–16-nt tiny t RFs represent substantial portions.The highly accumulated 13-nt and 16-nt tiny t RFs in Arabidopsis indicate that tiny t RFs are not random t RNA degradation products.Finally,we provide a user-friendly database for displaying the dynamic spatiotemporal expressions of t RNAs and t RFs in the model plants Arabidopsis and rice.

Plant transfer RNA-derived fragments:Biogenesis and functions

Processing of mature transfer RNAs(tRNAs)produces complex populations of tRNA-derived fragments(tRFs).Emerging evidence shows that tRFs have important functions in bacteria,animals,and plants.Here,we review recent advances in understanding plant tRFs,focusing on their biological and cellular functions,such as regulating stress responses,mediating plant-pathogen interactions,and modulating post-transcriptional gene silencing and translation.We also review sequencing strategies and bioinformatics resources for studying tRFs in plants.Finally,we discuss future directions for plant tRF research,which will expand our knowledge of plant non-coding RNAs.