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Owing to their intriguing appearance and unusual occurrence, as well as their significance in addressing magmatic processes, orbicules have attracted attention from geologists all over the world. We discovered an orbicule-bearing boulder in the Linzhi region, near the Eastern Himalayan Syntaxis, which is the first report of orbicules in the Gangdese magmatic belt, southern Tibet. The orbicules are composed of dioritic shells around monzodioritic cores, in a dioritic matrix. They typically have a single shell, composed of elongate and radially oriented hornblendes, with interstitial plagioclase. Zircon laser ablation−inductively coupled plasma−mass spectrometry U-Pb dating yields an indistinguishable age of ca. 28.8 Ma for both the orbicule core and matrix, indicating approximately coeval crystallization. Zircon Lu-Hf and whole-rock Sr-Nd isotopes reveal that the original magmas of both the orbicule matrix and orbicule core were relatively juvenile (ƐHf(t) = +2.2 to +6.0 for matrix and +1.2 to +3.9 for core; ƐNd(t) = −1.68 to −1.46 for matrix and −3.65 to −2.52 for core), similar to reported Oligocene−Miocene post-collisional adakites in the Gangdese belt. Zircon and hornblende geochemistry reveals that both the orbicule matrix and cores were generated from highly oxidized, high oxygen fugacity magmas. Hornblende composition further indicates that the original magmas of the matrix and the orbicule cores were water-rich, with H2O contents greater than 4 wt%. In combination with the whole-rock geochemistry, these results suggest that the orbicules were formed in a post-collisional setting, from magma generated by partial melting of the juvenile thickened lower crust of the Lhasa terrane triggered by convective removal of the Lhasa lithospheric root. The preferred orientation of euhedral igneous minerals in the matrix and the alignment and compaction of orbicules define a magmatic to submagmatic foliation. This, together with the subsolidus deformation microstructures exhibited by minerals within the orbicules, indicates that some flow or movement of orbicules took place under magmatic to submagmatic conditions, as the subsolidus plastic orbicules were jostled and transported within a hypersolidus liquid magma.

Abstract Colorectal cancer stem cells (CSCs) have the potential for self-renewal, proliferation, and differentiation. And LGR5 is a stem cell marker gene of colorectal cancer. Curcumin can suppress oncogenicity of many cancer cells, yet the effect and mechanism of curcumin in LGR5(+) colorectal cancer stem cells (CSCs) have not been studied. In this study, we studied the effect of curcumin on LGR5(+) colorectal CSCs using the experiments of tumorsphere formation, cell viability and cell apoptosis. Then autophagy analysis, RNA-Seq, and real-time PCR were used to identify the mechanism responsible for the inhibition of LGR5(+) colorectal CSCs. Our results showed that curcumin inhibited tumorsphere formation, decreased cell viability in a dose-dependent manner, and also promoted apoptosis of LGR5(+) colorectal CSCs. Next, we found curcumin induced autophagy of LGR5(+) colorectal CSCs. When LGR5(+) colorectal CSCs were co-treated with curcumin and the autophagy inhibitor (hydroxychloroquine), curcumin-induced cell proliferation inhibition decreased. In addition, we also found that curcumin inhibited the extracellular matrix (ECM)-receptor interaction pathway via the downregulation of the following genes: GP1BB, COL9A3, COMP, AGRN, ITGB4, LAMA5, COL2A1, ITGB6, ITGA1, and TNC. Further, these genes were transcriptionally regulated by TFAP2A, and the high expression of TFAP2A was associated with poor prognosis in colorectal cancer. In conclusion, curcumin suppressed LGR5(+) colorectal CSCs, potentially by inducing autophagy and repressing the oncogenic TFAP2A-mediated ECM pathway. Graphic abstract

