DNA-PKcs suppresses illegitimate chromosome rearrangements.

Two DNA repair pathways, non-homologous end joining (NHEJ) and alternative end joining (A-EJ), are involved in V(D)J recombination and chromosome translocation. Previous studies reported distinct repair mechanisms for chromosome translocation, with NHEJ involved in humans and A-EJ in mice predominantly. NHEJ depends on DNA-PKcs, a critical partner in synapsis formation and downstream component activation. While DNA-PKcs inhibition promotes chromosome translocations harboring microhomologies in mice, its synonymous effect in humans is not known. We find partial DNA-PKcs inhibition in human cells leads to increased translocations and the continued involvement of a dampened NHEJ. In contrast, complete DNA-PKcs inhibition substantially increased microhomology-mediated end joining (MMEJ), thus bridging the two different translocation mechanisms between human and mice. Similar to a previous study on Ku70 deletion, DNA-PKcs deletion in G1/G0-phase mouse progenitor B cell lines, significantly impairs V(D)J recombination and generated higher rates of translocations as a consequence of dysregulated coding and signal end joining. Genetic DNA-PKcs inhibition suppresses NHEJ entirely, with repair phenotypically resembling Ku70-deficient A-EJ. In contrast, we find DNA-PKcs necessary in generating the near-exclusive MMEJ associated with Lig4 deficiency. Our study underscores DNA-PKcs in suppressing illegitimate chromosome rearrangement while also contributing to MMEJ in both species.

Research progress in nano-drug delivery systems based on the characteristics of the liver cancer microenvironment.

The liver cancer has microenvironmental features such as low pH, M2 tumor-associated macrophage enrichment, low oxygen, rich blood supply and susceptibility to hematotropic metastasis, high chemokine expression, enzyme overexpression, high redox level, and strong immunosuppression, which not only promotes the progression of the disease, but also seriously affects the clinical effectiveness of traditional therapeutic approaches. However, nanotechnology, due to its unique advantages of size effect and functionalized modifiability, can be utilized to develop various responsive nano-drug delivery system (NDDS) by using these characteristic signals of the liver cancer microenvironment as a source of stimulation, which in turn can realize the intelligent release of the drug under the specific microenvironment, and significantly increase the concentration of the drug at the target site. Therefore, researchers have designed a series of stimuli-responsive NDDS based on the characteristics of the liver cancer microenvironment, such as hypoxia, weak acidity, and abnormal expression of proteases, and they have been widely investigated for improving anti-tumor therapeutic efficacy and reducing the related side effects. This paper provides a review of the current application and progress of NDDS developed based on the response and regulation of the microenvironment in the treatment of liver cancer, compares the effects of the microenvironment and the NDDS, and provides a reference for building more advanced NDDS.

Increased AID Results in Mutations at the CRLF2 Locus Implicated in Latin American ALL Health Disparities.

Activation-induced cytidine deaminase (AID) is a B cell-specific base editor required during class switch recombination and somatic hypermutation for B cell maturation and antibody diversification. However, it has also been implicated as a factor in the etiology of several B cell malignancies. Evaluating the AID-induced mutation load in patients at-risk for certain types of blood cancers is critical in assessing disease severity and treatment options. Here, we have developed a digital PCR (dPCR) assay that allows us to track the mutational landscape resulting from AID modification or DNA double-strand break (DSB) formation and repair at sites known to be prone to DSBs. Implementation of this new assay showed that increased AID levels in immature B cells increases genome instability at loci linked to translocation formation. This included the CRLF2 locus that is often involved in chromosomal translocations associated with a subtype of acute lymphoblastic leukemia (ALL) that disproportionately affects Latin Americans (LAs). To support this LA-specific identification of AID mutation signatures, we characterized DNA from immature B cells isolated from the bone marrow of ALL patients. Our ability to detect and quantify these mutation signatures will potentiate future risk identification, early detection of cancers, and reduction of associated cancer health disparities.

Shifted PAMs generate DNA overhangs and enhance SpCas9 post-catalytic complex dissociation.

