Identification of New EGFR Inhibitors by Structure-Based Virtual Screening and Biological Evaluation.

Epidermal growth factor receptor (EGFR) inhibitors have been used in clinical for the treatment of non-small-cell lung cancer for years. However, the emergence of drug resistance continues to be a major problem. To identify potential inhibitors, molecular docking-based virtual screening was conducted on ChemDiv and Enamine commercial databases using the Glide program. After multi-step VS and visual inspection, a total of 23 compounds with novel and varied structures were selected, and the predicted ADMET properties were within the satisfactory range. Further molecular dynamics simulations revealed that the reprehensive compound ZINC49691377 formed a stable complex with the allosteric pocket of EGFR and exhibited conserved hydrogen bond interactions with Lys 745 and Asp855 of EGFR over the course of simulation. All compounds were further tested in experiments. Among them, the most promising hit ZINC49691377 demonstrated excellent anti-proliferation activity against H1975 and PC-9 cells, while showing no significant anti-proliferation activity against A549 cells. Meanwhile, apoptosis analysis indicated that the compound ZINC49691377 can effectively induce apoptosis of H1975 and PC-9 cells in a dose-dependent manner, while having no significant effect on the apoptosis of A549 cells. The results indicate that ZINC49691377 exhibits good selectivity. Based on virtual screening and bioassays, ZINC4961377 can be considered as an excellent starting point for the development of new EGFR inhibitors.

Lung injuries induced by ozone exposure in female mice: Potential roles of the gut and lung microbes.

Ozone (O3) is one of the most harmful pollutants affecting health. However, the potential effects of O3 exposure on microbes in the gut-lung axis related to lung injuries remain elusive. In this study, female mice were exposed to 0-, 0.5- and 1-ppm O3 for 28 days, followed by routine blood tests, lung function tests and histopathological examination of the colon, nasal cavity and lung. Mouse faeces and lungs were collected for 16s rRNA sequencing to assess the overall microbiological profile and screen for key differential enriched microbes (DEMs). The key DEMs in faecal samples were Butyricimonas, Rikenellaceae RC9 and Escherichia-Shigella, whereas those in lung samples were DNF00809, Fluviicola, Bryobacter, Family XII AD3011 group, Sharpea, MND1 and unclassified Phycisphaeraceae. After a search in microbe-disease databases, these key DEMs were found to be associated with lung diseases such as lung neoplasms, cystic fibrosis, pneumonia, chronic obstructive pulmonary disease, respiratory distress syndrome and bronchiectasis. Subsequently, we used transcriptomic data from Gene Expression Omnibus (GEO) with exposure conditions similar to those in this study to cross-reference with Comparative Toxicogenomic Database (CTD). Il-6 and Ccl2 were identified as the key causative genes and were validated. The findings of this study suggest that exposure to O3 leads to significant changes in the microbial composition of the gut and lungs. These changes are associated with increased levels of inflammatory factors in the lungs and impaired lung function, resulting in an increased risk of lung disease. Altogether, this study provides novel insights into the role of microbes present in the gut-lung axis in O3 exposure-induced lung injury.

Allograft inflammatory factor-1 enhances inflammation and oxidative stress via the NF-κB pathway of bladder urothelium in diabetic rat model.

OBJECTIVES: To explore the role of allograft inflammatory factor-1 (AIF-1) both in diabetic rat bladder urothelium and in high-glucose-treated human urothelial cell line (SV-HUC-1). METHODS: Inflammation and oxidative stress (OS) promote diabetic cystopathy (DCP), but the mechanisms are not fully understood. The expression level of AIF-1 in diabetic rat bladder urothelium and in the SV-HUC-1 cells treated with high glucose was detected using tissue immunofluorescence, immunohistochemistry and western blot assays. AIF-1 was knocked down and NF-κB was suppressed with the specific inhibitor BAY 11-7082 in high-glucose-treated SV-HUC-1 cells. RESULTS: High-glucose condition induced AIF-1 upregulation in vivo and in vitro. The up-regulated AIF-1 induced the production of inflammatory factors IL-6 and TNF-α and elevation of ROS. Informatics analysis suggested that NF-κB pathway is implicated in DCP. Through knockdown of AIF-1, we confirmed that AIF-1 simulated NF-κB pathway by enhancing the phosphorylation of IκB (p-IκB) and promoting the translocation of NF-κB p65 from cytoplasm into nucleus. Additionally, High-glucose-induced inflammation in SV-HUC-1 cells was attenuated by the addition of NF-κB inhibitor. CONCLUSIONS: This study provides novel information to understand the molecular regulation mechanisms of AIF-1 in DCP.

