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This study presents the first incidence of intersex associated with testis-ova in spotted scat (Scatophagus argus) reared in a controlled environment. The testis-ova is associated with the abnormal occurrence of primary oocytes (POs) in some male testis and is referred to as ectopic primary oocytes (Ecto-PO), whiles individuals with Ecto-PO are called "Ecto-PO gonad/individuals." We investigated gonads of 129 male spotted scat aged 4-12 and 18 months after hatch (mah) by histological studies for the presence of female sexual characteristics. A total of 20 out of 88 gonads representing 22.7% of male fish aged 6-12, or 15.5% of all male fish sampled, were found to have visible Ecto-PO. At least, the Ecto-PO had an average of 7 oocytes per gonadal section, indicating high severity. The Ecto-PO appears after sex differentiation and degenerates during sexual maturation. The Ecto-PO did not significantly influence the expression pattern of male and female sex-related genes performed using qPCR. Immunofluorescence of 42sp50 specifically stained the Ecto-PO without influence from the surrounding testicular tissues. In addition, temperature did not correlate with the proliferation of the Ecto-PO, but rather gonad developmental strategy. The results show that the naturally occurring Ecto-PO might not be detrimental to testis development and could be considered a frequent-high-level incidence of natural aberration. This study highlights the intricacy of fish sex differentiation and provides a new research chapter to ascertain the mystery behind the occurrence of Ecto-PO.

Objective: Yes-associated protein 1 (YAP1) regulates cell proliferation and apoptosis. Abnormal miR-375 level was related to thyroid cancer. Software predicted a relationship between miR-375 and YAP1. Our study investigated whether miR-375 regulates YAP1 expression and affects thyroid cancer cells. Methods: The tumor tissues and adjacent tissues of thyroid cancer patients were collected to measure miR-375 and YAP1 expression. The dual luciferase reporter experiment verified the regulation between miR-375 and YAP1. Thyroid cancer cell line B-CPAP and TPC-1 cells were divided into miR-NC group and miR-375 mimic group followed by analysis of cell proliferation by flow cytometry, caspase-3 activity, and cell clone formation ability by plate cloning assay. Results: Compared with adjacent cancer tissues, miR-375 in thyroid cancer tissues was decreased and YAP1 was increased. miR-375 targets YAP1. Compared with Nthy-ori 3-1 cells, miR-375 in B-CPAP and TPC-1 cells was significantly reduced and YAP1 was increased. Transfection with miR-375 mimic significantly inhibited cell proliferation, increase caspase-3 activity, and reduced the ability of cells to form clones. Conclusion: miR-375 can inhibit YAP1 expression, decrease the proliferation of thyroid cancer cells, induce cell apoptosis, and reduce clone formation.

Supplementary Figure and Table Legends. List of supporting information

Supplementary Fig. S1-S9. Supplementary Fig. S1. miR-195 expression is significantly reduced in both human PCa cells and tissues; Supplementary Fig. S2. Kaplan-Meier analyses of biochemical recurrence (BCR)-free survival, non-metastatic BCR-free, survival overall survival and non-metastatic survival of prostate cancer (PCa) patients based on miR-195 expression in Taylor dataset; Supplementary Fig. S3. Knockdown of miR-195 expression enhances invasion, migration, but inhibits apoptosis of LNCaP and DU145 cells; Supplementary Fig. S4. The inhibition of miR-195 enhances tumor growth, angiogenesis and invasion in vivo; Supplementary Fig. S5. Top ten enriched KEGG pathways (A) and gene ontology (GO) biological processes (B) involved by differentially-expressed proteins induced by miR-195; Supplementary Fig. S6. The knockdown of RPS6KB1 could imitate the tumor suppressive effects of miR-195; Supplementary Fig. S7. The re-expression and knockdown of RPS6KB1 could respectively rescue and imitate the tumor suppressive effects of miR-195; Supplementary Fig. S8. Reverse correlation between miR-195 and RPS6KB1 expression in human PCa tissues; Supplementary Fig. S9. MMP-9, VEGF, BAD and E-cadherin function as downstream effectors of miR-195-RPS6KB1 axis.