Using Sanger sequencing and high-throughput genome sequencing of DNA cleavage reactions, we find that the Streptococcus pyogenes SpCas9 complex responds to internal mechanical strain by robustly generating a distribution of overhanging, rather than blunt, DNA ends. Internal mechanical strain is generated by shifting (increasing or decreasing) the spacing between the RNA-DNA hybrid and the downstream canonical PAM. Up to 2-base 3' overhangs can be robustly generated via a 2-base increase in the distance between hybrid and PAM. We also use single-molecule experiments to reconstruct the full course of the CRISPR-SpCas9 reaction in real-time, structurally and kinetically monitoring and quantifying R-loop formation, the first and second DNA-incision events, and dissociation of the post-catalytic complex. Complex dissociation and release of broken DNA ends is a rate-limiting step of the reaction, and shifted SpCas9 is sufficiently destabilized so as to rapidly dissociate after formation of broken DNA ends.

Environmental concentrations of anionic surfactants in lake surface microlayers enhance the toxicity of Microcystis blooms: Insight from photosynthesis, interspecies competition, and MC production.

Anionic surfactants represented by linear alkylbenzene sulfonate (LAS) exhibit vertical heterogeneity of concentrations in aquatic environments owing to their amphiphilic structure. Field investigations showed that the concentration of anionic surfactants (mainly LAS) in the water surface microlayer (SML) of Lake Taihu reached 580 µg/L, higher than that in the lower layer. Floating Microcystis blooms overlap in space with the high concentration of anionic surfactants in SML. However, few studies have focused on the effects of anionic surfactants (e.g., LAS) on the interspecies competition between toxic and nontoxic Microcystis. In this study, coculture and monoculture experiments were conducted with both toxic and nontoxic Microcystis species to explore how the environmental concentration of LAS regulates the dominance of toxic Microcystis and toxicity from the perspective of photosynthesis, species dominance, and MC production. The results showed that LAS concentrations above 0.267 or 0.431 mg/L (depending on light conditions) selectively promoted the photosynthetic competitive advantage of toxic Microcystis, leading to its higher population proportion in the community. Additionally, LAS concentrations above 0.5 mg/L induced the synthesis and release of microcystins (MCs). The results of chlorophyll fluorescence analysis, electron microscopy and transcriptome sequencing suggested that compared with nontoxic Microcystis, toxic Microcystis can better resist LAS stress by dissipating excess light, maintaining an intact membrane structure and maintaining cellular homeostasis. Transcriptome sequencing revealed that the photosynthetic damage of nontoxic Microcystis might be attributed to the impacts of LAS on the absorption and assimilation of nitrogen, which finally resulted in the degradation of phycobilisomes. This study can provide novel insight for establishing standards and safety management of wastewater discharge.

Adsorption characteristics and mechanism of ammonia nitrogen and phosphate from biogas slurry by Ca2+-modified soybean straw biochar.

The utilization of biogas slurry is critical for the sustainable development of animal husbandry. Biomass carbon adsorption is a feasible method for the recycling of nutrients from biogas slurry. However, research on the co-adsorption of ammonia nitrogen and phosphate is scarce. Herein, soybean straw was utilized as the raw material to prepare Ca2+-modified biochar (CaSSB), which was investigated for its ammonia nitrogen and phosphate adsorption mechanisms. Compared with natural biochar (SSB), CaSSB possesses a high H/C ratio, larger surface area, high porosity and various functional groups. Ca2+-modified soybean straw biochar exhibited excellent adsorption performance for NH4+-N (103.18 mg/g) and PO43--P (9.75 mg/g) at pH = 6, using an adsorbent dosage of 2 g/L. The experimental adsorption data of ammonia nitrogen by CaSSB corresponded to pseudo-second-order kinetics and the Langmuir isotherm model, suggesting that the adsorption process was homogeneous and that electrostatic attraction might be the primary adsorption mechanism. Meanwhile, the adsorption of phosphate conformed to pseudo-second-order kinetics and the Langmuir-Freundlich model, whose mechanism might be attributed to ligand exchange and chemical precipitation. These results reveal the potential of CaSSBs as a cost-effective, efficient adsorbent for the recovery of ammonium and phosphate from biogas slurry.

Comprehensive Mutation Profiling of Colorectal Cancer Patients With Lung or Liver Metastasis by Targeted Next-Generation Sequencing.