Umbilical cord mesenchymal stromal cells in serum-free defined medium display an improved safety profile.

BACKGROUND: Safety evaluations in preclinical studies are needed to confirm before translating a cell-based product into clinical application. We previously developed a serum-free, xeno-free, and chemically defined media (S&XFM-CD) for the derivation of clinical-grade umbilical cord-derived MSCs (UCMSCs), and demonstrated that intraperitoneal administration of UCMSCs in S&XFM-CD (UCMSCS&XFM-CD) exhibited better therapeutic effects than UCMSCs in serum-containing media (SCM, UCMSCSCM). However, a comprehensive investigation of the safety of intraperitoneal UCMSCS&XFM-CD treatment should be performed before clinical applications. METHODS: In this study, the toxicity, immunogenicity and biodistribution of intraperitoneally transplanted UCMSCS&XFM-CD were compared with UCMSCSCM in rats via general vital signs, blood routine, blood biochemistry, subsets of T cells, serum cytokines, pathology of vital organs, antibody production and the expression of human-specific gene. The tumorigenicity and tumor-promoting effect of UCMSCS&XFM-CD were compared with UCMSCSCM in nude mice. RESULTS: We confirmed that intraperitoneally transplanted UCMSCS&XFM-CD or UCMSCSCM did not cause significant changes in body weight, temperature, systolic blood pressure, diastolic blood pressure, heart rate, blood routine, T lymphocyte subsets, and serum cytokines, and had no obvious histopathology change on experimental rats. UCMSCS&XFM-CD did not produce antibodies, while UCMSCSCM had very high chance of antibody production to bovine serum albumin (80%) and apolipoprotein B-100 (60%). Furthermore, intraperitoneally injected UCMSCS&XFM-CD were less likely to be blocked by the lungs and migrated more easily to the kidneys and colon tissue than UCMSCSCM. In addition, UCMSCS&XFM-CD or UCMSCSCM showed no obvious tumorigenic activity. Finally, UCMSCS&XFM-CD extended the time of tumor formation of KM12SM cells, and decreased tumor incidence than that of UCMSCSCM. CONCLUSIONS: Taken together, our data indicate that UCMSCS&XFM-CD display an improved safety performance and are encouraged to use in future clinical trials.

Invisible Hand behind Female Reproductive Disorders: Bisphenols, Recent Evidence and Future Perspectives.

Reproductive disorders are considered a global health problem influenced by physiological, genetic, environmental, and lifestyle factors. The increased exposure to bisphenols, a chemical used in large quantities for the production of polycarbonate plastics, has raised concerns regarding health risks in humans, particularly their endocrine-disrupting effects on female reproductive health. To provide a basis for future research on environmental interference and reproductive health, we reviewed relevant studies on the exposure patterns and levels of bisphenols in environmental matrices and humans (including susceptible populations such as pregnant women and children). In addition, we focused on in vivo, in vitro, and epidemiological studies evaluating the effects of bisphenols on the female reproductive system (the uterus, ovaries, fallopian tubes, and vagina). The results indicate that bisphenols cause structural and functional damage to the female reproductive system by interfering with hormones; activating receptors; inducing oxidative stress, DNA damage, and carcinogenesis; and triggering epigenetic changes, with the damaging effects being intergenerational. Epidemiological studies support the association between bisphenols and diseases such as cancer of the female reproductive system, reproductive dysfunction, and miscarriage, which may negatively affect the establishment and maintenance of pregnancy. Altogether, this review provides a reference for assessing the adverse effects of bisphenols on female reproductive health.

