Pan-cancer analysis and experimental validation of DTL as a potential diagnosis, prognosis and immunotherapy biomarker.

BACKGROUND: DTL has been found to be related with multiple cancers. However, comprehensive analyses, which identify the prediction value of DTL in diagnosis, prognosis, immune infiltration and treatment, have rarely been reported so far. METHODS: Combined with the data online databases, the gene expression, gene mutation, function enrichment and the correlations with the immunity status and clinical indexes of DTL were analyzed. Expression of DTL and the degree of immune cell infiltration were examined by immunofluorescence (IF) and immunohistochemistry (IHC) and analyzed by statistical analysis. Furthermore, the influences of DTL on the cell cycle, cell proliferation and apoptosis were detected by live cell imaging, IF and flow cytometric (FC) analysis. Genomic stability assays were conducted by chromosome slide preparation. RESULTS: DTL was widely expressed in various cells and tissues, while it was overexpressed in tumor tissues except acute myeloid leukemia (LAML). Pan-cancer bioinformatics analysis showed that the expression of DTL was correlated with the prognosis, immunotherapy, and clinical indexes in various cancers. In addition, gene set enrichment analysis (GSEA) uncovered that DTL was enriched in oocyte meiosis, pyrimidine metabolism, the cell cycle, the G2M checkpoint, mTORC1 signaling and E2F targets. Furthermore, the overexpression of DTL, and its association with immune cell infiltration and clinical indexes in liver hepatocellular carcinoma (LIHC), bladder urothelial carcinoma (BLCA) and stomach adenocarcinoma (STAD) were verified in our study. It was also verified that overexpression of DTL could regulate the cell cycle, promote cell proliferation and cause genomic instability in cultured cells, which may be the reason why DTL plays a role in the occurrence, progression and treatment of cancer. CONCLUSIONS: Collectively, this study suggested that DTL is of clinical value in the diagnosis, prognosis and treatment of various cancers, and may be a potential biomarker in certain cancers.

Long-range high-speed laser imaging based on VCSEL array and MPPC array.

Flash LiDAR is a photoelectric system that can acquire a 3D image by emitting a diffuse pulsed laser beam, and hence is suitable for both autopilot and spacecraft flight control. Achieving long-range and high-speed, especially in outdoor applications with strong solar background illumination, are challenging requirements. In this paper, a set of laser imaging prototype based on 2×6 VCSEL array and 32×32 MPPC array image sensor is developed, the range calibration is completed, and relevant experimental research is carried out. The frame rate of the system can reach 10kHz, the detection probability of 120m range can reach 86.23%, and the maximum walk error is about 0.6m under different reflectivity. The 3D imaging of the vehicle can be realized at about 70m, the horizontal spatial resolution is less than 5cm, and the ranging precision after ten shots average is within 10cm by calculating the centroid of a histogram. The detection probability can be improved by using the time-gating method. After multiple measurements, a 120m "laser imaging through window" can be realized in sunlight. This LiDAR system has the advantages of small volume, light weight and fast detection speed.

Arabidopsis choline transporter-like 1 (CTL1) regulates secretory trafficking of auxin transporters to control seedling growth.

Auxin controls a myriad of plant developmental processes and plant response to environmental conditions. Precise trafficking of auxin transporters is essential for auxin homeostasis in plants. Here, we report characterization of Arabidopsis CTL1, which controls seedling growth and apical hook development by regulating intracellular trafficking of PIN-type auxin transporters. The CTL1 gene encodes a choline transporter-like protein with an expression pattern highly correlated with auxin distribution and is enriched in shoot and root apical meristems, lateral root primordia, the vascular system, and the concave side of the apical hook. The choline transporter-like 1 (CTL1) protein is localized to the trans-Golgi network (TGN), prevacuolar compartment (PVC), and plasma membrane (PM). Disruption of CTL1 gene expression alters the trafficking of 2 auxin efflux transporters-Arabidopsis PM-located auxin efflux transporter PIN-formed 1 (PIN1) and Arabidopsis PM-located auxin efflux transporter PIN-formed 3 (PIN3)-to the PM, thereby affecting auxin distribution and plant growth and development. We further found that phospholipids, sphingolipids, and other membrane lipids were significantly altered in the ctl1 mutant, linking CTL1 function to lipid homeostasis. We propose that CTL1 regulates protein sorting from the TGN to the PM through its function in lipid homeostasis.