OBJECTIVES: Primary tumor tissue is often analyzed to search for predictive biomarkers and DNA-guided personalized therapies, but there is an incomplete understanding of the discrepancies in the genomic profiles between primary tumors and metastases, such as liver and lung metastases. METHODS: We performed in-depth targeted next-generation sequencing of 520 key cancer-associated genes for 47 matched primary and metastatic tumor samples which were retrospectively collected. RESULTS: A total of 699 mutations were detected in the 47 samples. The coincidence rate of primary tumors and metastases was 51.8% (n = 362), and compared to patients with liver metastases, patients with lung metastases had a significantly greater coincidence rate (P = .021). The number of specific mutations for the primary tumors and liver and lung metastases was 186 (26.6%), 122 (17.5%), and 29 (4.1%), respectively. Analysis of a patient with all three occurrences, including a primary tumor, liver metastasis, and lung metastasis, indicated a possible polyclonal seeding mechanism for liver metastases. Remarkably, multiple samples from patients with primary and metastatic tumors supported a mechanism of synchronous parallel dissemination from primary tumors to metastatic tumors that were not mediated through pre-metastatic tumors. We also found that the PI3K-Akt signaling pathway significantly altered lung metastases compared to matched primary tumors (P = .001). In addition, patients with mutations in CTCF, PIK3CA, or TP53 and LRP1B, AURKA, FGFR1, ATRX, DNMT3B, or GNAS had larger primary tumor sizes and metastases, especially patients with both LRP1B and AURKA mutations. Interestingly, CRC patients with TP53-disruptive mutations were more likely to have liver metastases (P = .016). CONCLUSION: In this study, we demonstrate significant differences in the genomic landscapes of colorectal cancer patients based on the site of metastasis. Notably, we observe a larger genomic variation between primary tumors and liver metastasis compared to primary tumors and lung metastasis. These findings can be used for tailoring treatments based on the specific metastatic site.

Quantitative proteomics profiling reveals the inhibition of trastuzumab antitumor efficacy by phosphorylated RPS6 in gastric carcinoma.

BACKGROUND: The anti-HER2 antibody trastuzumab is a standard treatment for gastric carcinoma with HER2 overexpression, but not all patients benefit from treatment with HER2-targeted therapies due to intrinsic and acquired resistance. Thus, more precise predictors for selecting patients to receive trastuzumab therapy are urgently needed. METHODS: We applied mass spectrometry-based proteomic analysis to 38 HER2-positive gastric tumor biopsies from 19 patients pretreated with trastuzumab (responders n = 10; nonresponders, n = 9) to identify factors that may influence innate sensitivity or resistance to trastuzumab therapy and validated the results in tumor cells and patient samples. RESULTS: Statistical analyses revealed significantly lower phosphorylated ribosomal S6 (p-RPS6) levels in responders than nonresponders, and this downregulation was associated with a durable response and better overall survival after anti-HER2 therapy. High p-RPS6 levels could trigger AKT/mTOR/RPS6 signaling and inhibit trastuzumab antitumor efficacy in nonresponders. We demonstrated that RPS6 phosphorylation inhibitors in combination with trastuzumab effectively suppressed HER2-positive GC cell survival through the inhibition of the AKT/mTOR/RPS6 axis. CONCLUSIONS: Our findings provide for the first time a detailed proteomics profile of current protein alterations in patients before anti-HER2 therapy and present a novel and optimal predictor for the response to trastuzumab treatment. HER2-positive GC patients with low expression of p-RPS6 are more likely to benefit from trastuzumab therapy than those with high expression. However, those with high expression of p-RPS6 may benefit from trastuzumab in combination with RPS6 phosphorylation inhibitors.

Cyanobacterial organic matter (COM) positive feedback aggravates lake eutrophication by changing the phosphorus release characteristics of sediments.

