Cells respond to stress by controlling gene expression at several levels, with little known about the role of translation. Here, we demonstrate a coordinated translational stress response system ...involving stress-specific reprogramming of tRNA wobble modifications that leads to selective translation of codon-biased mRNAs representing different classes of critical response proteins. In budding yeast exposed to four oxidants and five alkylating agents, tRNA modification patterns accurately distinguished among chemically similar stressors, with 14 modified ribonucleosides forming the basis for a data-driven model that predicts toxicant chemistry with >80% sensitivity and specificity. tRNA modification subpatterns also distinguish SN1 from SN2 alkylating agents, with SN2-induced increases in m3C in tRNA mechanistically linked to selective translation of threonine-rich membrane proteins from genes enriched with ACC and ACT degenerate codons for threonine. These results establish tRNA modifications as predictive biomarkers of exposure and illustrate a novel regulatory mechanism for translational control of cell stress response.
Evapotranspiration (ET) is an important part of surface–atmosphere interactions, connecting the transfer of matter and energy. Land surface heterogeneity is a natural attribute of the Earth’s surface ...and is an inevitable problem in calculating ET with coarse resolution remote sensing data, which results in significant error in the ET estimation. This study aims to explore the effect and applicability of the evaporative fraction and area fraction (EFAF) method for correcting 1 km coarse resolution ET. In this study we use the input parameter upscaling (IPUS) algorithm to estimate energy fluxes and the EFAF method to correct ET estimates. Five ground stations in the midstream and downstream regions of the Heihe River Basin (HRB) were used to validate the latent heat flux (LE) calculated by the IPUS algorithm and EFAF method. The evaluation results show that the performance of the EFAF method is superior to that of the IPUS algorithm, with the coefficient of determination (R2) increasing, the root mean square error (RMSE) decreasing, and the mean bias error (MBE) decreasing by 17 W/m2 on average. In general, the EFAF method is suitable for correcting the deviation in LE estimated based on Sentinel data caused by land surface heterogeneity and can be applied to obtain accurate estimates of ET.
Toxoplasma gondii is a highly successful protozoan parasite that infects all warm-blooded animals and causes severe disease in immunocompromised and immune-naïve humans. It has an unusual global ...population structure: In North America and Europe, isolated strains fall predominantly into four largely clonal lineages, but in South America there is great genetic diversity and the North American clonal lineages are rarely found. Genetic variation between Toxoplasma strains determines differences in virulence, modulation of host-signaling pathways, growth, dissemination, and disease severity in mice and likely in humans. Most studies on Toxoplasma genetic variation have focused on either a few loci in many strains or low-resolution genome analysis of three clonal lineages. We use whole-genome sequencing to identify a large number of SNPs between 10 Toxoplasma strains from Europe and North and South America. These were used to identify haplotype blocks (genomic regions) shared between strains and construct a Toxoplasma haplotype map. Additional SNP analysis of RNA-sequencing data of 26 Toxoplasma strains, representing global diversity, allowed us to construct a comprehensive genealogy for Toxoplasma gondii that incorporates sexual recombination. These data show that most current isolates are recent recombinants and cannot be easily grouped into a limited number of haplogroups. A complex picture emerges in which some genomic regions have not been recently exchanged between any strains, and others recently spread from one strain to many others.
With the great progress made recently in next generation sequencing (NGS) technology, sequencing accuracy and throughput have increased, while the cost for data has decreased. Various human leukocyte ...antigen (HLA) typing algorithms and assays have been developed and have begun to be used in clinical practice. In this study, we compared the HLA typing performance of three HLA assays and seven NGS-based HLA algorithms and assessed the impact of sequencing depth and length on HLA typing accuracy based on 24 benchmarked samples. The algorithms HISAT-genotype and HLA-HD showed the highest accuracy at both the first field and the second field resolution, followed by HLAscan. Our internal capture-based HLA assay showed comparable performance with whole exome sequencing (WES). We found that the minimal depth was 100X for HISAT-genotype and HLA-HD to obtain more than 90% accuracy at the third field level. The top three algorithms were quite robust to the change of read length. Thus, we recommend using HISAT-genotype and HLA-HD for NGS-based HLA genotyping because of their higher accuracy and robustness to read length. We propose that a minimal sequence depth for obtaining more than 90% HLA typing accuracy at the third field level is 100X. Besides, targeting capture-based NGS HLA typing may be more suitable than WES in clinical practice due to its lower sequencing cost and higher HLA sequencing depth.