Supplementary Table S1 shows the list of primary antibodies used for immunohistochemical staining and immunoblotting assays. Supplementary Table S2 shows the clinical characteristics of 626"driver-gene-negative" LUAD patients from four cohorts. Supplementary Table S3 shows the clinical characteristics of 52 "driver-gene-negative" LUAD patients whose samples were used for microarray analysis. Supplementary Table S4 shows the microarray results of the genes in the Wnt-signaling pathway. Supplementary Table S5 shows the univariate association of 41 candidate genes with overall survival in the training SYSUFH cohort. Supplementary Table S6 shows the C-index of the three enrolled factors in the nomogram in the SYSUFH training cohort. Supplementary Table S7 indicates the summary of relevant findings of ITH analysis of twenty-one patients with "driver-gene-negative" LUAD. Supplementary Figure S1 shows the workflow to determine "driver-gene-negative" status in LUAD patients. Supplementary Figure S2 shows the pathological diagnosis of enrolled LUAD patients. Supplementary Figure S3 shows the study flowchart. Supplementary Figure S4 shows the signaling GO analysis and cellular component classification analysis for the genome-wide microarray. Supplementary Figure S5 shows the β-Catenin expression characteristics in patients with "driver-gene-negative" LUAD from the SYSUFH training cohort. Supplementary Figure S6 shows the different expression profiles of β-catenin in EGFRmt, KRASmt, and ALKft LUAD. Supplementary Figure S7 shows the protein expression characteristics of 41 candidate genes in 8 "driver-gene-negative" LUAD patients. Supplementary Figure S8 shows these representative immunohistochemical staining for 41 candidate molecules in 626 "driver-gene-negative" LUAD patient tissue samples. Supplementary Figure S9 shows kaplan-Meier estimates of progression-free survival (PFS) based on the CSDW signature in the four cohorts. Supplementary Figure S10 shows that the CSDW signature predicts clinical outcomes in all 626 patients with "driver-gene-negative" LAUD. Supplementary Figure S11 shows that the optimum cutoff value of the four prognostic markers was determined using the X-tile program in the training set and Kaplan-Meier analysis of all 626 LUAD samples. Supplementary Figure S12 shows the correlation between the four genes in the CSDW signature and tumor size, lymphatic metastasis and distant organ metastasis. Supplementary Figure S13 shows that kaplan-Meier analysis was used to compare the performance of the CSDW signature in all 626 LUAD patients with different clinicopathological risk factors. Supplementary Figure S14 shows that the nomogram to predict the 3-year and 5-year overall survival (OS) of "driver-gene-negative" LUAD patients. Supplementary Figure S15 shows that time-dependent ROC curves to evaluate the sensitivity and specificity of the nomogram in predicting overall survival in "driver-gene-negative" LUAD patients. Supplementary Figure S16 shows that intra- and inter-sample variability of β-catenin, SOX9, DVL3 and Wnt2b protein levels detected by IHC.

Supplementary Tab S1-S9. Supplementary Tab. S1. Follow-up clinicopathological information of patients from MGH cohort; Supplementary Tab. S2. ligonucleotide Sequence for all the primers used in the study; Supplementary Tab.S3. The antibodies used in this study; Supplementary Tab.S4. Associations of miR-195 and RPS6KB1 protein expression with clinicopathological features of prostate cancer (PCa) patients; Supplementary Tab.S5. Prognostic value of miR-195 expression for the biochemical recurrence-free survival in univariate and multivariate analysis by Cox Regression; Supplementary Tab. S6 Differentially expressed proteins detected by iTRAQ; Supplementary Tab. S7 Canonical pathways analysis by IPA; Supplementary Tab. S8 Diseases and bio functions analysis by IPA; Supplementary Tab.S9. Prognostic value of RPS6KB1 expression for the biochemical recurrence-free survival in univariate and multivariate analysis by Cox Regression.

Purpose:Examining the role of developmental signaling pathways in “driver gene–negative” lung adenocarcinoma (patients with lung adenocarcinoma negative for EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as “driver gene–negative”) may shed light on the clinical research and treatment for this lung adenocarcinoma subgroup. We aimed to investigate whether developmental signaling pathways activation can stratify the risk of “driver gene–negative” lung adenocarcinoma.Experimental Design:In the discovery phase, we profiled the mRNA expression of each candidate gene using genome-wide microarrays in 52 paired lung adenocarcinoma and adjacent normal tissues. In the training phase, tissue microarrays and LASSO Cox regression analysis were applied to further screen candidate molecules in 189 patients, and we developed a predictive signature. In the validation phase, one internal cohort and two external cohorts were used to validate our novel prognostic signature.Results:Kyoto Encyclopedia of Genes and Genomes pathway analysis based on whole-genome microarrays indicated that the Wnt/β-catenin pathway was activated in “driver gene–negative” lung adenocarcinoma. Furthermore, the Wnt/β-catenin pathway–based gene expression profiles revealed 39 transcripts differentially expressed. Finally, a Wnt/β-catenin pathway–based CSDW signature comprising 4 genes (CTNNB1 or β-catenin, SOX9, DVL3, and Wnt2b) was developed to classify patients into high-risk and low-risk groups in the training cohort. Patients with high-risk scores in the training cohort had shorter overall survival [HR, 10.42; 6.46–16.79; P < 0.001) than patients with low-risk scores.Conclusions:The CSDW signature is a reliable prognostic tool and may represent genes that are potential drug targets for “driver gene–negative” lung adenocarcinoma.

Purpose: To investigate the involvement of hsa-miRNA-195-5p (miR-195) in progression and prognosis of human prostate cancer.Experimental Design: qRT-PCR was performed to detect miR-195 expression in both prostate cancer cell lines and clinical tissue samples. Its clinical significance was statistically analyzed. The roles of miR-195 and its candidate target gene, ribosomal protein S6 kinase, 70 kDa, polypeptide 1 (RPS6KB1) in prostate cancer progression were confirmed on the basis of both in vitro and in vivo systems.Results: miR-195 downregulation in prostate cancer tissues was significantly associated with high Gleason score (P = 0.001), positive metastasis failure (P < 0.001), and biochemical recurrence (BCR, P < 0.001). Survival analysis identified miR-195 as an independent prognostic factor for BCR-free survival of prostate cancer patients (P = 0.022). Then, we confirmed the tumor suppressive role of miR-195 through prostate cancer cell invasion, migration, and apoptosis assays in vitro, along with tumor xenograft growth, angiogenesis, and invasion in vivo according to both gain-of-function and loss-of-function experiments. In addition, RPS6KB1 was identified as a novel direct target of miR-195 through proteomic expression profiling combined with bioinformatic target prediction and luciferase reporter assay. Moreover, the reexpression and knockdown of RPS6KB1 could respectively rescue and imitate the effects induced by miR-195. Importantly, RPS6KB1 expression was closely correlated with aggressive progression and poor prognosis in prostate cancer patients as opposed to miR-195. Furthermore, we identified MMP-9, VEGF, BAD, and E-cadherin as the downstream effectors of miR-195–RPS6KB1 axis.Conclusion: The newly identified miR-195–RPS6KB1 axis partially illustrates the molecular mechanism of prostate cancer progression and represents a novel potential therapeutic target for prostate cancer treatment. Clin Cancer Res; 21(21); 4922–34. ©2015 AACR.