Phosphorus is a key nutrient that causes eutrophication in lakes. Our investigation of 11 eutrophic lakes found that the concentrations of soluble reactive phosphorus (SRP) in the water column and EPC0 in sediments decreased with aggravated eutrophication. There was a significant negative correlation between the SRP concentrations and eutrophication parameters such as chlorophyll a (Chl-a), total phosphorus (TP) and algal biomass (P < 0.001). In addition, SRP concentrations were significantly affected by EPC0 (P < 0.001), while EPC0 was significantly affected by the content of cyanobacterial organic matter (COM) in sediments (P < 0.001). Based on these findings, we hypothesized that COM can alter the phosphorus release characteristics of sediments, including the phosphorus adsorption parameters of sediment (PAPS) and the phosphorus release rate of sediment (PRRS), thereby stabilizing SRP concentrations at lower levels and rapidly replenishing them when depleted by phytoplankton, which in turn benefits cyanobacteria due to their low SRP adaptation strategies. Simulation experiments were conducted to confirm this hypothesis by adding higher plant OM and COM to sediments. The results showed that all types of OM could significantly increase the maximum phosphorus adsorption capacity (Qmax), but only COM could reduce sediment EPC0 and promote PRRS (P < 0.001). Changes in these parameters (i.e., Qmax, EPC0, and PRRS) resulted in a larger SRP adsorption quantity and faster SRP release rate at low SRP concentrations. This promotes the competitive edge of cyanobacteria due to they have a higher affinity for phosphorus than other algae. As an important component of cyanobacteria, EPS can change the phosphorus release characteristics (i.e., PAPS and PRRS) by reducing sediment particle size and increasing sediment surface functional groups. This study revealed the positive feedback effect of COM accumulation in sediments on lake eutrophication from the perspective of phosphorus release characteristics of sediments, which provides a basic reference for the risk assessment of lake eutrophication.

Integrating network pharmacology and pharmacological evaluation to reveal the therapeutic effects and potential mechanism of S-allylmercapto-N-acetylcysteine on acute respiratory distress syndrome.

In this research, we sought to examine the effectiveness of S-allylmercapto-N-acetylcysteine (ASSNAC) on LPS-provoked acute respiratory distress syndrome (ARDS) and its potential mechanism based on network pharmacology. To incorporate the effective targets of ASSNAC against ARDS, we firstly searched DisGeNET, TTD, GeneCards and OMIM databases. Then we used String database and Cytoscape program to create the protein-protein interaction network. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis both identified the potential pathways connected to genes. Cytoscape software was used to build the network of drug-targets-pathways and the SwissDock platform was applied to dock the molecule of ASSNAC with the key disease targets. Correspondingly, an ARDS model was established by instillation of LPS in mice to confirm the underlying action mechanism of ASSNAC on ARDS as indicated by the network pharmacology analysis. Results exhibited that 27 overlapping targets, including TLR4, ICAM1, HIF1A, MAPK1, NFKB1, and others, were filtered out. The in vivo experiments showed that ASSNAC alleviated LPS-induced lung injury by downregulating levels of pro-inflammatory mediators and lung dry-wet ratio. Also, ASSNAC attenuated oxidative stress evoked by LPS via diminishing MDA production and SOD consumption as well as upregulating HO-1 level through Nrf2 activation. Results from western blot, quantitative real-time PCR and immunohistochemistry suggested that ASSNAC developed its therapeutic effects by regulating TLR4/MyD88/NF-κB signaling pathway. In conclusion, our research presented the efficacy of ASSNAC against ARDS. Furthermore, the mechanism of ASSNAC on ARDS was clarified by combining network pharmacology prediction with experimental confirmation.

A combined diagnostic model based on circulating tumor cell in patients with solitary pulmonary nodules.