Ectopic pregnancy adjacent to iliac vessels managed successfully by minimally invasive treatment using local methotrexate injection: An extremely rare case and literature review.

A case report of successfully treated retroperitoneal ectopic pregnancy (REP) is presented. A 36-year-old woman, gravida 3, para 2, was admitted to hospital for suspected ectopic pregnancy with light vaginal bleeding and mild abdominal pain for 3 days at 45 days of gestation by the last menstrual period.Multiple transvaginal ultrasonography and two times laparoscopic probes led to the diagnosis of REP located to the iliac blood vessels closely. Eventually the patient was cured with the treatment using local methotrexate injection under real-time ultrasound guidance and systemic methotrexate administration. We also summarized another 31 cases of REP to further understand this disease, sharing them to arouse clinical attention for the diagnosis and treatment of REP timely.

Genome-wide identification of the TCP gene family in Chrysanthemum lavandulifolium and its homologs expression patterns during flower development in different Chrysanthemum species.

TCP proteins, part of the transcription factors specific to plants, are recognized for their involvement in various aspects of plant growth and development. Nevertheless, a thorough investigation of TCPs in Chrysanthemum lavandulifolium, a prominent ancestral species of cultivated chrysanthemum and an excellent model material for investigating ray floret (RF) and disc floret (DF) development in Chrysanthemum, remains unexplored yet. Herein, a comprehensive study was performed to analyze the genome-wide distribution of TCPs in C. lavandulifolium. In total, 39 TCPs in C. lavandulifolium were identified, showing uneven distribution on 8 chromosomes. Phylogenetic and gene structural analyses revealed that ClTCPs were grouped into classes I and II. The class II genes were subdivided into two subclades, the CIN and CYC/TB1 subclades, with members of each clade having similar conserved motifs and gene structures. Four CIN subclade genes (ClTCP24, ClTCP25, ClTCP26, and ClTCP27) contained the potential miR319 target sites. Promoter analysis revealed that ClTCPs had numerous cis-regulatory elements associated with phytohormone responses, stress responses, and plant growth/development. The expression patterns of ClTCPs during capitulum development and in two different florets were determined using RNA-seq and qRT-PCR. The expression levels of TCPs varied in six development stages of capitula; 25 out of the 36 TCPs genes were specifically expressed in flowers. Additionally, we identified six key ClCYC2 genes, which belong to the class II TCP subclade, with markedly upregulated expression in RFs compared with DFs, and these genes exhibited similar expression patterns in the two florets of Chrysanthemum species. It is speculated that they may be responsible for RFs and DFs development. Subcellular localization and transactivation activity analyses of six candidate genes demonstrated that all of them were localized in the nucleus, while three exhibited self-activation activities. This research provided a better understanding of TCPs in C. lavandulifolium and laid a foundation for unraveling the mechanism by which important TCPs involved in the capitulum development.

Evolutionary origin of genomic structural variations in domestic yaks.

Yak has been subject to natural selection, human domestication and interspecific introgression during its evolution. However, genetic variants favored by each of these processes have not been distinguished previously. We constructed a graph-genome for 47 genomes of 7 cross-fertile bovine species. This allowed detection of 57,432 high-resolution structural variants (SVs) within and across the species, which were genotyped in 386 individuals. We distinguished the evolutionary origins of diverse SVs in domestic yaks by phylogenetic analyses. We further identified 334 genes overlapping with SVs in domestic yaks that bore potential signals of selection from wild yaks, plus an additional 686 genes introgressed from cattle. Nearly 90% of the domestic yaks were introgressed by cattle. Introgression of an SV spanning the KIT gene triggered the breeding of white domestic yaks. We validated a significant association of the selected stratified SVs with gene expression, which contributes to phenotypic variations. Our results highlight that SVs of different origins contribute to the phenotypic diversity of domestic yaks.

Hypso- or bathochromic phosphorescent mechanochromic mononuclear Cu(I) complexes with a bis(2-diphenylphosphinophenyl)ether auxiliary ligand.