Supplementary Methods

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-017-0615-x.

Spotted scat (Scatophagus argus) is an important mariculture fish that is of great economic significance in East and Southeast Asia. To date, there are no studies on ovary development and regulation in S. argus. Herein, the ovary transcriptome profiles of S. argus at different stages were constructed, and the genes and pathways potentially involved in secondary follicle growth were identified. A total of 25,426 genes were detected by sequencing the mRNAs from the ovary libraries at stage III (n=3) and IV (n=3). Notably, 2950 and 716 genes were up-regulated and down-regulated in the stage IV ovary, respectively, compared to the stage III ovary. The differentially expressed genes (DEGs) were found to be mostly involved in regulating steroidogenesis, vitellogenesis, lipid metabolism, and meiosis. Up-regulation of steroid hormone synthesis pathway genes (fshr, cyp17a1, and foxl2) and insulin-like growth factor pathway genes (igf1r, ifg2r, igfbp1, igfbp3, and igfbp7) in the ovary at stage IV was possibly the reason for the increased serum estrogen. Moreover, ppara, ppard, fabp3, and lpl were up-regulated in the stage IV ovary and were potentially involved in the lipid droplet formation in the oocyte. Many DEGs were involved in the cellular cycle, meiosis, and cAMP or cGMP synthesis and hydrolysis, indicating that meiosis was restarted at stage IV ovary. In addition, numerous TGF-beta signal pathway genes were up-regulated in the stage IV ovary. This ovary transcript dataset forms a baseline for investigating functional genes associated with oogenesis in S. argus.

COVID-19, referred to as new coronary pneumonia, is an acute infectious disease caused by a new type of coronavirus SARS-CoV-2. To evaluate the effect of integrated Chinese medicine and Western medicine in patients with COVID-19 from overseas. Data were collected from 178 COVID-19 patients overseas at First Affiliated Hospital of Xiamen University from April 1, 2021 to July 31, 2021. These patients received therapy of integrated Chinese medicine and western medicine. Demographic data and clinical characteristics were extracted and analyzed. In addition, the prescription which induced less length of PCR positive days and hospitalization days than the median value was obtained. The top 4 frequently used Chinese medicine and virus-related genes were analyzed by network pharmacology and bioinformatics analysis. According to the chest computed tomography (CT) measurement, abnormal lung findings were observed in 145 subjects. The median length of positive PCR/hospitalization days was 7/7 days for asymptomatic subjects, 14/24 days for mild subjects, 10/15 days for moderate subjects, and 14/20 days for severe subjects. The most frequently used Chinese medicine were Scutellaria baicalensis (Huangqin), Glycyrrhiza uralensis (Gancao), Bupleurum chinense (Chaihu), and Pinellia ternata (Banxia). The putative active ingredients were baicalin, stigmasterol, sigmoidin-B, cubebin, and troxerutin. ACE, SARS-CoV-2 3CL, SARS-CoV-2 Spike, SARS-CoV-2 ORF7a, and caspase-6 showed good binding properties to active ingredients. In conclusion, the clinical results showed that integrated Chinese medicine and Western medicine are effective in treating COVID-19 patients from overseas. Based on the clinical outcomes, the putative ingredients from Chinese medicine and the potential targets of SARS-CoV-2 were provided, which could provide a reference for the clinical application of Chinese medicine in treating COVID-19 worldwide.

GLP-1 receptor (GLP-1R) and neuropeptide Y

The origin of low δ18O signals in zircons from the Early Cretaceous A-type granites in eastern China has long been disputed. It is uncertain whether the 18O-depleted features were inherited from high-temperature hydrothermal altered source rock or resulted from water-rock interaction after emplacement. In this paper, zircon oxygen isotopes in the ∼130 Ma Kulongshan A-type granites in the northern North China Craton are analyzed. The zircons could be subdivided into 5 types based on their luminescent intensity and internal structures in CL images. Their δ18O values also vary in different types and show negative correlation with U and Th contents and accompanying cumulative α-decay doses, implying that their δ18O values may have been modified to various degrees by meteoric water-rock interaction after the accumulation of radiation damage. The idea is further confirmed by oxygen isotopic equilibrium calculation between co-existing mineral pairs. It is inferred that only the least-influenced zircons, with slightly elevated δ18O values than normal mantle, have preserved the magmatic oxygen isotopes. In combination with other evidences, it is proposed that the A-type granites are lower-crustal-derived, unnecessarily invoking a high-temperature hydrothermal altered source. The proposition is applicable to many other Cretaceous A-type granites that have similar zircon behaviors.