BACKGROUND: Although many prediction models in diagnosis of solitary pulmonary nodules (SPNs) have been developed, few are widely used in clinical practice. It is therefore imperative to identify novel biomarkers and prediction models supporting early diagnosis of SPNs. This study combined folate receptor-positive circulating tumor cells (FR+ CTC) with serum tumor biomarkers, patient demographics and clinical characteristics to develop a prediction model. METHODS: A total of 898 patients with a solitary pulmonary nodule who received FR+ CTC detection were randomly assigned to a training set and a validation set in a 2:1 ratio. Multivariate logistic regression was used to establish a diagnostic model to differentiate malignant and benign nodules. The receiver operating curve (ROC) and the area under the curve (AUC) were calculated to assess the diagnostic efficiency of the model. RESULTS: The positive rate of FR+ CTC between patients with non-small cell lung cancer (NSCLC) and benign lung disease was significantly different in both the training and the validation dataset (p < 0.001). The FR+ CTC level was significantly higher in the NSCLC group compared with that of the benign group (p < 0.001). FR+ CTC (odds ratio, OR, 95% confidence interval, CI: 1.13, 1.07-1.19, p < 0.0001), age (OR, 95% CI: 1.06, 1.01-1.12, p = 0.03) and sex (OR, 95% CI: 1.07, 1.01-1.13, p = 0.01) were independent risk factors of NSCLC in patients with a solitary pulmonary nodule. The area under the curve (AUC) of FR+ CTC in diagnosing NSCLC was 0.650 (95% CI, 0.587-0.713) in the training set and 0.700 (95% CI, 0.603-0.796) in the validation set, respectively. The AUC of the combined model was 0.725 (95% CI, 0.659-0.791) in the training set and 0.828 (95% CI, 0.754-0.902) in the validation set, respectively. CONCLUSIONS: We confirmed the value of FR+ CTC in diagnosing SPNs and developed a prediction model based on FR+ CTC, demographic characteristics, and serum biomarkers for differential diagnosis of solitary pulmonary nodules.

Traditional uses, chemical composition, and pharmacological effects of diaphragma juglandis fructus: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: In traditional Uyghur medicine, diaphragma juglandis fructus (DJF) has been conventionally used in treating insomnia and nourishing the kidneys. According to traditional Chinese medicine, DJF can boosts kidney and astringent essence, strengthen the spleen and kidney, exert diuretic effect, clear heat, stop eructation, and treat vomiting. AIM OF THE REVIEW: Research on DJF has increased gradually in recent years, but reviews of its traditional uses, chemical composition, and pharmacological activities are scarce. The purpose of this review is to analyze the traditional uses, chemical composition, and pharmacological activities of DJF and provide an overview of the findings for further research and development of DJF resources. MATERIALS AND METHODS: Data on DJF were obtained from different databases, including Scifinder, PubMed, Web of Science, Science Direct, Springer, Wiley, ACS, CNKI, Baidu Scholar, and Google Scholar; books; and Ph.D. and MSc theses. RESULTS: According to traditional Chinese medicine, DJF has astringent properties, inhibits bleeding and banding, strengthens the spleen and kidneys, acts as a sleeping aid by reducing anxiety, and relieves dysentery due to heat exposure. The components of DJF include flavonoids, phenolic acids, quinones, steroids, lignans, and volatile oils, which exhibit good antioxidant, antitumor, antidiabetic, antibacterial, anti-inflammatory, and sedative-hypnotic properties, and present therapeutic potential for kidney diseases. CONCLUSIONS: Based on its traditional use, chemical composition, and pharmacological activities, DJF is a promising source of natural medicine in the development of functional foods, drugs, and cosmetics.

Metabolomic analysis and antibacterial and antioxidant activities of three species of Artemisia plants in Tibet.

BACKGROUND: Artemisia is important medicinal plants in China and are widely used in medicine, agriculture, and food. Pharmacologically active components of the plants remain to be investigated. METHODS: This study sought to identify and compare the chemical constituents of three species of Artemisia in Tibet using a widely-targeted metabolomics approach and their antibacterial and antioxidant capacities were determined. RESULT: A total of 1109 metabolites within 10 categories were detected from the three species of Artemisia, including lipids, amino acids, nucleotides, flavonoids, terpenes, coumarins, organic acids, and phenolic acids. 732 different metabolites have been identified between Artemisia sieversiana and Artemisia annua, 751 different metabolites were identified between Artemisia wellbyi and A. sieversiana, and 768 differential metabolites were differentially detected from A. wellbyi and A. annua. Differentially identified compounds included flavonoids, phenolic acids, artemisinins and coumarin. A. annua contained the highest relative content of artemisinin among three Artemisia. The antimicrobial experiments showed that the three Artemisia species had strong antibiotic activities against Bacillus subtilis, Escherichia coli, Staphylococcus aureus, Proteus mirabilis and Pseudomonas aeruginosa. The biochemical analysis showed that the three species of Artemisia have strong antioxidant capacity. CONCLUSIONS: This is the first reported attempt to comparatively determine the types of the metabolites of the three widely distributed Artemisia species in Tibet. The information should help medicinal research and facilitate comprehensive development and utilization of Artemisia species in Tibet.