Six phosphorescence-emitting metal-organic mononuclear Cu(I) complexes, namely four quinoline-containing three-coordinate Cu(I) complexes and two N-heterocyclic carbene-containing four-coordinate Cu(I) complexes, have been successfully developed and fully characterized. All these Cu(I) complexes include the same bis(2-diphenylphosphinophenyl)ether bidentate auxiliary ligand. Significantly, four-coordinate Cu(I) complexes 1 and 2 display typical aggregation-induced emission phenomena. Their solid samples of luminogenic complexes 1-6 emit a variety of different phosphorescence. Furthermore, solid-state phosphorescence of these Cu(I) complexes can be effectively manipulated by external mechanical force. Remarkably, luminophores 1, 2 and 5 exhibit blue-shifted mechanoluminochromism responses, while luminophores 3, 4 and 6 present red-shifted mechanoluminochromism characteristics. All of the observed mechano-responsive phosphorescence changes of solids 1-6 are reversible by the method of solvent fuming. Powder X-ray diffraction results confirm that the reversible mechanically induced phosphorescence changes of complexes 1-6 are due to the mutual transformation of ordered crystalline and metastable amorphous states.

Molecular mechanisms of physiological change under acute total dissolved gas supersaturation stress in yellow catfish (Pelteobagrus fulvidraco).

During the dam discharging period, the strong aeration of high-speed water leads to the supersaturation of total dissolved gas (TDG) in the downstream water, which causes gas bubble disease (GBD) in fish and threatens their survival. TDG supersaturation has now become an ecological and environmental issue of global concern; however, the molecular mechanism underlying the physiological effect of TDG supersaturation on fish is poorly known. Here, we comprehensively investigated the effect of TDG supersaturation on Pelteobagrus fulvidraco at the histopathological, biochemical, transcriptomic, and metabolomic levels. After exposure to 116% TDG, P. fulvidraco exhibited classic GBD symptoms and pathological changes in gills. The level of superoxide dismutase was highly significantly decreased. Transcriptomic results revealed that heat shock proteins (HSPs) and a large number of genes involved in immunity were increased by TDG stress. A key environmental sensor PI3K/Akt/mTOR pathway was significantly stimulated for defence against stress. Integrated transcriptomic and metabolomic analyses revealed that key metabolites and genes were upregulated in the triacylglycerol synthesis pathway and that amino acid levels decreased, which might be associated with TDG supersaturation stress. The present study demonstrated that TDG supersaturation could cause severe physiological damage in fish. HSP genes, immune functions, and energy metabolic pathways were enhanced to counteract the adverse effects.

Case Report: Cord blood-derived natural killer cells as new potential immunotherapy drug for solid tumor: a case study for endometrial cancer.

Adoptive transfer of natural killer (NK) cells represents a viable treatment method for patients with advanced malignancies. Our team previously developed a simple, safe, and cost-effective method for obtaining high yields of pure and functional NK cells from cord blood (CB) without the need for cell sorting, feeder cells, or multiple cytokines. We present the case of a 52-year-old female patient diagnosed with poorly differentiated stage IVB (T3N2M1) endometrial cancer, who exhibited leukemoid reaction and pretreatment thrombocytosis as paraneoplastic syndromes. The patient received two courses of CB-derived NK (CB-NK) cell immunotherapy between March and September 2022, due to her extremely low NK cell activity. Two available CB units matched at 8/10 HLA with KIR-mismatch were chosen, and we were able to produce NK cells with high yield (>1.0×1010 NK cells), purity (>90%), and function (>80%) from CB without cell sorting, feeder cells, or multiple cytokines. These cells were then adoptively transferred to the patient. No adverse effects or graft-versus-host disease were observed after infusion of CB-NK cells. Our clinical experience supports the efficacy of CB-NK cell treatment in increasing NK cell activity, depleting tumor activity, improving quality of life, and reducing the size of abdominal and pelvic masses with the disappearance of multiple lymph node metastases through the regulation of systemic antitumor immunity. Remarkably, the white blood cell and platelet counts decreased to normal levels after CB-NK cell immunotherapy. This clinical work suggests that CB-NK cell immunotherapy holds promise as a therapeutic approach for endometrial cancer.