The combination of incretin-based therapies and PYY analogue has shown great potential for the treatment of type 2 diabetes (T2DM) and obesity. In this study we developed the first example of a unimolecular triple agonist peptide to simultaneously target GLP-1, glucagon and Y

Cholinesterase and monoamine oxidase are potential targets for the therapy of Alzheimer's disease. A series of novel AP2238-clorgiline hybrids as multi-target agents were designed, synthesized and investigated in vitro for their inhibition of cholinesterases and monoamine oxidases. Many compounds displayed balanced and good inhibitory activity against AChE, BuChE and MAO-B with an obvious selective inhibitory effect on MAO-B. Among them, Compound 5l showed the most balanced potency to inhibit ChEs (eeAChE: IC

42Sp50 is an isoform of the eukaryotic translation elongation factor 1 A (eEF1A) and is vital for fish ovarian development. Spotted scat (Scatophagus argus) is a popular marine cultured fish species in Southern Asia and China, and its artificial reproduction is complicated, with a relatively low success ratio in practice. In this study, the 42Sp50 gene was cloned from spotted scat. Tissue distribution analysis showed that 42Sp50 was mainly expressed in the ovary. qRT-PCR showed that 42Sp50 expression levels gradually decreased insignificantly in the ovaries from phase II to IV. Western blot analysis showed that 42Sp50 was highly expressed in the ovary, while it was almost undetectable in the testis. Immunohistochemistry analysis stained 42Sp50 mainly in the cytoplasm of the previtellogenic oocytes in ovaries of normal XX-female and sex-reversed XY-female. Aside from fish and amphibians, 42Sp50 was also identified in some reptile species using genomic database searching. Analyses of the transcriptome data from four different fish species (Hainan medaka (Oryzias curvinotus), silver sillago (Sillago sihama), Nile tilapia (Oreochromis niloticus), and Hong Kong catfish (Clarias fuscus)) revealed ovaries biased expression of 42Sp50 in all, similar to spotted scat. While the neighbor genes of 42Sp50 did not show ovary biased expression in the fish species analyzed. Bisulfite Sequencing PCR (BSP) results showed that the DNA methylation level of 42Sp50 promoter was low in ovaries, testes, and muscles. The luciferase reporter assay demonstrated that Dmrt4 activated 42Sp50 expression in the presence of Sf1 or Foxh1. These results suggest that 42Sp50 may be involved in regulating the early phase oocytes development of spotted scat.

In the aquaculture industry, fish oil is widely used as a nutritional supplement to promote the gonadal maturation of broodstocks, while the mechanism of fish oil on ovary development remain unclear. Herein, female adult spotted scat (Scatophagus argus) with most ovaries at phase II were fed with diets containing 8% soybean oil (SO) or 8% fish oil (FO) for 60 days. The final average fish body weight was similar between FO and SO groups. The average gonadosomatic index (GSI) of FO group was higher (non-significant) than that of SO group. Finally, the phase IV ovary of the FO and SO groups were 7 and 5 out of 10, respectively. The serum estradiol (E2) level of the FO group was significantly higher than that of the SO group. The proportions of n-3 long-chain polyunsaturated fatty acids (LC-PUFA, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)) in the ovaries were much higher in the FO group than in the SO group. These results suggest that the maturity level of the FO group is relatively higher than that of the SO group. Transcriptome sequencing was used to detect the ovary gene expression. Comparatively, the ovary transcriptome analysis showed 68 up-regulated and 193 down-regulated genes in the FO group. The expression levels of Jund and Jun necessary for the ovary maturation were up-regulated in the FO group, while Pparγ and Cxcl12, which could inhibit the ovary development, were down-regulated in the FO group. Cyp3a27 coding the enzyme for degrading the estrogen was significantly down-regulated in the FO group and coincided with the increase of its serum E2. Kif5b which could regulate the glucose metabolism was up-regulated in the FO group. Serum insulin level was also increased in the FO group. Additionally, Aldh3a2 and Plin2 related to lipid metabolism were significantly down-regulated in the FO group. Briefly, dietary fish oil can influence the expression of genes related to steroid hormone, glucose and lipid metabolism. This study will clarify the mechanism of dietary fish oil in promoting ovary development in teleost fish.

The reproductive-related studies, including genetic and genomic such as gonadal transcriptome analyses, have previously focused on the adult spotted scat, with little information on juvenile fish. Transcriptomics is a powerful tool that allows for massive parallel analysis to identify differential expression and the patterns of gene expression holistically at a particular stage in a cell or tissue development. This study presents the first report on gonadal transcriptome analysis of the differentiating (juvenile; 4 months after hatch; stage I ovary and testis) spotted scat gonads. The study revealed potential reproduction and gonadal development-related genes. A total of 25936 genes were identified, of which 16248 were co-expressed, 17893 and 17258 expressed in males and females, respectively, from sequence data of testis I (n = 3) and ovary I (n = 2). A total of 6549 differentially expressed genes (DEGs) were identified between males and females. Genes attributable to male gonad development pathway such as dmrt1, gsdf, and amh are significantly expressed in differentiating testes, while female-related genes such as foxl2, cyp19a1a, 42sp50 and sox3 were expressed considerably in differentiating ovaries. In addition, dmrt1/dmrt1y was not expressed in the female (FPKM=0.00), while its paralog dmrt1b was expressed in both males and females. In the male pathway, dmrt1y and gsdf are critical for sex determination and maintenance while foxl2/foxl3 and cyp19a1a are critical in the female development pathway. The current studies provide an insight into the expression patterns of sex and gonadal-related genes in differentiating gonads of spotted scat.