Transport and homeostasis of potassium and phosphate: limiting factors for sustainable crop production.

Potassium (K) and phosphate (Pi) are both macronutrients essential for plant growth and crop production, but the unrenewable resources of phosphorus rock and potash have become limiting factors for food security. One critical measure to help solve this problem is to improve nutrient use efficiency (NUE) in plants by understanding and engineering genetic networks for ion uptake, translocation, and storage. Plants have evolved multiple systems to adapt to various nutrient conditions for growth and production. Within the NUE networks, transport proteins and their regulators are the primary players for maintaining nutrient homeostasis and could be utilized to engineer high NUE traits in crop plants. A large number of publications have detailed K+ and Pi transport proteins in plants over the past three decades. Meanwhile, the discovery and validation of their regulatory mechanisms are fast-track topics for research. Here, we provide an overview of K+ and Pi transport proteins and their regulatory mechanisms, which participate in the uptake, translocation, storage, and recycling of these nutrients in plants.

Microencapsulation of green coffee oil by complex coacervation of soy protein isolate, sodium casinate and polysaccharides: Physicochemical properties, structural characterisation, and oxidation stability.

This study developed a combination method between protein-polysaccharide complex coacervation and freezing drying for the preparation of green coffee oil (GCO) encapsulated powders. Different combinations of soy protein isolate, sodium caseinate, sodium carboxymethylcellulose, and sodium alginate were utilised as wall materials. The occurrence of complexation between the biopolymers were compared to the final emulsion of the individual protein and confirmed by fourier transform infrared spectrometry and X-ray diffraction. The mean diameter and estimated PDI of GCO microcapsules were 72.57-295.00 µm and 1.47-2.02, respectively. Furthermore, the encapsulation efficiency of GCO microcapsules was between 61.47 and 90.01 %. Finally, oxidation kinetics models of GCO and its microcapsules demonstrated that the zero-order model of GCO microcapsules was found to have a higher fit, which could better reflect the quality changes of GCO microcapsules during storage. Different combinations of proteins and polysaccharides exhibited effective oxidative stability against single proteins because of polysaccharide addition. This research revealed that soy protein isolate, sodium caseinate combined with polysaccharides can be used as a promising microencapsulating agent for microencapsulation of GCO, especially with sodium carboxymethylcellulose and sodium alginate, and provided useful information for the potential use of GCO in the development of powder food.

Identification of a novel partner gene, TPR, fused to FGFR1 in 8p11 myeloproliferative syndrome.

The 8p11 myeloproliferative syndrome (EMS) is an aggressive neoplasm caused by the fusion of various partner genes to fibroblast growth factor receptor 1 (FGFR1). Various FGFR1 fusions are associated with subtly distinct disease phenotypes. Here, we report a new translocation at the FGFR1 locus in a patient who carried t(1;8)(q25;p11.2) and presented with myeloproliferative neoplasm-like symptoms. The patient was characterized by myeloid hyperplasia of bone marrow, markedly elevated numbers of monocytes, and normal to mildly elevated eosinophils. Initial fluorescent in situ hybridization analysis confirmed that FGFR1 in this patient was disrupted. Subsequent analysis led to the identification of a novel translocation, in which exon 23 of the translocated promoter region (TPR) gene at chromosome band 1q25 was fused to exon 13 of FGFR1 (RefSeq NM_0231102.2). The TPR portion of the fusion protein contains putative functional motifs including an N-terminal TprMet domain, nuclear pore complexes associating domain, and multiple coiled-coil domains. It is likely that one or more of the motifs from TPR contribute to dimerization, resulting in constitutive activation of the FGFR1 kinase domain. Our results further support a critical role of FGFR1 in the pathogenesis of EMS and may lead to more accurate diagnosis and potential targeted therapy.

Pharmacological Activities and Pharmacokinetics of Glycycoumarin.

