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BRAF or RAS mutation-induced aberrant activation of the mitogen-activated protein kinase (MAPK) pathway is frequently observed in human cancers. As the key downstream node of MAPK pathway, ERK1/2 is as an important therapeutic target. GDC-0994 (ravoxertinib), an orally bioavailable, highly selective small-molecule inhibitor of ERK1/2, showed acceptable safety and pharmacodynamic profile in a recent phase I clinical trial. In this study, we investigated dependence of the anti-tumor effect of ERK inhibitor GDC-0994 on genetic alterations in the MAPK pathway. The results showed that GDC-0994 sharply inhibited cell proliferation and colony formation and induced remarkable G1 phase cell-cycle arrest in cancer cells harboring BRAF mutation but had little effect on cell behaviors in most RAS mutant or wild-type cell lines. The expression of a large number of genes, particularly the genes in the cell cycle pathway, were significantly changed after GDC-0994 treatment in BRAF mutant cells, while no remarkable expression change of such genes was observed in wild-type cells. Moreover, GDC-0994 selectively inhibited tumor growth in a BRAF mutant xenograft mice model. Our findings demonstrate a BRAF mutation-dependent anti-tumor effect of GDC-0994 and provide a rational strategy for patient selection for ERK1/2 inhibitor treatment.

ABSTRACT: This study aimed to analyze the polymorphism of the vasoactive intestinal peptide receptor-1 (VIPR-1) gene and its association with growth traits in quail using the PCR-RFLP and sequencing techniques. Genomic DNA was extracted from blood samples of 36 female Savimalt (SV) quails and 49 female French Giant (FG) quails. Growth traits were measured and used for VIPR-1 gene analysis, as body weight (BW), tibia length (TL), chest width (CW), chest depth (CD), sternum length (SL), body length (BL), and tibia circumference (TC). The results showed that 2 SNPs (BsrD I and HpyCH4 IV) were detected in exon 4 to 5 and exon 6 to 7 of the VIPR-1 gene, respectively. The results of association showed that the BsrD I site was not significantly associated with growth traits at 3 or 5 wk of age in the SV strain (P < 0.05), while the BsrD I site was significantly associated with BL at 3 or 5 wk of age in FG (P < 0.05). The HpyCH4 IV site was significantly associated with TL, CW, CD, SL, and BL at 3 wk of age in the SV strain (P < 0.05), while the HpyCH4 IV site was significantly correlated with BW, CW, SL, and BL at 5 wk of age in SV (P < 0.05). The HpyCH4 IV site was significantly associated with TL and TC at 3 wk of age in FG (P < 0.05), while the HpyCH4 IV site was significantly associated with TC at 5 wk of age in FG (P < 0.05). Four haplotype combinations based on 2 SNPs showed significantly association with BW, CW, CD, SL, BL, and TC at 3 or 5 wk of age in SV (P < 0.05). There was not significant association between 3 haplotype combinations with growth trait at 3 or 5 wk of age in FG (P > 0.05). In conclusion, the VIPR-1 gene could be used as a molecular genetic marker to improve growth traits in quail.

ABSTRACT: Insulin-like growth factor 1 receptor (IGF-1R) gene is the main effector of insulin-like growth factor (IGF), which plays an important role in growth, development and reproduction of the animal organism. This study aimed to investigate the association of IGF-1R gene single nucleotide polymorphisms (SNPs) with egg quality and carcass traits of quail by direct sequencing. In this study, genomic DNA was extracted from quail blood samples of 46 Chinese yellow (CY) quail, 49 Beijing white (BW) quail and 48 Korean (KO) quail strains. Egg quality and carcass traits were measured and used for IGF-1R gene analysis in 3 quail strains. The results showed that 2 SNPs (A57G and A72T) of the IGF-1R gene were detected in 3 quail strains. The A57G was significantly associated with yolk width (YWI) in BW strain (P < 0.05). Whereas A72T was significantly associated with egg shell thickness (EST) in BW strain (P < 0.05), and significantly associated with egg weight (EW), egg long (EL), and egg short (ES) in KO strain (P < 0.05). Haplotypes based on 2 SNPs showed significant effect on EST in 3 quail strains (P < 0.05), it also has a significant effect on EW in KO strain (P < 0.05). Meanwhile, A72T was significantly associated with liver weight (LW) and dressing percentage (DP) in 3 strains (P < 0.05). Haplotypes showed significant effect on LW (P < 0.05). Therefore, the IGF-1R gene may be a molecular genetic marker to improve egg quality and carcass traits in quails.