Bisphenol B and bisphenol AF exposure enhances uterine diseases risks in mouse.

Bisphenol A (BPA) analogs, bisphenol B (BPB) and bisphenol AF (BPAF) have been widely detected in the environment and human products with increasing frequency. However, uterine health risks caused by BPB and BPAF exposure need to be further elucidated. The study aimed to explore whether BPB or BPAF exposure will induce adverse outcomes in uterus. Female CD-1 mice were continuously exposed to BPB or BPAF for 14 and 28 days. Morphological examination showed that BPB or BPAF exposure caused endometrial contraction, decreased epithelial height, and increased number of glands. Bioinformatics analysis indicated that both BPB and BPAF disturbed the immune comprehensive landscape of the uterus. In addition, survival and prognosis analysis of hub genes and tumor immune infiltration evaluation were performed. Finally, the expression of hub genes was verified by quantitative real-time PCR (qPCR). Disease prediction found that eight of the BPB and BPAF co-response genes, which participated in the immune invasion of the tumor microenvironment, were associated with uterine corpus endometrial carcinoma (UCEC). Importantly, the gene expression levels of Srd5a1 after 28-day BPB and BPAF exposure were 7.28- and 25.24-fold higher than those of the corresponding control group, respectively, which was consistent with the expression trend of UCEC patients, and its high expression was significantly related to the poor prognosis of patients (p = 0.003). This indicated that Srd5a1 could be a valuable signal of uterus abnormalities caused by BPA analogs exposure. Our study revealed the key molecular targets and mechanisms of BPB or BPAF exposure induced uterine injury at the transcriptional level, providing a perspective for evaluating the safety of BPA substitutes.

The Novel Structural Variation in the GHR Gene Is Associated with Growth Traits in Yaks (Bos grunniens).

The growth hormone receptor (GHR) is a member of the cytokine/hematopoietic factor receptor superfamily, which plays an important role in the growth and development, immunity, and metabolism of animals. This study identified a 246 bp deletion variant in the intronic region of the GHR gene, and three genotypes, including type II, type ID, and type DD, were observed. Genotype analysis of structural variation (SV) was performed on 585 individuals from 14 yak breeds, and it was found that 246 bp deletion was present in each breed. The II genotype was dominant in all yak breeds except for SB yak. The association analysis of gene polymorphisms and growth traits in the ASD yak population showed that the 246 bp SV was significantly associated with body length at 6 months (p < 0.05). GHR messenger RNA (mRNA) was expressed in all the tested tissues, with significantly higher levels in the liver, muscle, and fat than in other organs. The results of transcription activity showed that the luciferase activity of the pGL4.10-DD vector was significantly higher than that of the pGL4.10-II vector (p < 0.05). Additionally, the transcription-factor binding prediction results showed that the SV in the runt-related transcription factor 1 (Runx1) transcription-factor binding site may affect the transcriptional activity of the GHR gene, regulating yak growth and development. This study showed that the novel SV of the GHR gene could be used as a candidate molecular marker for the selection of the early growth trait in ASD yak.

Design, synthesis, and biological evaluation of diaryl heterocyclic derivatives targeting tubulin polymerization with potent anticancer activities.

A series of diaryl heterocyclic analogues were designed and synthesized as tubulin polymerization inhibitors. Among them, compound 6y showed the highest antiproliferative activity against HCT-116 colon cancer cell line with an IC50 values of 2.65 µM. Compound 6y also effectively inhibited tubulin polymerization in vitro (IC50 of 10.9 µM), and induced HCT-116 cell cycle arrest in G2/M phase. In addition, compound 6y exhibited high metabolic stability on human liver microsomes (T1/2 = 106.2 min). Finally, 6y was also effective in suppressing tumor growth in a HCT-116 mouse colon model without apparent toxicity. Collectively, these results suggest that 6y represents a new class of tubulin inhibitors deserving further investigation.