Glycycoumarin is a representative coumarin compound with significant pharmacological activities isolated from Glycyrrhiza uralensis Fisch., Fabaceae. Studies have shown that glycycoumarin has many biological activities, such as anti-tumor, liver protection, antispasmodic, antibacterial, and antivirus. However, the poor solubility of glycycoumarin in water and the accompanying reactions of the phase I (hydroxylation) and II (glucuronidation) metabolism limit its druggability, which manifests as low absorption in the body after oral administration and low free drug concentration, ultimately leading to low bioavailability. Therefore, a comprehensive review of the pharmacological effects and pharmacokinetics of glycycoumarin is presented to provide a reference for further research and application as a therapeutic agent. Supplementary Information: The online version contains supplementary material available at 10.1007/s43450-022-00342-x.

Survey of mosquito species and mosquito-borne viruses in residential areas along the Sino-Vietnam border in Yunnan Province in China.

Mosquitoes are capable of carrying complex pathogens, and their feeding habits on the mammalian blood can easily mediate the spread of viruses. Surveillance of mosquito-based arbovirus enables the early prevention and control of mosquito-borne arboviral diseases. The climate and geography of Yunnan Province in China are ideal for mosquitoes. Yunnan shares borders with several other countries; therefore, there exists a high risk of international transmission of mosquito-mediated infectious diseases. Previous studies have focused more on the Sino-Laos and Sino-Myanmar borders. Therefore, we focused on the neighborhoods of Malipo and Funing counties in Wenshan Prefecture, Yunnan Province, China, which are located along the Sino-Vietnam border, to investigate the species of mosquitoes and mosquito-borne viruses in the residential areas of this region. This study collected 10,800 mosquitoes from 29 species of 8 genera and grouped to isolate mosquito-borne viruses. In total, 62 isolates were isolated and classified into 11 viral categories. We demonstrated a new distribution of mosquito-borne viruses among mosquitoes in border areas, including Tembusu and Getah viruses, which can cause animal outbreaks. In addition, Dak Nong and Sarawak viruses originating from Vietnam and Malaysia, respectively, were identified for the first time in China, highlighting the complexity of mosquito-borne viruses in the Sino-Vietnam border region. The awareness of the importance of viral surveillance and prevention measures in border areas should be further encouraged to prevent future outbreaks of potentially infectious diseases.

Long non-coding RNA NRAV enhances proliferation and invasion of hepatocellular carcinoma cells by modulating the Wnt/ß-catenin signaling pathway.

Many dysregulated lncRNAs have been reported to perform an integral function in hepatocellular carcinoma (HCC). However, the role of long non-coding RNA (lncRNA) NRAV in HCC has not been elucidated. To address this issue, we investigated the function of NRAV in HCC in this research. Through bioinformatics prediction and real-time quantitative polymerase chain reaction validation, we found that NRAV plays an upmodulating role in HCC cells and tissues, and patients with high NRAV expression showed a poor prognosis. Cell viability was examined by conducting a Cell Counting Kit-8 analysis. Subsequently, the proliferation capacity of the cells was analyzed utilizing cell colony formation assay, and transwell invasion experiments were conducted to identify the cell invasion ability. To determine the association between NRAV and miR-199a-3p, and CDGSH iron-sulfur domain-containing protein 2 (CISD2), we conducted a dual luciferase assay. The protein and gene expressions were estimated utilizing Western blot. Findings illustrated that the overexpression of NRAV enhanced the HCC cell viability, proliferation and invasion, whereas they were inhibited significantly by down expression of NRAV. The dual-luciferase assay showed that miR-199a-3p is not only a target for NRAV but also interacts with the 3' UTR of CISD2 in HCC cells. MiR-199a-3p/CISD2 axis performs a function in NRAV-mediated cell behavior regulation. NRAV may trigger the Wnt/ß-catenin signaling via the modulation of the miR-199a-3p/CISD2 axis in HCC. The findings of this work can provide novel insights into clinical diagnosis and the treatment of HCC in the future.Abbreviations: HCC, hepatocellular carcinoma; LncRNA, long non-coding RNA; CISD2, CDGSH iron-sulfur domain-containing protein 2; CCK-8, Cell Counting Kit-8; cDNA, single-stranded complementary DNA; RT-qPCR, real-time quantitative polymerase chain reaction; BCA, bicinchoninic acid; ceRNA, competing endogenous RNAs.