ABSTRACT: This study aimed to identify polymorphisms of gonadotropin-releasing hormone (GnRH) gene and their association with growth traits in quail by PCR and direct sequencing. Genomic DNA was extracted from quail blood samples of 36 from Savimalt (SV) and 49 from French Giant (FG). Growth traits were measured and used for candidate gene analysis, as body weight (BW), shank length (SL), chest width (CW), chest depth (CD), breastbone length (BBL), body length (BL), and shank circumference (SC). The results showed that a total of 20 SNPs were detected in GnRH gene, whereas 8 SNPs were significantly associated with growth traits (P < 0.05). The T215C, G279A, C458T, A520G, and C547G were significantly associated with SL at 3 wk of age in the FG strain, whereas A583T was significantly related to BBL and BL, and C591T was significantly related to SL, BBL, and BL, whereas A592G was significantly correlated with SL, CW, CD, BBL, and BL (P < 0.05). The 8 SNPs were significantly related to CW, CD, and BBL at 3 wk of age in the SV strain, whereas A583T, C591T, and A592G were significantly associated with BW (P < 0.05). The G279A showed significant correlations with SL at 5 wk of age in FG, whereas A583T showed significant associations with SC in FG, and C591T was significantly associated with BW and SC in FG, whereas A592T was significantly related to BW, SL, and CD in FG (P < 0.05). The T215C, G279A, C458T, A520G, and C547G were significantly correlated with BW, CW, BBL, and BL at 5 wk of age in SV, whereas A583T, C591T, and A592G were significantly related to BW, SL, CW, BBL, and BL (P < 0.05). Haplotypes based on 8 SNPs showed significant correlation with BW, SL, CW, CD, BBL, BL, and SC in FG (P < 0.05). In conclusion, the GnRH gene could be used as a molecular genetic marker to provide theoretical foundation to improve growth traits in quail.

Snow is an efficient scavenger for the deposition of contaminants. Atmospheric transport and snow deposition jointly control the distribution of pollutants in remote mountain/polar regions. But can the contaminants contained within snow be used to reflect the interactions of air circulation patterns? The physicochemical properties of perfluoroalkyl substances (PFASs) are unique because of their high water solubilities. Taking advantage of this, 15 surface-snow and 3 snow-pit samples were collected across a vast area of western China (spanning 20° of latitude and 25° of longitude), to investigate the concentrations, composition profiles (fingerprints), and deposition fluxes of PFASs. Both a high concentration (3974 pg/L) and deposition flux (4.0 μg/m2/yr) for a total of 16 PFASs were found in the snow at Yulong, the most southern sample site, possibly because of its close proximity to source regions of pollutants in South Asia and high rate of snow deposition. Perfluorobutanoic acid was the most commonly found chemical in snow, but in general the PFAS composition in the snow of western China showed large spatial differences, with long-chain (C > 10) PFASs being relatively dominant in the north and west of the region and short-chain (C

The purpose of this work is to investigate the function of SNHG1, a long non-coding RNA implicated in disease progression, apoptosis, and proliferation, in order to solve the problem of hypoxic-ischemic encephalopathy (HIE) in newborn care. We investigated the impact of overexpressing SNHG1 on hypoxia-induced apoptosis and studied its expression in BV2 microglial cells under hypoxic circumstances. As a result of modifying YY1 expression, SNHG1′s overexpression prevents apoptosis, as our data demonstrate that it is considerably downregulated under hypoxia. We demonstrate that SNHG1 might potentially reduce microglial ischemia-reperfusion damage by using sophisticated nanoengineering drug delivery technologies to target it. This provides encouraging information for the therapy of ischemic epilepsy.

The drinking water quality index (DWQI) transforms multiple water quality parameters into a dimensionless number, thus, presenting comprehensive status of drinking water in an intuitive manner. However, there are very few studies summarize the current progress of DWQI. Thus, we systematically reviewed 514 articles to evaluated the methods used in each DWQI developmental step with the aim of helping environmental workers choose the most appropriate index-generation model for local application. We observed that existing studies usually select 10–15 (55.4% of the studies) physicochemical parameters (such as Cl, pH, SO4, Ca, Mg etc.) to develop a DWQI. The weights of selected parameters are most often assigned using the five-scale method (53.7%), but these values varied considerably among the different studies due to the lack of clear evaluation standards. Semiquantitative and quantitative methods have been applied to overcome the subjectivity involved in these steps, including the analytical hierarchy process, information entropy, and factor analysis etc. The measurement results are normalized using the permissible limit, and multiplied by the corresponding weight, then added up to get the final DWQI result. Specifically, two distinct approaches, fuzzy logic and WQI adopted by Canadian Council of Ministers of the Environment (CCME-WQI) are discussed. Comparing with the more common approach based on classic set theory, fuzzy logic can better resolve the inherent uncertainty in the assessment of DWQI, whereas, the CCME-WQI is more appropriate for evaluating the spatiotemporal variations in DWQI over a given period. Some studies have assessed the robustness of the developed DWQI by conducting sensitivity analyses and its effectiveness was validated by comparisons with expert scores, existing WQIs or toxicological endpoints. Fifty-seven predefined classification schemes have been proposed to interpret DWQI value. As no one-size-fits-all approach exists for DWQI development, we recommended here to clarify the principles to be followed at each step, disclose the details of each method, and validate the developed index in future research. Meanwhile, additional efforts are required to develop new water quality monitoring methods and conduct DWQI studies on central water supply system.