[Determination of trace perfluorinated compounds in environmental water samples by dispersive solid- phase extraction-high performance liquid chromatography-tandem mass spectrometry using carbon nanotube composite materials].

In this work, carbon nanotubes (CNTs) on silica rod (SiO2) composite materials were prepared to extract six perfluorinated compounds (PFCs) in real environmental water samples by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The as-synthesized sorbents, hereafter referred to as CNT@SiO2, were employed for dispersive solid-phase extraction (d-SPE). Perfluoroheptanoic acid (PFHpA), perfluorohexane sulfonate (PFHxS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorooctane sulfonate (PFOS), and perfluorodecanoic acid (PFDA) were selected as target analytes. The main extraction parameters were systematically optimized using the single-factor optimization method. The optimum adsorption parameters were as follows: adsorption time of 30 min, sorbent amount of 10 mg, pH 6 and NaCl concentration of 1.7 mol/L for sample solution, and 4 mL acetone as desorption solvent, desorption for 4 min. LC-triple quadrupole MS was conducted to quantify the selected PFCs in water samples. The mobile phase was 5 mmol/L ammonium acetate and methanol, the flow rate was set to 0.4 mL/min, the column temperature was set to 40 ℃, and the injection volume was 5.0 µL. The chromatographic separation system was equipped with a Kinetex C18 column (100 mm×2.1 mm, 1.7 µm). The mass spectrometer was operated with negative electrospray ionization in multi-reaction monitoring mode. CNT@SiO2 was prepared in five batches and used as the d-SPE sorbent, and the relative standard deviations (RSDs) of the PFC recoveries among these five batches ranged from 4.9% to 9.3%. The reusability of the CNT@SiO2 sorbent was assessed. After eight d-SPE cycles using the same sorbent, the RSDs of the PFC recoveries were 3.7%-8.2%. These results indicated that the sorbent had good stability and reusability for d-SPE. Excellent results were achieved under optimal extraction conditions. The method validation results indicated that the linear ranges were 0.4-1000 ng/L for PFNA, PFOS, and PFDA, 0.9-1000 ng/L for PFHpA, 0.7-1000 ng/L for PFHxS, and 0.6-1000 ng/L for PFOA. The correlation coefficients were 0.973-0.997. The limit of detection (LOD) and limit of quantification of the method were 0.10-0.26 ng/L and 0.33-0.87 ng/L, respectively. At 20 ng/L, the RSDs of the intra- and inter-day precisions were 2.73%-7.75% and 3.38%-8.21%, respectively. At 100 ng/L, the RSDs of the intra- and inter-day precisions were 2.95%-8.46% and 4.16%-9.14%, respectively. Finally, at 500 ng/L, the RSDs of the intra- and inter-day precisions were 2.51%-7.48% and 3.59%-9.63%, respectively. The developed method was applied to analyze six PFCs in tap water, barreled drinking water, and river water samples. PFOA and PFOS were determined in tap water at mass concentrations of 5.6 and 8.7 ng/L, respectively. No PFCs were found in barreled drinking water and river water. Satisfactory recoveries of 72.1%-109.6% at low, middle, and high spiking levels were also obtained. In conclusion, the d-SPE-LC-MS/MS method based on CNT@SiO2 composite sorbents is accurate and sensitive. The results of this study demonstrate that CNT@SiO2 is a good choice for the rapid and effective determination of PFCs from water samples. Further exploration of the use of CNT@SiO2 sorbents for the extraction and determination of trace organic pollutions in environmental samples is in progress.

Activation of long-non-coding RNA NEAT1 sponging microRNA-147 inhibits radiation damage by targeting PDPK1 in troxerutin radioprotection.