Construction of MnxCoyO4/Ti electrocatalysts for efficient bifunctional water splitting.

In this work, we report the design and synthesis of non-noble metal-based electrocatalysts for effective overall water splitting in alkaline solutions for the development of hydrogen energy. The electrocatalysts were synthesized by a one-step hydrothermal method similar to microflower structure electrocatalysts. The synergistic effect between the special Echinops sphaerocephalus nanostructure and the nanowire can greatly improve the conductivity of the nanomaterial due to its high activity quality, fast ion transport, and exposure of more active sites, thus resulting in a better catalytic activity and a longer material stability of the electrocatalyst. For MnxCoyO4/Ti in alkaline aqueous solutions, a current density of 10 mA cm-2 is required when the voltage is only 1.60 V. In addition, the hydrogen evolution activity of electrocatalysts is 168 mV at 10 mA cm-2, the Tafel slope is 174 mV dec-1, and the oxygen evolution activity of electrocatalysts is 229 mV at 10 mA cm-2, which showed good long-term stability within 12 h, even better than that of previously reported electrocatalysts.

A prognostic model for cervical cancer based on ferroptosis-related genes.

Background: Ferroptosis is widely involved in the occurrence and development of various cancers, but a specific mechanism involving ferroptosis in cervical cancer is still unclear. Methods: Based on the expressions of ferroptosis-related genes, a prognostic model was constructed using lasso regression, and the overall predictive performance of this model was verified. An in-depth analysis of the prognostic model was then conducted. Results: The prognostic model showed good predictive performance in both the validation and test sets. Mechanism analysis indicated that differences in the tumor microenvironment were the basis of the predictive ability of the model. Notably, CA9 mRNA was significantly overexpressed in cervical carcinoma, tissues but not in normal cervix tissues. A pair of ceRNAs (CA9/ULBP2) could be involved in the carcinogenesis and development of cervical cancer, and the potential target might be hsa-miR-34a. In addition, predicted miRNAs and drugs for these DEGs were identified. Conclusions: We constructed a prognostic model with good predictive performance, based on the expression of ferroptosis-related genes. Further research found that the ceRNA pairs of ULBP2/CA9 could regulate cervical cancer through hsa-miR-34a. These results identified the mechanism of ferroptosis in cervical cancer, and might provide novel therapeutics for cervical cancer patients.

Full Mitochondrial Genomes Reveal Species Differences between the Venerid Clams Ruditapes philippinarum and R. variegatus.

In natural sea areas along the coast of China, venerid clams Ruditapes philippinarum and R. variegatus exhibit similar adult shell forms and are especially difficult to distinguish as spat and juveniles. This study used comparative mitochondrial genome analysis to reveal differences between these species. The results showed that: (1) the mitochondrial genomes of R. philippinarum and R. variegatus share a large number of similar gene clusters arranged in consistent order, yet they also display noncommon genes, with both gene rearrangements and random losses found; (2) the 13 protein-coding genes in R. philippinarum as well as two-fold and four-fold degenerate sites in R. variegatus have an evident AT bias; (3) the Ka/Ks ratio of the mitochondrial ATP8 gene was significantly higher in R. philippinarum than in R. variegatus, and an analysis of selection pressure revealed that the mitochondrial NADH dehydrogenase subunit 2 gene and NADH dehydrogenase subunit 6 gene of R. variegatus were under great selective pressure during its evolution; and finally, (4) the two species clustered into one branch on a phylogenetic tree, further affirming their phylogenetic closeness. Based on these results, we speculate that the species differences between R. variegatus and R. philippinarum are largely attributable to adaptive evolution to the environment. The present findings provide a reference for the development of germplasm identification.

Theoretical Study on Metasurfaces for Transverse Magneto-Optical Kerr Effect Enhancement of Ultra-Thin Magnetic Dielectric Films.