The characteristics of head and neck squamous cell carcinoma (HNSCC) across different anatomic sites in the Chinese population have not been studied. To determine the genomic abnormalities underlying ...HNSCC across different anatomic sites, the alterations of selected cancer-related genes were evaluated.
Genomic DNA samples obtained from formalin-fixed, paraffin-embedded tissues were analyzed using targeted sequencing in a panel of 383 cancer-related genes to determine the genomic alterations.
A total of 317 formalin-fixed, paraffin-embedded HNSCC specimens were collected, and a total of 2,156 protein-coding mutations, including 1,864 single nucleotide variants and 292 insertions and deletions, were identified across more than six different anatomic sites. Mutation loads were distinct across the anatomic sites. Larynx carcinoma was found with the highest mutation loads, whereas nasopharynx carcinoma showed the lowest mutation loads. A total of 1,110 gains and 775 losses were identified in the 317 specimens. Patients who had at least one clinically actionable alteration (levels 1-4 in OncoKB) were identified. One patient had an actionable alteration with level 1 evidence in OncoKB,
-
fusion, who may benefit from larotrectinib or entrectinib treatment.
The genomic profiling of HNSCC using targeted sequencing can identify rational therapeutic candidate genes suitable for the treatment of the HNSCCs.
The identification of indeterminate pulmonary nodules (IPNs) following a low-dose computed tomography (LDCT) is a major challenge for early diagnosis of lung cancer. The inadequate assessment of ...IPNs' malignancy risk results in a large number of unnecessary surgeries or an increased risk of cancer metastases. However, limited studies on non-invasive diagnosis of IPNs have been reported.
In this study, we identified and evaluated the diagnostic value of circulating small extracellular vesicle (sEV) microRNAs (miRNAs) in patients with IPNs that had been newly detected using LDCT scanning and were scheduled for surgery. Out of 459 recruited patients, 109 eligible patients with IPNs were enrolled in the training cohort (n = 47) and the test cohort (n = 62). An external cohort (n = 99) was used for validation. MiRNAs were extracted from plasma sEVs, and assessed using Small RNA sequencing. 490 lung adenocarcinoma samples and follow-up data were used to investigate the role of miRNAs in overall survival.
A circulating sEV miRNA (CirsEV-miR) model was constructed from five differentially expressed miRNAs (DEMs), showing 0.920 AUC in the training cohort (n = 47), and further identified in the test cohort (n = 62) and in an external validation cohort (n = 99). Among five DEMs of the CirsEV-miR model, miR-101-3p and miR-150-5p were significantly associated with better overall survival (p = 0.0001 and p = 0.0069). The CirsEV-miR scores were calculated, which significantly correlated with IPNs diameters (p < 0.05), and were able to discriminate between benign and malignant PNs (diameter ≤ 1 cm). The expression patterns of sEV miRNAs in the benign, adenocarcinoma in situ/minimally invasive adenocarcinoma, and invasive adenocarcinoma subgroups were found to gradually change with the increase in aggressiveness for the first time. Among all DEMs of the three subgroups, five miRNAs (miR-30c-5p, miR-30e-5p, miR-500a-3p, miR-125a-5p, and miR-99a-5p) were also significantly associated with overall survival of lung adenocarcinoma patients.
Our results indicate that the CirsEV-miR model could help distinguish between benign and malignant PNs, providing insights into the feasibility of circulating sEV miRNAs in diagnostic biomarker development.
Chinese Clinical Trials: ChiCTR1800019877. Registered 05 December 2018, https://www.chictr.org.cn/showproj.aspx?proj=31346 .
Objective
The role of tumor-infiltrating lymphocytes (TILs) has not yet been characterized in sarcomas. The aim of this bioinformatics study was to explore the effect of TILs on sarcoma survival and ...genome alterations.