Mesozoic intermediate-felsic magmatic rocks in the eastern North China Craton commonly show geochemical similarity to adakites. However, the lack of direct constraints from partial melting experiments at high pressures and temperatures fuels a debate over the origin of these rocks. In this work, we performed partial melting experiments at 1.5 ​GPa and 800–950 ​°C on amphibolite samples collected from the vicinity of the Mesozoic potassium-rich adakitic rocks in the Zhangjiakou area, northern margin of the North China Craton. The experimental melts range from granitic to granodioritic compositions, with SiO2 ​= ​56.4–72.6 ​wt.%, Al2O3 ​= ​16.1–19.3 ​wt.%, FeO∗ ​= ​2.4–9.6 ​wt.%, MgO ​= ​0.3–2.0 ​wt.%, CaO ​= ​0.6–3.8 ​wt.%, Na2O ​= ​4.7–5.3 ​wt.%, and K2O ​= ​2.6–3.9 ​wt.%, which are in the ranges of the surrounding Mesozoic potassium-rich adakitic rocks, except for the higher Al2O3 contents and the data point at 1.5 ​GPa and 800 ​°C. Trace element compositions of the melts measured by LA-ICP-MS are rich in Sr (849–1067 ​ppm) and light rare earth elements (LREEs) and poor in Y (

A compact wideband coplanar waveguide (CPW) excited slot antenna with dual-circular polarization (DCP) is presented and fabricated in this paper. Two inverted-L-shaped patches are implanted in a square slot to achieve wideband DCP characteristic. The feed line is terminated on an inverted-L-shaped patch. Moreover, two rectangular slots are added on the corners of the antenna to improve the bandwidth of axial ratio (AR) and the voltage standing wave ratio (VSWR). The simulated results show that the designed antenna can generate a good impedance bandwidth of 70.4% and a 3-dB AR bandwidth of 48.6%, respectively. This antenna possesses the qualities of small size, simple structure, and good dual-circular polarization.

Diabetes is characterized by pancreas dysfunction and is commonly associated with obesity. Hypoglycemic agents capable of improving β-cell function and reducing body weight therefore are gaining increasing interest. Though glucagon-like peptide 1 receptor (GLP-1R)/cholecystokinin 2 receptor (CCK-2R) dual agonist ZP3022 potently increases β-cell mass and improves glycemic control in diabetic db/db mice, the in vivo half-life (t1/2) is short, and its body weight reducing activity is limited. Here, we report the discovery of a series of novel GLP-1R/CCK-2R dual agonists. Starting from Xenopus GLP-1, dual cysteine mutation was conducted followed by covalent side chain stapling and albumin binder incorporation, resulting in a stabilized secondary structure, increased agonist potency, and improved stability. Further C-terminal conjugation of gastrin-6 generated GLP-1R/CCK-2R dual agonists, among which 6a and 6b showed higher stability and hypoglycemic activity than liraglutide and ZP3022. Desirably, 6a and 6b exhibited prominent metabolic benefits in diet-induced obesity mice without causing nausea responses and exerted considerable effects on β-cell restoration in db/db mice. These preclinical studies suggest the potential role of GLP-1R/CCK-2R dual agonists as effective agents for treating diabetes and related metabolic disorders.

Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor dual agonist have promising therapeutic effects in the treatment of obesity and diabetes. Moreover, GLP-1 and cholecystokinin 2 (CCKThe in vitro potency of this novel peptide Xenopus (x) GLP-1/GCG/CCKxGLP/GCG/gastrin was a potent and selective GLP-1, GCG and CCKThese results demonstrate the therapeutic potential of xGLP-1/GCG/gastrin for the treatment of obesity and diabetes.

Unlike mammals and birds, many fishes have young sex chromosomes, providing excellent models to study sex chromosome differentiation at early stages. Previous studies showed that spotted scat possesses an XX-XY sex determination system. The X has a complete