We study how to enhance the transverse magneto-optical Kerr effect (TMOKE) of ultra-thin magnetic dielectric films through the excitation of strong magnetic resonances on metasurface with a metal nanowire array stacked above a metal substrate with an ultra-thin magnetic dielectric film spacer. The plasmonic hybridizations between the Au nanowires and substrate result in magnetic resonances. The periodic arrangement of the Au nanowires can excite propagating surface plasmon polaritons (SPPs) on the metal surface. When the SPPs and the magnetic resonances hybridize, they can strongly couple to form two strong magnetic resonances, which are explained by a coupled oscillator model. Importantly, benefitting from the strong magnetic resonances, we can achieve a large TMOKE signal up to 26% in the ultra-thin magnetic dielectric film with a thickness of only 30 nm, which may find potential applications in nanophotonics, magnonics, and spintronics.

Perfect Absorption and Refractive-Index Sensing by Metasurfaces Composed of Cross-Shaped Hole Arrays in Metal Substrate.

Achieving perfect electromagnetic wave absorption with a sub-nanometer bandwidth is challenging, which, however, is desired for high-performance refractive-index sensing. In this work, we theoretically study metasurfaces for sensing applications based on an ultra-narrow band perfect absorption in the infrared region, whose full width at half maximum (FWHM) is only 1.74 nm. The studied metasurfaces are composed of a periodic array of cross-shaped holes in a silver substrate. The ultra-narrow band perfect absorption is related to a hybrid mode, whose physical mechanism is revealed by using a coupling model of two oscillators. The hybrid mode results from the strong coupling between the magnetic resonances in individual cross-shaped holes and the surface plasmon polaritons on the top surface of the silver substrate. Two conventional parameters, sensitivity (S) and figure of merit (FOM), are used to estimate the sensing performance, which are 1317 nm/RIU and 756, respectively. Such high-performance parameters suggest great potential for the application of label-free biosensing.

MiR-32-5p Regulates Radiosensitization, Migration And Invasion Of Colorectal Cancer Cells By Targeting TOB1 Gene.

BACKGROUND: MicroRNAs (miRNAs) play key roles in the development and progression of various cancers. However, the precise functions and regulation mechanisms of miRNAs in human tumors remain elusive. METHODS: Quantitative real time-PCR (qRT-PCR) was performed to detect the level of miR-32-5p in colorectal cancer tissues. The relationships between miR-32-5p level with clinicopathological characteristics and prognosis were analyzed. The miR-32-5p inhibitor was employed to knock down the expression of miR-32-5p. The overexpression plasmid and si-RNA targeting TOB1 were generated. Clone formation assays under radiant exposure were used to evaluate the radiosensitization. Transwell migration and invasion were employed to test the ability of cell migration and invasion. Luciferase reporter assays were used to confirm the regulation of miR-32-5p on the expression of TOB1. Rescue experiments were conducted to investigate the effects of TOB1 on the functions of miR-32-5p. RESULTS: In this study, we found that miR-32-5p was significantly upregulated in colorectal cancer tissues compared with adjacent normal tissues. The level of miR-32-5p was positively correlated with tumor differentiation and metastasis. Log-rank tests showed that high level of miR-32-5p was significantly correlated with poor overall survival and disease-free survival. Anti-miR-32-5p remarkably enhanced the radiosensitivity and inhibited migration and invasion of colorectal cancer cells. In addition, overexpression of TOB1 obviously increased the radiosensitivity and inhibited migration and invasion of colorectal cancer cells. Moreover, bioinformatics analysis and luciferase reporter assays demonstrated that miR-32-5p suppressed the expression of TOB1 through directly binding to the 3'-UTR of TOB1 mRNA. Rescue experiments indicated that miR-32-5p regulated the radiosensitivity, migration and invasion of colorectal cancer cells through inhibiting TOB1 expression. CONCLUSION: This study suggested that miR-32-5p may serve as a prognostic and therapeutic target for colorectal cancer, and downregulation of miR-32-5p enhanced the radiosensitivity and inhibited migration and invasion through promoting TOB1 expression.