Methods
Whole-exome sequencing, transcriptome sequencing, and survival data of sarcoma were obtained from The Cancer Genome Atlas. Immune infiltration scores were calculated using the Tumor Immune Estimation Resource. Potential associations between abundance of infiltrating TILs and survival or genome alterations were examined.
Results
Levels of CD4+ T cell infiltration were associated with overall survival of patients with pan-sarcomas, and higher CD4+ T cell infiltration levels were associated with better survival. Somatic copy number alterations, rather than mutations, were found to correlate with CD4+ T cell infiltration levels.
Conclusions
This data mining study indicated that CD4+ T cell infiltration levels predicted from RNA sequencing could predict sarcoma prognosis, and higher levels of CD4+ T cells infiltration indicated a better chance of survival.
Indoxacarb is an important insecticide for the selective control of Helicoverpa armigera. It can be bioactivated to the more effective N-decarbomethoxylated indoxacarb (DCJW) by esterases in pests. ...It was observed that both field and laboratory selected populations of H. armigera showed negative cross-resistance between indoxacarb and methoxyfenozide. The Handan population exhibited moderate resistance to indoxacarb, but was susceptible to methoxyfenozide; the Baoding and Yishui populations exhibited moderate resistance to methoxyfenozide, but they were susceptible to indoxacarb. Moreover, the toxicity of indoxacarb was enhanced 1.83-fold in the laboratory methoxyfenozide-resistant H. armigera, and susceptibility to methoxyfenozide was increased 2.81-fold in the laboratory indoxacarb-resistant H. armigera. In vivo, DCJW concentrations in the susceptible and methoxyfenozide-selected (laboratory methoxyfenozide-resistant) populations were 4.59- and 4.31-fold greater than in the indoxacarb-resistant Handan population 1 h after dosing. After 2 h, the highest concentrations of DCJW and indoxacarb appeared in the methoxyfenozide-selected population. Meanwhile, increased carboxyl esterase (CarE) and decreased glutathione S-transferase (GST) activities were observed in the methoxyfenozide-selected population. However, the indoxacarb-selected (laboratory indoxacarb-resistant) and Handan populations showed a higher disappearance of indoxacarb and DCJW, and the activity of cytochrome P450 mono-oxygenase in these populations were significantly increased. This study showed that the improved toxicity of indoxacarb, as observed in the methoxyfenozide-selected H. armigera, was correlated with increased CarE activity, decreased GST activity, and the in vivo accumulation of indoxacarb and DCJW. The significantly increased cytochrome P450 activity and higher disappearance of indoxacarb and DCJW in indoxacarb-resistant H. armigera resulted in the decreased toxicity of indoxacarb.
Gallbladder carcinoma (GBC) is a lethal biliary tract malignant neoplasm. Patient-derived primary cancer cell lines (PDPCs) are appropriate models to explore biological characteristics and potential ...therapeutics; however, there is a lack of PDPCs in GBC. In this study, we aimed to establish and characterize the GBC PDPCs, and further investigated the intra-tumor heterogeneity (ITH). Multi-region sampling (3–9 regions) of the operable tumor tissue samples was used to establish PDPCs. Short tandem repeat genotyping for cell authentication and karyotyping was performed, followed by whole-exome sequencing and RNA sequencing to assess the ITH at the genetic and transcriptional levels, respectively. Thirty-eight PDPCs were successfully established from seven GBC patients and characterized. ITH was observed with a median of 38.3% mutations being heterogeneous (range, 26.6–59.4%) across all patients. Similar with other tumor types,
TP53
mutations were always truncal. In addition, there were three genes,
KMT2C
,
CDKN2A
, and
ARID1A
, with truncal mutations in at least two patients. A median of 370 differentially expressed genes (DEGs) was identified per patient. Distinct expression patterns were observed between major histocompatibility complex (MHC) class I and II genes. We found the expression of MHC class II genes in the PDPC samples was closely regulated by
CIITA
, while that of MHC class I genes were not correlated with
CIITA
expression. The PDPCs established from GBC patients can serve as novel in vitro models to identify the ITH, which may pave a crucial molecular foundation for enhanced understanding of tumorigenesis and progression.
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