Basaltic underplating revealed by lower crustal xenoliths is usually considered to be manifested by younger zircon ages than those of the pre-existing crust and/or Sr–Nd isotopic heterogeneity resulting from mixing between mantle-derived basaltic melts and crust. The Hannuoba mafic lower crustal xenoliths have long been regarded as a typical example of Mesozoic underplating owing to the presence of 80–160 Ma zircons and evolved Sr–Nd isotopic compositions. However, our integrated study shows that most Mesozoic zircons in the Hannuoba mafic xenoliths precipitated from partial melts derived from the ancient lower crust. Although a few young zircons may record Mesozoic underplating, none of the xenoliths are products of Mesozoic underplating. It provides the first direct evidence that some zircons in lower crustal xenoliths could be exotic. The contrasting O–Hf isotopic compositions of Mesozoic zircons from the Hannuoba lower crustal xenoliths allow us to distinguish zircons that were grown from different hydrous melts from those that represent recrystallized pre-existing zircons. This has major implications for geological interpretation of the age diversity commonly observed in deep-seated xenoliths worldwide. Furthermore, at Hannuoba both the ∼1.8 Ga zircon ages from the granulite terrain and most of the 1.8–1.9 Ga zircon ages from a previously reported banded granulite xenolith also reflect metamorphism rather than underplating. It demonstrates that high-grade metamorphism or partial melting of Archean rocks can result in zircons with significantly younger U–Pb and THfDM ages. We infer that some granulite xenoliths previously regarded as products of Paleoproterozoic basaltic underplating from other regions (e.g., the Wyoming craton and the Siberian craton) may actually be remnants or derivatives of the pre-existing Archean lower crust. The large range in Sr–Nd isotopic compositions for various Hannuoba lower crustal xenoliths is unlikely to have resulted from mixing between basaltic melts and crust but was rather inherited from the ancient lower crust. Most of the Hannuoba mafic xenoliths can be best explained as residues left after partial melting of the late Archean lower crust that may be represented by the granulite terrain to produce the voluminous 125–143 Ma intermediate–felsic magmatic rocks. Therefore, young zircon ages and heterogeneous Sr–Nd isotopic compositions are insufficient criteria to infer recent underplating. Combined with literature data, it shows that Archean mafic granulite xenoliths are widespread globally, thus arguing against previous suggestion that mafic granulites from the lower crust of most Archean cratons might have formed from post-Archean basaltic underplating. It is implied that the role of basaltic underplating in the evolution of the lower crust in many regions may need to be re-evaluated.

Rationale: Cancer stem cells (CSCs) are considered to be essential for tumorigenesis, recurrence, and metastasis and therefore serve as a biomarker for tumor progression in diverse cancers. Recent studies have illustrated that specific miRNAs exhibit novel therapeutic potential by controlling CSC properties. miR-1275 is upregulated in lung adenocarcinoma (LUAD) and enhances its stemness. However, the underlying mechanisms have not been elucidated. Methods: miRNA expression microarray of LUAD and adjacent nontumor tissues was used to identify miRNAs involved in LUAD malignant progression. miR-1275 expression level was determined using quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH), and its correlation with clinicopathological characteristics was analyzed in LUAD specimens. The upstream regulator of miR-1275 was validated by chromatin immunoprecipitation (ChIP). The biological functions and underlying mechanisms of miR-1275 were investigated both in vitro and in vivo. Results: MiR-1275 was highly upregulated in lung cancer cell lines and LUAD tissues. Overexpression of miR-1275 in lung cancer patients was associated with shorter overall- and recurrence-free-survival. Proto-oncogene HIF-1ɑ was identified as the transcription mediator of miR-1275. Activation of Wnt/β-catenin and Notch signaling by miR-1275 was found to enhance the stemness of LUAD cells, while antagonizing miR-1275 or suppressing Wnt/β-catenin and Notch pathways potently reversed miR-1275-induced pathway co-activation and stemness. Enhanced stemness dramatically promoted tumorigenicity, recurrence, and metastasis. miR-1275 directly targeted multiple antagonists of Wnt/β-catenin and Notch pathways, including DKK3, SFRP1, GSK3β, RUNX3, and NUMB, respectively, which resulted in signaling activation. Conclusions: Our findings identified miR-1275 as a potential oncogene in LUAD that exerts its tumorigenic effect through co-activating Wnt/β-catenin and Notch signaling pathways. Thus, HIF-1ɑ-regulated miR-1275 might be a potential therapeutic target for LUAD.

A series of chromone and donepezil hybrids were designed, synthesized, and evaluated as multipotent cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors for the potential therapy of Alzheimer's disease (AD). In vitro studies showed that the great majority of these compounds exhibited potent inhibitory activity toward BuChE and AChE and clearly selective inhibition for hMAO-B. In particular, compound 5c presented the most balanced potential for ChE inhibition (BuChE: IC(50) = 5.24 μM; AChE: IC(50) = 0.37 μM) and hMAO-B selectivity (IC(50) = 0.272 μM, SI = 247). Molecular modeling and kinetic studies suggested that 5c was a mixed-type inhibitor, binding simultaneously to peripheral and active sites of AChE. It was also a competitive inhibitor, which occupied the substrate and entrance cavities of MAO-B. Moreover, compound 5c could penetrate the blood–brain barrier (BBB) and showed low toxicity to rat pheochromocytoma (PC12) cells. Altogether, these results indicated that compound 5c might be a hopeful multitarget drug candidate with possible impact on Alzheimer's disease therapy.