A better understanding of the molecular mechanism involving the lncRNA-miRNA-mRNA network underlying radiation damage can be beneficial for radioprotection. This study was designed to investigate the potential role of lncRNA NEAT1, miR-147 and Phosphoinositide Dependent Protein Kinase 1 (PDPK1) interaction in radioprotection by troxerutin (TRT). We first demonstrated that NEAT1 sponged miR-147, and PDPK1 mRNA was the primary target of miR-147. In the cells, the NEAT1 and PDPK1 levels were downregulated after the radiation but increased after the treatment with TRT. The miR-147 level was significantly induced by radiation and inhibited by TRT. NEAT1 negatively regulated the expression of miR-147, whereas miR-47 targeted PDPK1 to downregulate its expression. In radioprotection, TRT effectively upregulated NEAT1 to inhibit miR-147 and to upregulate PDPK1. We concluded that TRT could promote radioprotection by stimulating NEAT1 to upregulate PDPK1 expression by suppressing miR-147. NEAT1 could be a critical therapeutic target of radiation damage.

Geosmin disrupts energy metabolism and locomotor behavior of zebrafish in early life stages.

Geosmin has been commonly detected both in various aquatic environments and biota, but its exact toxicological mechanisms to organisms need further experimentation. In the present study, zebrafish embryos were exposed to geosmin at nominal concentrations of 50, 500 and 5000 ng/L for 120 h post-fertilization (hpf), followed by locomotor activity and biochemical parameter examination, and multi-omics investigation of the transcriptome and metabolome. The results showed that geosmin exposure significantly reduced the mitochondrial electron transport chain (ETC) complexes I-V, ATP content and mitochondrial respiration and suppressed the locomotor behavior of zebrafish larvae. Transcriptomics analysis revealed that the transcripts of genes involved in oxidative phosphorylation, glycolysis, and lipid metabolism were significantly affected, indicating that geosmin disrupts energy metabolism. Furthermore, metabolomics results showed that 3 classes of lipids, namely glycerophospholipids (GPs), sphingolipids (SLs) and fatty acyls (FAs) were significantly decreased after geosmin exposure. This study provides novel insight into the underlying mechanisms of geosmin-induced energy metabolism and highlights the need for concern about geosmin exposure.

Genomic and clinicopathological features of lung adenocarcinomas with micropapillary component.

Background: Lung adenocarcinoma (LA) with a micropapillary component (LAMPC) is a histological subtype of lung cancer that has received increasing attention due to its correlation with poor prognosis, and its tendency to recur and metastasize. At present, comprehensive genomic profiles and clinicopathological features for LAMPC remain unclear and require further investigation. Methods: From September 2009 to October 2020, a total of 465 LAMPC patients were recruited and divided into four groups according to MPC proportions, and the correlations between varying proportions of MPCs and clinicopathological characteristics were analyzed. Twenty-nine (29) LAMPC patients and 89 LA patients without MPC (non-MPC) that had undergone NGS testing were selected for further study The comprehensively analyze genomic variations and the difference between LAMPC and MPC were determined. In addition, Gene alterations of LAMPC between Chinese and Western populations were also compared using cBioPortal data. Results: A higher proportion of MPCs, associated with higher tumor stage, pleural invasion, and vascular tumor thrombus formation, was determined in LA patients. Compared to non-MPC patients, LAMPC patients were determined to have a lower frequency of single nucleotide variants and a higher frequency of insertion-deletion mutations. Mutations in TP53, CTNNB1, and SMAD4, and ALK rearrangements/fusions were significantly more frequent in LAMPC patients. ERBB2 mutations were only detected in non-MPC patients. Gene mutations in the Wnt pathway were significantly more common in LAMPC patients as compared to non-MPC patients. ALK fusions were more prevalent in younger patients. Patients with KRAS or LBP1B mutations had significantly larger tumor diameters than patients with wild-type KRAS or LBP1B. Patients with KRAS mutations were more likely to develop vascular tumor thrombus. Using the cBioPortal public database, we determined that mutations in EGFR were significantly higher in Chinese patients than in a Memorial Sloan Kettering Cancer Center (MSKCC) Western cohort. ALK fusions were exclusively detected in the Chinese cohort, while mutations in KEAP1 and NOTCH4 were only detected in the MSKCC cohort. Our analysis of signaling pathways revealed that Wnt pathway gene mutations were significantly higher in the Chinese cohort. Conclusion: LA patients with higher proportions of MPCs were determined to have a higher tumor stage, pleural invasion, and vascular tumor thrombosis formation. We comprehensively analyzed the genomic mutation characteristics of LAMPC patients and identified multiple, novel MPC-related gene alterations and pathway changes. Our data provide further understanding of the nature of the LAMPC and potential drug-targeted gene alterations, which may lead to new therapeutic strategies.