The final assembly of Gondwana, known as the late Pan-African orogeny, is characterized by Ediacaran–early Cambrian ultrahigh temperature (UHT) metamorphism, which is widely identified within reconstructed East Gondwana. This distinctive feature likely provides a reliable criterion for identifying new Gondwanan terranes that lack paleo-geomagnetic data. Here we present zircon U–Pb geochronology and phase equilibria calculations for a variety of granulite types newly recognized from western Qaidam, China, which provide the first evidence that the Qaidam block, at least western Qaidam, experienced high-grade metamorphism in excess of 900 °C before/at 540–520 Ma. These UHT metamorphic rocks, similar to many well-known Pan-African UHT metamorphic terranes, is inferred to evolve along a clockwise P–T path that is usually related to collisional orogens. Comparison between new metamorphic zircon U–Pb ages from western Qaidam and the published age data from the UHT metamorphic terranes within East Gondwana suggests that the UHT metamorphic rocks found in western Qaidam similarly records the final assembly of Gondwana. Although the exact paleo-geographical location of the Qaidam block during the Gondwana period is unknown yet because of lacking paleo-geomagnetic data, new Pan-African UHT metamorphic record found in western Qaidam indicates, for the first time, that the Qaidam block is a Gondwanan terrane that split from this semi-supercontinent after the Pan-African orogeny.

Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men. Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes. Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. CFAP58 is predominantly expressed in the testis and encodes a cilia- and flagella-associated protein. Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece. Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants. We generated Cfap58-knockout mice via CRISPR/Cas9 technology. The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men. Overall, our findings in humans and mice strongly suggest that CFAP58 plays a vital role in sperm flagellogenesis and demonstrate that bi-allelic loss-of-function variants in CFAP58 can cause axoneme and peri-axoneme malformations leading to male infertility. This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia.

Objective We sought to evaluate the efficacy of using a quick response (QR) code within video education to guide proper use of fentanyl transdermal patches and control pain, depression, and anxiety levels in cancer patients. Methods Patients using a fentanyl transdermal patch for the first time were enrolled in the study and then given an information leaflet as well as an informed consent form. We asked them to complete the first questionnaire (Q1) prior to first use of the fentanyl transdermal patch, and then used a random number table to randomize those who completed it into two groups. Participants in group A received a QR code (to make it easier for them to obtain additional video information) and a traditional information leaflet, whereas those in group B (control group) only received a traditional information leaflet. Thereafter, we requested all participants to complete standard questionnaires, which comprised a Numeric Rating Scale (NRS), a Spielberger State-Trait Anxiety Inventory (STAI), as well as a Hospital Anxiety and Depression Scale (HADS). The resulting continuous (with a normal distribution) and categorical data were analyzed using Student's t- and chi-square tests, respectively. We also recorded parameters such as NRS, STAI, and HADS, as well as the frequency of rescue medication in both groups. Results A total of 154 cancer patients who first used a fentanyl transdermal patch were recruited during the study period, from April to May 2020. Among these, 138 completed follow-up, with 70 and 68 in group A and B, respectively. Participants in both groups had similar baseline and clinical characteristics, whereas significant differences were observed between the groups with regard to the other parameters. Specifically, participants in group A recorded a lower STAI state (38.2 vs 38.9, P=0.027) and HADS (3.9 vs 4.2, P=0.001) anxiety scores, as well as NRS (2.1 vs 2.4, P=0.025) and frequency of rescue medication (0.4 vs 1.4, P