Gonadal somatic cell-derived factor (Gsdf) is a member of the TGF-β superfamily, which exists mainly in fishes. Homozygous

Objective: Identification and validation of genes that functionally account for the growth and metastasis of prostate cancer. Methods: DU145-KO cell line was constructed by transfecting DU145 cells with lentivirus packaged with the genome-wide knockout library. The DU145-KO cells were transplanted into the armpits of immunocompromised Nu/Nu mice, followed by the tissue collection from lung at week 3 (early lung tissue) or week 7 (late lung tissue with micro-metastasis), as well as from primary tumor site at week 7 (late primary tumor) after inoculation. Lung metastasis were retrieved at various time points for DNA sequencing analysis to identify enriched sgRNAs, thus candidate genes/miRNAs. Further bioinformatics analysis and limited functional validation studies were carried out. Results: DU145-KO cells promoted the formation of transplanted tumors in mice and promoted the growth and metastasis of primary tumors, compared to the controls (DU145-NC cells). The analysis of sequence data showed that the abundance of sgRNAs significantly changed in the primary tumor and micro-metastasis site. Fifteen target genes（C1QTNF9B, FAM229A, hsa-mir-3929, KRT23, TARS2, CRADD, GRIK4, PLA2G15, LOXL1, SLITRK6, CDC42EP5, SLC2A4, PTGDS, MYL9 and ACOX2 for the enriched sgRNAs have been selected for experimental validation, which showed that knockout of any of these genes led to enhanced potential of invasion and metastasis of DU145 cells. Conclusion: Genome-wide CRISPR-Cas9 knockout screening technology combined with high-throughput sequencing analysis identified genes that potentially relate to prostate tumor invasion and metastasis. Analysis of these genes provided insights into biological pathways relevant to the disease and disclosed innovative markers for diagnosis or prognosis as well as potential targets for therapy.

Nuclear pore complex (NPC) embedded in the nuclear envelope, is the only channel for macromolecule nucleocytoplasmic transportation and has important biological functions. However, the deregulation of specific nucleoporins (Nups) and NPC-Nup-based mechanisms and their function in tumour progression remain poorly understood. Here, we aimed to identify the Nups that contribute to HCC progression and metastasis in 729 primary hepatocellular carcinoma (HCC) cases using molecular, cytological, and biochemical techniques. Our results revealed elevated Nup93 expression in HCC tissues, especially in cases with metastasis, and was linked to worse prognosis. Furthermore, Nup93 knockdown suppressed HCC cell metastasis and proliferation, while Nup93 overexpression promoted these activities. We observed that Nup93 promotes HCC metastasis and proliferation by regulating β-catenin translocation. In addition, we found that Nup93 interacted with β-catenin directly, independent of importin. Furthermore, LEF1 and β-catenin facilitated the Nup93-mediated metastasis and proliferation in HCC via a positive feedback loop. Thus, our findings provide novel insights into the mechanisms underlying the Nup93-induced promotion of HCC metastasis and suggest potential therapeutic targets in the LEF1-Nup93-β-catenin pathway for HCC therapeutics.

Our previously reported carboxyl-containing DPP-4 inhibitors were highly potent but were poorly bioavailable. Esters of the carboxyl analogs exhibited a significant DPP-4 potency loss albeit with enhanced oral absorption. Herein, we described identification and structure–activity relationship (SAR) exploration of a novel series of benzoic acid and ester derivatives as low single-digit nanomolar DPP-4 inhibitors. Importantly, the esters displayed comparable activities to the acids counterparts. Molecular simulation revealed that ester adopts a similar binding mode to acid. Moreover, the selected esters and acids demonstrated high selectivity and low cytotoxicity, as well as good metabolic stability. And more importantly, the esters possessed excellent pharmacokinetic profiles for oral administration. The best compound ester 19b demonstrated long DPP-4 inhibition in vivo, and robustly improved the glucose tolerance in normal and db/db mice while ensuring glucose-lowering potency in chronic treatment. Our results supported that the compound 19b can be served as a potential candidate for the treatment of type 2 diabetes.

Substantial quantities of sediments are known to enter the deep lithosphere at subduction zones, but the extent to which sediments melt and the process involved in sediment contribution to the deep lithosphere are inadequately understood. Vigorous debate continues about whether the subducted sediment component is terrigenous or pelagic and transported as a hydrous melt, an aqueous fluid, or bulk sediment. In this contribution, we conduct an integrated study on a variety of deep-seated xenoliths in the Neogene Hannuoba basalts from the northern margin of the North China Craton. Among these xenoliths, clinopyroxenite xenoliths are compositionally and isotopically distinct. Mineral chemistry shows that the clinopyroxenite xenoliths come from a depth near the MOHO, rather than from the mantle as suggested previously. The clinopyroxenite xenoliths have extremely evolved Sr-Nd-Hf isotopic compositions and are interpreted to have a late Archean protolith age. The extremely low contents of Cr and Ni for the clinopyroxenite xenoliths preclude a magmatic origin. Instead, a metasomatic origin is suggested, which is strongly supported for the clinopyroxenites by the occurrence of hydrous minerals and high contents of large-ion-lithophile elements (K, Rb, Ba, Th and Sr) and light rare earth elements, as well as elevated δ 18 O (9.9-11.3‰) and light δ 26 Mg (-1.04‰ to -1.42‰) isotopic compositions. Furthermore, their high high-field-strength element (Nb, Ta, Zr and Hf) contents indicate that the metasomatic agent is a hydrous melt, rather than an aqueous fluid. The metasomatic melts are considered to be derived from a mixed source of sedimentary carbonates and ancient, felsic continental materials. A combination of zircon ages and oxygen isotope data for the clinopyroxenite xenoliths further restricts the timing of metasomatism to the late Paleozoic. Considering the regional tectonic setting, the sediments most likely came from the subducted Paleo-Asian oceanic slab. Thus the Hannuoba clinopyroxenite xenoliths provide direct evidence for melting of the subducted Paleo-Asian oceanic slab sediment and its interaction with the deep lithosphere. The data show that melting of subducted sediments can take place at a much shallower depth than commonly thought and place an independent constraint on future models of slab geotherms.