Exploration of the damage and mechanisms of BPS exposure on the uterus and ovary of adult female mice.

Bisphenol S (BPS) has been followed with interest for its endocrine disrupting effects, but exploration on the reproductive system of adult females is lack of deep investigation. In the present study, adult female CD-1 mice were treated with BPS for 28 days at 300 µg/kg/day. After that, uteruses and ovaries were harvested for histopathological examination, RNA-seq analysis, and diseases risk prediction. Hematoxylin-eosin (H&E) staining results showed significant histological alterations in the uterus and ovary of the BPS-exposed mice. Bioinformatics analysis of the RNA-seq screened a certain number of differentially expressed genes (DEGs) in both uterus and ovary between BPS group and their corresponding vehicle control groups (Veh), respectively. Functional enrichment analysis of DEGs found that hormone metabolism and immunoinflammatory related pathways were enriched. Disease risk evaluation of the hub genes was performed and the results indicated that diseases associated with uterus and ovary were mainly related to tumors and cancers. Further pan cancer and ovarian cancer survival analysis based on human diseases database pointed out, Foxa1, Gata3, S100a8 and Shh for uterus, Itgam, Dhcr7, Fdps, Hmgcr, Hsd11b1, Hsd3b1, Ptges, F3, Fn1, Ptger4 and Srd5a1 for ovary were significant correlation with cancer. The findings suggest that BPS causes some histopathological changes, alters the expressions of hub genes, enhances uterine and ovarian tumors or even cancer risks.

Nickel recovery from electroplating sludge via bipolar membrane electrodialysis.

In this study, nickel (Ni) was recovered from electroplating sludge in the form of Ni(OH)2 using a bipolar membrane electrodialysis (BMED) system. The results showed that the H+ generated by the bipolar membrane could effectively desorb Ni from the sludge to the solution and the solution pH considerably affected Ni desorption. The desorption process can be described using the first-order kinetic model. The current density and solid/liquid ratio (m/v) considerably affected Ni recovery. Moreover, 100% of Ni was removed from the electroplating sludge and 93.5% of Ni was recovered after 28 h under a current density of 20 mA/cm2, a solid/liquid ratio of 1.0:15 and an electroplating-sludge particle size of 100 mesh. As the number of electroplating compartments increased from one to two and three, the current efficiency for recovering Ni changed from 12.1% to 11.8% and 11.9%, respectively, and the specific energy consumption decreased from 0.064 to 0.048 and 0.039 kW·h/g, respectively. Fourier-transform infrared spectroscopy and Raman spectroscopy showed that the precipitate obtained in this study is similar to commercial Ni(OH)2 and the purity of Ni(OH)2 in the obtained precipitate was 79%. Thus, the results showed that the BMED system is effective for recovering Ni from electroplating sludge.

Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death.

Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A-SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A-SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.

Recovery of nickel in the form of Ni(OH)2 from plating wastewater containing Ni-EDTA using bipolar membrane electrodialysis.

Ni is often present in plating wastewater as a complexing state. It is difficult to remove this Ni using traditional chemical precipitation technology. In this study, a bipolar membrane electrodialysis system was used to recover Ni in the form of Ni(OH)2 from plating wastewater containing Ni-ethylenediaminetetraacetic acid (Ni-EDTA) without adding chemical reagents. The stable structure of Ni-EDTA can be destroyed by H+ produced by the bipolar membrane to obtain free Ni2+, which can combine with OH- produced by the bipolar membrane to form Ni(OH)2. When the electrolyte Na2SO4 concentration, current density and initial Ni-EDTA concentration were 0.2 mol/L, 16 mA/cm2 and 1000 mg/L, respectively, 99.0% of Ni-EDTA was removed after 32 h. When the system was used to treat actual plating wastewater, 92.1% of Ni-EDTA was removed and 88.7% was recovered. When the number of wastewater compartments in the system was increased from one to three, the current efficiency increased from 1.7% to 5.8%, and the specific energy consumption decreased from 0.39 to 0.19 kW h/g. The results of an X-ray diffraction study indicate that the Ni(OH)2 obtained in this study is similar to commercial Ni(OH)2. Moreover, the recovery mechanism of Ni-EDTA was analysed. Thus, bipolar membrane electrodialysis can be regarded as an effective method to recover Ni from wastewater containing Ni-EDTA.