Disease-related compound identification based on deeping learning method.

Acute lung injury (ALI) is a serious respiratory disease, which can lead to acute respiratory failure or death. It is closely related to the pathogenesis of New Coronavirus pneumonia (COVID-19). Many researches showed that traditional Chinese medicine (TCM) had a good effect on its intervention, and network pharmacology could play a very important role. In order to construct "disease-gene-target-drug" interaction network more accurately, deep learning algorithm is utilized in this paper. Two ALI-related target genes (REAL and SATA3) are considered, and the active and inactive compounds of the two corresponding target genes are collected as training data, respectively. Molecular descriptors and molecular fingerprints are utilized to characterize each compound. Forest graph embedded deep feed forward network (forgeNet) is proposed to train. The experimental results show that forgeNet performs better than support vector machines (SVM), random forest (RF), logical regression (LR), Naive Bayes (NB), XGBoost, LightGBM and gcForest. forgeNet could identify 19 compounds in Erhuang decoction (EhD) and Dexamethasone (DXMS) more accurately.

Key factors for differential drought tolerance in two contrasting wild materials of Artemisia wellbyi identified using comparative transcriptomics.

BACKGROUND: Drought is a significant condition that restricts vegetation growth on the Tibetan Plateau. Artemisia wellbyi is a unique semi-shrub-like herb in the family Compositae, which distributed in northern and northwest of Tibetan Plateau. It is a dominant species in the community that can well adapt to virous environment stress, such as drought and low temperature. Therefore, A. wellbyi. has a potential ecological value for soil and water conservation of drought areas. Understanding the molecular mechanisms of A. wellbyi. that defense drought stress can acquire the key genes for drought resistance breeding of A. wellbyi. and provide a theoretical basis for vegetation restoration of desertification area. However, they remain unclear. Thus, our study compared the transcriptomic characteristics of drought-tolerant "11" and drought-sensitive "6" material of A. wellbyi under drought stress. RESULTS: A total of 4875 upregulated and 4381 downregulated differentially expressed genes (DEGs) were induced by drought in the tolerant material; however, only 1931 upregulated and 4174 downregulated DEGs were induced by drought in the sensitive material. The photosynthesis and transcriptional regulation differed significantly with respect to the DEGs number and expression level. We found that CDPKs (calmodulin-like domain protein kinases), SOS3 (salt overly sensitive3), MAPKs (mitogen-activated protein kinase cascades), RLKs (receptor like kinase), and LRR-RLKs (repeat leucine-rich receptor kinase) were firstly involved in response to drought stress in drought tolerant A. wellbyi. Positive regulation of genes associated with the metabolism of ABA (abscisic acid), ET (ethylene), and IAA (indole acetic acid) could play a crucial role in the interaction with other transcriptional regulatory factors, such as MYBs (v-myb avian myeloblastosis viral oncogene homolog), AP2/EREBPs (APETALA2/ethylene-responsive element binding protein family), WRKYs, and bHLHs (basic helix-loop-helix family members) and receptor kinases, and regulate downstream genes for defense against drought stress. In addition, HSP70 (heat shock protein70) and MYB73 were considered as the hub genes because of their strong association with other DEGs. CONCLUSIONS: Positive transcriptional regulation and negative regulation of photosynthesis could be associated with better growth performance under drought stress in the drought-tolerant material. In addition, the degradation of sucrose and starch in the tolerant A. wellbyi to alleviate osmotic stress and balance excess ROS. These results highlight the candidate genes that are involved in enhancing the performance of drought-tolerant A. wellbyi and provide a theoretical basis for improving the performance of drought-resistant A. wellbyi.