Purpose Polyphyllin VI, a main active saponin isolated from traditional medicinal plant Paris polyphylla, has exhibited antitumor activities in several cancer cell lines. In the present study, we investigated the antitumor effect of Polyphyllin VI against human osteosarcoma cells (U2OS) and the underlying molecular mechanisms. Methods The U2OS cell lines were used to determine the antiproliferative effect of Polyphyllin VI by CCK8 assay. Cell cycle was analyzed by flow cytometry. The Polyphyllin VI-induced apoptosis was determined by Annexin V-APC/7-AAD apoptosis detection kit and JC-1 staining. Meanwhile, the autophagy was determined by acridine orange staining. The apoptosis and autophagy-related proteins were monitored by Western blot assay. Subsequently, intracellular hydrogen peroxide (H2O2) and the activation of ROS/JNK pathway were detected. Results Polyphyllin VI could potently inhibit cell proliferation by causing G2/M phase arrest. Polyphyllin VI induced mitochondria-mediated apoptosis with the upregulation of proapoptotic proteins Bax and poly ADP-ribose polymerase, and downregulation of antiapoptotic protein Bcl-2 in U2OS cells. Concomitantly, Polyphyllin VI provoked autophagy with the upregulation of critical Atg proteins and accumulation of LC3B-II. Intracellular H2O2 production was triggered upon exposure to Polyphyllin VI, which could be blocked by ROS scavenger. Polyphyllin VI dramatically promoted JNK phosphorylation, whereas it decreased the levels of phospho-p38 and ERK. Conclusion Our results reveal that Polyphyllin VI may effectively induce apoptosis and autophagy to suppress cell growth via ROS/JNK activation in U2OS cells, suggesting that Polyphyllin VI is a potential drug candidate for the treatment of osteosarcomas.

A new bergamotane-type sesquiterpene, named axanthiol A (1), and six known compounds (2–7) were isolated from the rhizomes of Amomum villosum var. xanthioides. Their structures were established on the basis of extensive spectroscopic analysis and the absolute configuration of 1 was confirmed by the Mosher ester method. Moreover, all the isolates were evaluated for their effects on LPS-induced nitric oxide (NO) production, and compound 5 showed efficacious inhibitory activity with IC50 value of 34.81 μM.

To investigate whether circulating tumor cells (CTCs) are detectable in patients with gestational choriocarcinoma (GC) and evaluate the prognostic value of CTC enumeration. In this multicenter study, the presence of CTCs was examined in 180 GC patients using a semi-automated NanoVelcro system, among whom 106 patients underwent CTC re-evaluation after one cycle of chemotherapy. Approximately 96% of the GC patients contained ≥2 CTCs in 7.5 mL of blood. The number of CTCs per 7.5 mL of blood was much higher in patients with distant metastases (n = 95; range, 0 to 104) than in patients without distant metastases (n = 85; range, 0 to 6). Applying a 90-patient training and 90-patient validation cohort, a cutoff value of ≥6 CTCs was defined as the prognostic threshold for progression-free survival (PFS) and overall survival (OS). The presence of ≥6 CTCs was significantly associated with worse PFS and OS (both P < 0.001). A multivariate analysis showed that the CTC number (≥6 CTCs) was the strongest predictor of OS (hazard ratio [HR], 15.8; 95% confidence interval [CI], 4.3–57.9; P < 0.001). The number of CTCs decreased after one cycle of chemotherapy; univariate analyses demonstrated that the CTC count after the first chemotherapy cycle was a strong predictor of OS (HR, 36.1; 95% CI, 4.8–271.5; P < 0.001). CTCs are a promising prognostic factor for GC. The absolute CTC count after one cycle of chemotherapy in the context of this disease is a strong predictor of chemotherapy response.

Metastasis is responsible for the high mortality rate of lung cancer, but its underlying molecular mechanisms are poorly understood. Here, we demonstrated that the expression of diacylglycerol kinase alpha (DGKA) was elevated in the metastatic lesions of non-small cell lung cancer (NSCLC) and correlated with poor survival. Mechanistic studies revealed a direct physical interaction as well as a mutual regulation among DGKA, proto-oncogene tyrosine-protein kinase Src (SRC), and focal adhesion kinase 1 (FAK) proteins. The C-terminal domain of DGKA was responsible for the SRC SH3 domain binding, while the catalytic domain of DGKA interacted with the FREM domain of FAK. DGKA phosphorylated the SRC protein at Tyr416 and the FAK protein at Tyr397 to form and activate the DGKA/SRC/FAK complex, thus initiating the downstream WNT/β-catenin and VEGF signaling pathways, promoting epithelial-mesenchymal transition (EMT) and angiogenesis, and resulting in the metastasis of NSCLC. DGKA knockdown inhibited the invasive phenotype of NSCLC cells in vitro. Pharmacologic ablation of DGKA inhibited the metastasis of NSCLC cells in vivo, and this was reversed by the overexpression of DGKA. These results suggested that DGKA was a potential prognostic biomarker as well as a promising therapeutic target for NSCLC, especially when there was lymphatic or distant metastasis.