Epigallocatechin gallate enhances the motor neuron survival and functional recovery after brachial plexus root avulsion by regulating FIG4.

The survival of motor neurons (MNs) is the key to recovery of the motor function after brachial plexus root avulsion (BPRA). (-)-epigallocatechin-3-gallate (EGCG) exerts neuroprotective roles in neurons under different pathological conditions. However, the role of EGCG in regulating motor neurons under BPRA remains to be unclear. In the present study, we investigated the functional role of EGCG both in vitro and in vivo. In an in vitro study, we observed that EGCG obviously increased the cell survival rate of MNs and FIG4 protein levels compared with the vehicle control, with a peak level observed at 50 µM; EGCG can also upregulate FIG4 to reduce the cell death of MNs and increase the neurite outgrowth under oxidative stress; moreover, EGCG can upregulate FIG4 to promote the functional recovery and the survival of MNs in the ventral horn in mice after BPRA. These combined results may lay the foundation for EGCG to be a novel strategy for the treatment of BPRA.

A randomized phase II, open-label and multicenter study of combination regimens of bortezomib at two doses by subcutaneous injection for newly diagnosed multiple myeloma patients.

PURPOSE: Combinations of bortezomib (Velcade), cyclophosphamide and dexamethasone have shown significant efficacy and safety for patients of newly diagnosed multiple myeloma (NDMM). In this study, we compared the efficacy and safety of modified VCD regimens with novel changes in bortezomib dose and schedule for NDMM. METHODS: Eighty-five NDMM patients from multiple centers were randomly assigned to a high-dose (1.6 mg/m2) (group A) or a low-dose (1.3 mg/m2) (group B) bortezomib, administrated on days 1, 6, 11, and 16 subcutaneously in a 4-week cycle for nine cycles, combined with 40 mg dexamethasone on bortezomib days and cyclophosphamide 300 mg/m2 on days 1-3 intravenously. RESULTS: After four cycles, complete response (CR) or better in group A (43.6%) was higher than that in group B (12.8%) (P = 0.002). During induction, for patients with R-ISS stage III, the CR or better rate in group A was superior to that in group B (P = 0.01). Of patients < 65, the CR or better rate of group A was superior to that of group B (P = 0.004). Rapid onset of CR occurred in group A (P < 0.01). Meanwhile, rate of 3-4 diarrhea was higher in group A (P = 0.03), which caused higher rate of dose reduction for patients ≥ 65 (P = 0.041). No significant difference between the two groups in PFS and OS. CONCLUSIONS: The studied high-dose VCD as induction regimen had an improved CR rate, especially in patients < 65 or with R-ISS stage III, and is feasible for young and high-risk patients. Trial registration ClinicalTrials.gov: NCT02086942.

Mechanistic toxicity of DEHP at environmentally relevant concentrations (ERCs) and ecological risk assessment in the Three Gorges Reservoir Area, China.

Di-(2-ethylhexyl) phthalate (DEHP) associated in vitro/vivo toxicity at current environmentally relevant concentration (ERC) with attendant ecological risks in the Three Gorges Reservoir Area (TGRA) is still elusive. Responding to this challenge, a novel integrated study based on analytical and biological assays was designed to elucidate the underlying mechanisms for toxicity of DEHP and its ecological risks at ERC. In this study, GC-MS analysis showed that the highest environmental concentration of DEHP in the TGRA surface water was nearly double that of WHO and USEPA standards. Both distribution and ecological risk decreased from the upper to middle and lower reaches of the TGRA. In vitro toxicity was assessed by cell viability and DNA damage assays: DEHP exposure at ERCs (100-800 µg/L) caused significant reduction in cell viability and elevated DNA damage. Further, DEHP exposure above 400 µg/L resulted in enhanced migration behavior of cancer cells. For in vivo toxicity assessment, short term acute exposure (7 d, 400 µg/L) apparently activated the PI3K-AKT-mTOR pathway, and chronic low-level exposure (3 months, 10-33 µg/L) suppressed the hypothalamus pituitary thyroid (HPT) axis pathway in zebrafish. In addition, acute low-level exposure (5 d, 33-400 µg/L) to DEHP increased aryl hydrocarbon receptor (AhR) activity in Tg(cyp1a:gfp) zebrafish in a concentration-dependent manner. In short, DEHP at ERC has extended potential to induce diverse in vitro and in vivo toxicity at concentrations that also cause impairment of biochemical function in aquatic species of the TGRA.