Objective. RAD51 homolog 1 (RAD51) plays significant roles in DNA damage repair and apoptosis. These pathways are tightly associated with tumor initiation and progression. To unravel the roles of RAD51 in oncogenesis and progression of different cancers, herein, a comprehensive analysis of the RAD51 was carried out using multiomics datasets of 33 cancers. Methods. Raw data were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. We analyzed the correlation between RAD51 expression and drug response using datasets from CellMiner. Next, clinical characteristics and prognostic values of RAD51 were conducted based on TCGA data. The correlation between RAD51 expression and tumor immune infiltration was explored. This was followed by gene set enrichment analysis by Rsoftware. In addition, pan-cancer analysis was conducted to investigate genetic and epigenetic alterations, respectively. Results. RAD51 was upregulated in most tumors, and this was associated with poor overall survival (OS), progression-free survival (PFS), and disease-specific survival (DSS). The expression level of RAD51 is significantly associated with the IC50 of multiple antitumor drugs and the proportion of stromal and immune components in tumor microenvironment (TME). Moreover, RAD51 expression showed a positive relationship with multiple key immune checkpoint and immunosuppressive genes, including death-ligand 1 (PD-L1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), CD28, and several TNF-related immune genes. Gene set enrichment analysis uncovered that RAD51 correlated with cell cycle, cell division, and immune system pathways in diverse cancers. Our results revealed a strong link between RAD51 expression and microsatellite instability (MSI) or tumor mutation burden (TMB). Conclusions. Our pan-cancer analysis provides a comprehensive overview of the roles of RAD51 in multiple human cancers and infers that RAD51 has the potential as a biomarker for progression and immune infiltration of different tumor types.

Background China is the largest producer and consumer of pigs in the world. It is of strategic significance for China to ensure the stable supply of pigs and improve the production quality of pigs. As a high-risk industry, the pig industry faces six risks: market, capital, disease, policy, environment and transportation. In view of this, the ultimate goal of industry organizations such as cooperatives is to reduce industry risks by reducing transaction costs and establishing governance mechanisms. This study will explore from the perspective of risk perception and action driven Subjects and Methods This paper takes pig cooperatives as the research object. From the perspective of risk perception, based on the analytical framework of “transaction relationship governance mechanism”, this paper divides the transaction relationship of pig farmers into five categories. These five types are: short-term and repeated trading relationship, long-term and stable trading relationship, trading relationship based on written contract, relationship based strategic alliance and equity based strategic alliance. In addition, this paper also defines the corresponding governance mechanisms as market governance, contract governance, relationship governance and equity governance. Based on the analysis framework, through the in-depth analysis and comparison of a large number of cases, this paper mainly analyzes the characteristics of the pig industry organization system, the development and evolution of the transaction relationship of pig farmers and the impact of relevant governance mechanisms. Results It was found that pig cooperatives played an important role in reducing farmers' risk. Specifically, in the upstream relationship, cooperatives reduce farmers' production costs by uniformly purchasing means of production; In the downstream relationship, they increase farmers' income by uniformly selling pigs. In addition, through case comparative analysis, it is found that each transaction relationship has more than one governance mechanism, in which market mechanism is the basis, relationship mechanism is the means, contract mechanism is the guarantee, and equity mechanism is the deepening. In order to better study the changes in risk perception and action, this study used (DASS-21) to conduct a questionnaire survey on the sample. The form was compiled by Ji Jiajun and Lu Jiamei. It has 25 questions and is divided into six dimensions, including emotional perception, emotional evaluation, emotional regulation self-efficacy, effective application of emotional strategies, emotional control and emotional regulation reflection, Presented in the form of self-report of the respondents. For each question, from the six options, please choose one that is in line with your actual situation. From completely inconsistent to fully consistent with the six options, score 1, 2, 3, 4, 5 and 6 respectively. On the six dimensions of this questionnaire α The coefficient is tested to obtain the results of each sub dimension α The coefficients were 0.726, 0.668, 0.831, 0.772, 0.637 and 0.629 respectively α The coefficient is 0.881.cooperatives are important intermediary organizations between the upstream and downstream subjects of agricultural industry. There was a significant positive correlation between the improvement of the index and the ability of emotion regulation (P < 0.01), indicating that the higher the degree of participation, the stronger the ability of emotion regulation. The six dimensions were significantly positively correlated (P < 0.01); At the same time, there was a significant negative correlation between the state of psychological problems and the ability of emotion regulation (P < 0.01). Self control was negatively correlated with emotion perception, emotion evaluation, emotion control and emotion regulation reflection (P < 0.01), negatively correlated with emotion regulation self-efficacy (P < 0.05), and had no correlation with applied emotion strategies. There was a significant positive correlation between emotion regulation ability and all dimensions (P < 0.01); There was a significant positive correlation between encouraging autonomy and emotion regulation ability and each dimension (P < 0.01); There was a significant negative correlation between self-control and emotion regulation ability and each dimension (P < 0.01). Conclusion Since cooperatives are developed by the main body to find a way out, cooperatives have become an effective means of governance and play a vital role in improving farmers' risk awareness, reducing risks and increasing income. Therefore, this study has theoretical and pragmatic significance. Acknowledgments Supported by a project grant from the National Natural Science Foundation of China (Grant No. 71903178).