Biochemical, transcriptomic and metabolomic responses to total dissolved gas supersaturation and their underlying molecular mechanisms in Yangtze sturgeon (Acipenser dabryanus).

With the rapid development of hydropower facility construction, the total dissolved gas (TDG) generated by dam discharge is seriously threatening the survival of fish and has become an ecological environmental issue of global concern. However, how TDG affects fish physiology and the underlying molecular mechanism remain poorly known. In this study, Acipenser dabryanus, an ancient living fossil that is a flagship species of the Yangtze River, was exposed to water supersaturated with TDG at a level of 116% for 48 h. A comprehensive analysis was performed to study the effect of TDG supersaturation stress on A. dabryanus, including histopathological, biochemical, transcriptomic and metabolomic analyses. The histopathological results showed that mucosal-associated lymphoid tissues were seriously damaged after TDG supersaturation stress. Plasma catalase levels increased significantly under TDG supersaturation stress, while superoxide dismutase levels decreased significantly. Transcriptomic analysis revealed 289 upregulated genes and 162 downregulated genes in gill tissue and 535 upregulated and 104 downregulated genes in liver tissue. Metabolomic analysis revealed 63 and 164 differentially abundant metabolites between the control group and TDG group in gill and liver, respectively. The majority of heat shock proteins and genes related to ubiquitin and various immune-related pathways were significantly upregulated by TDG supersaturation stress. Integrated transcriptomic and metabolomic analyses revealed the upregulation of amino acid metabolism and glycometabolism pathways under TDG supersaturation stress. Glycerophospholipid metabolism was increased which might be associated with maintaining cell membrane integrity. This is the first study revealing the underlying molecular mechanisms of effects of TDG supersaturation on fish. Our results suggested that acute TDG supersaturation stress could enhance immune and antioxidative functions and activate energy metabolic pathways as an adaptive mechanism in A. dabryanus.

Genome-wide detection of RNA editing events during the hair follicles cycle of Tianzhu white yak.

BACKGROUND: The hair coat is available for the yak to live in the harsh environment of the plateau. Besides, improving the hair production of yak is necessary for its textile industry development. Hair grows from hair follicles (HFs). The HFs undergo periodic growth after birth and are regulated by the complex gene regulatory network. However, the molecular mechanism of HFs regeneration in the Tianzhu white yak remains unclear. RNA editing is a post-transcriptional mechanism that regulates gene expression and produces new transcripts. Hence, we investigated the influence of the A-to-I RNA editing events on the HFs cycle of the Tianzhu white yak. RESULTS: We finally identified 54,707 adenosine-to-inosine (A-to-I) RNA editing sites (RESs) from RNA sequencing data of the HFs cycle in the Tianzhu white yak. Annotation results showed RESs caused missense amino acid changes in 7 known genes. And 202 A-to-I editing sites altered 23 target genes of 140 microRNAs. A total of 1,722 differential RESs were identified during the HFs cycle of Tianzhu white yak. GO and KEGG enrichment analysis revealed several signaling pathways and GO terms involved skin development, hair growth, and HFs cycle. Such as genes with differential RNA editing levels were significantly enriched in the peroxisome, metabolic pathways, Notch signaling pathway, and PPAR signaling pathway. Besides, the editing sites in HFs development-related genes FAS, APCDD1, WWOX, MPZL3, RUNX1, KANK2, DCN, DSC2, LEPR, HEPHL1, and PTK2B were suggested as the potential RESs involving HFs development. CONCLUSION: This study investigated the global A-to-I RNA editing events during the HFs cycle of yak skin tissue and expanded the knowledge of A-to-I RNA editing on the HFs cycle. Furthermore, this study revealed that RNA editing-influenced genes may regulate the HFs cycle by participating in the HFs development-related pathways. The findings might provide new insight into the regulation of RNA editing in hair growth.