New toxicogenetic insights and ranking of the selected pharmaceuticals belong to the three different classes: A toxicity estimation to confirmation approach.

Tetracycline hydrochloride (TH), indomethacin (IM), and bezafibrate (BF) belong to the three different important classes of pharmaceuticals, which are well known for their toxicity and environmental concerns. However, studies are still elusive to highlight the mechanistic toxicity of these pharmaceuticals and rank them using both, the toxicity prediction and confirmation approaches. Therefore, we employed the next generation toxicity testing in 21st century (TOX21) tools and estimated the in vitro/vivo toxic endpoints of mentioned pharmaceuticals, and then confirmed them using in vitro/vivo assays. We found significant resemblance in the results obtained via both approaches, especially in terms of in vivo LC50 s and developmental toxicity that ranked IM as most toxic among the studied pharmaceuticals. However, TH appeared most toxic with the lowest estimated AC50s, the highest experimental IC50s, and DNA damages in vitro. Contrarily, IM was found as congener with priority concern to activate the Pi3k-Akt-mTOR pathway in vitro at concentrations substantially lower than that of TH and BF. Further, IM exposure at lower doses (2.79-13.97 µM) depressed the pharmaceuticals detoxification phase I (CYP450 s), phase II (UGTs, SULTs), and phase III (TPs) pathways in zebrafish, whereas, at relatively higher doses, TH (2.08-33.27 µM) and BF (55.28-884.41 µM) partially activated these pathways, which ultimately caused the developmental toxicity in the following order: IM > TH > BF. In addition, we also ranked these pharmaceuticals in terms of their particular toxicity to myogenesis, hematopoiesis, and hepatogenesis in zebrafish embryos. Our results revealed that IM significantly affected myogenesis, hematopoiesis, and hepatogenesis, while TH and BF induced prominent effects on hematopoiesis via significant downregulation of associated genetic markers, such as drl, mpx, and gata2a. Overall, our findings confirmed that IM has higher toxicity than that of TH and BF, therefore, the consumption of these pharmaceuticals should be regulated in the same manner to ensure human and environmental safety.

Diverse toxicological risks of PAHs in surface water with an impounding level of 175m in the Three Gorges Reservoir Area, China.

The impounding level of 175m for the Three Gorges Reservoir (TGR) is of vital importance for efficient flood control, power generation and convenient navigation in China. However, little is known about the spatial distribution and toxicological risks of major pollutants in the Three Gorges Reservoir Area (TGRA) at that stage. The aim of this study is to probe the ubiquitous polycyclic aromatic hydrocarbons (PAHs) contamination and toxicological impacts in the surface water of the TGRA at the highest water impoundment level of 175m. Our results showed that the Æ©PAHs levels ranged from 83 to 1631ng/L in the upper reaches, 354 to 1159ng/L in the middle reaches, and 23 to 747ng/L in the lower reaches of the TGRA. Source apportionment of PAHs indicated that coal combustion, industrial emissions, heavy traffic, agriculture and shipping activities were the primary sources. Compositional pattern highlighted >85% dominancy of low molecular weight (LMW) PAHs in the reservoir. Risk assessment based on risk quotients (RQs) implied moderate to high ecological risks: the upper reaches>the middle reaches>the lower reaches. However, gene expression profiles portrayed contrary scenario because of the presence of relatively higher footprints of high molecular weight (HMW) PAHs in the middle and the lower reaches, which was confirmed by Cox hazard proportional model. Moreover, the transgenic zebrafish Tg(cyp1a:gfp) induced by PAHs also expressed stronger fluorescent signals in the middle and lower reaches. Taken together, different approaches were employed to firstly reveal the real status of ecological toxicity of PAHs and explore the underlying mechanisms at the highest impounding level of 175m in the TGRA.