Moonlighting genes may involve in the progression of hepatocellular carcinoma (HCC), and the establishment of a prognostic signature based on moonlighting genes may help predict the prognosis of HCC patients.This study aimed to construct a prognostic signature based on moonlighting genes in HCC and determine whether there is a correlation with tumor microenvironment or immune responses. Then we used HCC cell lines and an HCC cDNA microarray to illuminate the role of moonlighting gene in prognosis of HCC.We constructed an original prognostic signature based on eight moonlighting genes (ABCB1, S100A9, NCL, PRDX6, ALAD, YBX1, POU2F1, RPL5) with strong prognosis prediction capability. The prognostic signature may demonstrate the immune status of patients with HCC, because high-risk subgroups had significantly higher scores for regulatory T cells, dendritic cells, T follicular helper cells, macrophages, and major histocompatibility complex-I, and different expression levels of immune checkpoint molecules. Importantly, patients in the high-risk subgroup exhibited higher tumor immune dysfunction and exclusion scores, suggesting that they might be less sensitive to immunotherapy. The roles of ABCB1, S100A9, NCL, PRDX6, YBX1, and POU2F1 in HCC have been reported. However, there have been no reports on the association between ALAD and HCC. Then we used bioinformatics to confirm that ALAD expression was lower in HCC and low expression of ALAD was an indicator of poor prognosis. Moreover, we found that ALAD expression was lower in HCC cells than that in normal human hepatocytes or tumor-adjacent tissues, it was negatively correlated with the pathological grade, and low expression of ALAD was related to poor prognosis in patients with HCC.We have successfully established a novel prognostic signature based on moonlighting genes, with a strong predictive capability for prognosis, immune status, and possible response to immunotherapy. Additionally, we have identified ALAD as a prognostic biomarker for HCC.

Background Potassium channels are important for the structure and function of the spermatozoa. As a potassium transporter, the mSlo3 is essential for male fertility as Slo3 knockout male mice were infertile with the series of functional defects in sperm cells. However, no pathogenic variant has been detected in human SLO3 to date. Here we reported a human case with homozygous SLO3 mutation. The function of SLO3 in human sperm and the corresponding assisted reproductive strategy are also investigated. Methods We performed whole-exome sequencing analysis from a large cohort of 105 patients with asthenoteratozoospermia. The effects of the variant were investigated by quantitative RT-PCR, western blotting, and immunofluorescence assays using the patient spermatozoa. Sperm morphological and ultrastructural studies were conducted using haematoxylin and eosin staining, scanning and transmission electron microscopy. Results We identified a homozygous missense variant (c.1237A > T: p.Ile413Phe) in the sperm-specific SLO3 in one Chinese patient with male infertility. This SLO3 variant was rare in human control populations and predicted to be deleterious by multiple bioinformatic tools. Sperm from the individual harbouring the homozygous SLO3 variant exhibited severe morphological abnormalities, such as acrosome hypoplasia, disruption of the mitochondrial sheath, coiled tails, and motility defects. The levels of SLO3 mRNA and protein in spermatozoa from the affected individual were reduced. Furthermore, the acrosome reaction, mitochondrial membrane potential, and membrane potential during capacitation were also afflicted. The levels of acrosome marker glycoproteins and PLCζ1 as well as the mitochondrial sheath protein HSP60 and SLO3 auxiliary subunit LRRC52, were significantly reduced in the spermatozoa from the affected individual. The affected man was sterile due to acrosome and mitochondrial dysfunction; however, intra-cytoplasmic sperm injection successfully rescued this infertile condition. Conclusions SLO3 deficiency seriously impact acrosome formation, mitochondrial sheath assembly, and the function of K+ channels. Our findings provided clinical implications for the genetic and reproductive counselling of affected families.

The granulitized eclogites from the Luliangshan terrane of the North Qaidam UHP metamorphic belt occur as lenses within pelitic gneisses and orthogneisses. Combined petrologic data and phase equilibrium modeling indicate a multi-stage metamorphic history of the granulitized eclogites: (1) an earlier eclogite facies metamorphism (P>18.5 kbar, T> 830 °C) is deduced from omphacite relics in the matrix and rare omphacite inclusions within garnet. The possible assemblage is garnet+omphacite+rutile+ quartz; (2) the early stage of high pressure granulite facies assemblages (garnet+clinopyroxene+ plagioclase+rutile+quartz+liquid) developed in the early decompression process has a P-T regime of 17.5 kbar and 852–858 °C, constrained by plagioclase and clinopyroxene inclusions in garnet. The late stage of high pressure granulite assemblages (garnet+clinopyroxene+amphibole+plagioclase+rutile+quartz+liquid) records an isothermal decompression process with the pressure successively declining from 17.5 to 14.7 kbar and to 11.3 kbar at 858 °C; (3) the later medium pressure granulite facies assemblage (garnet+ orthopyroxene+ clinopyroxene+amphibole+plagioclase+ilmenite+liquid+quartz) indicates a drop in pressure and rise in temperature at P-T conditions of 7.6–7.7 kbar and 878–883 °C; (4) retrogressive amphibolite facies stage, which is represented by amphibole+plagioclase kelyphitic rims around garnet, formed under conditions of

As the products of early Paleozoic continental collision, widespread eclogite facies rocks crop out in the Yuka terrane, western North Qaidam Mountains, NW China. Eclogites commonly reach ultrahigh pressure (UHP) metamorphic conditions. However, whether the associated metapelitic rocks also experience UHP metamorphism has not been thoroughly elucidated to date. In this contribution, we chose two eclogite samples and one metapelite sample to investigate their metamorphic evolution. Combining with petrographic observation and P–T pseudosections, similar clockwise P–T paths with peak stages at 25–34 kbar, 580–633 °C were obtained for eclogites and metapelites. Eclogite ZM871 records a prograde metamorphic condition at 21.6 kbar/552 °C, defined by the assemblage garnet + omphacite + epidote + lawsonite + talc (+quartz + phengite + rutile) and a peak metamorphic condition at 34.0 kbar/633 °C by the assemblage garnet + omphacite + lawsonite + talc (+coesite + phengite + rutile). Eclogite ZM641 records a prograde metamorphic condition at 21.5 kbar/520 °C, defined by the assemblage garnet + omphacite + glaucophane + lawsonite (+quartz + phengite + rutile) and a peak condition at 30 kbar/616 °C by the assemblage garnet + omphacite + lawsonite + talc (+quartz + phengite + rutile). Metapelite ZM8–1 records a prograde metamorphic condition at 18.2 kbar/530 °C defined by the assemblage garnet + chloritoid + chlorite (+quartz + phengite + rutile), a peak condition at 25 kbar/580 °C by the assemblage garnet + kyanite + chloritoid (+quartz + phengite + rutile), and a retrograde condition at 16.2 kbar/595–598 °C by the assemblage garnet + kyanite + chloritoid + chlorite (+quartz + phengite + rutile). Combined with previous data from orthogneiss and impure marble in the Yuka terrane, which also recorded UHP metamorphic conditions, the Yuka eclogite–bearing unit commonly underwent UHP metamorphism, although further investigation is warranted to verify whether the Yuka unit represents a single coherent UHP metamorphic terrane or a collage of different UHP metamorphic slices.

The role of long non-coding RNA ACTA2 antisense RNA 1 (LncRNA ACTA2-AS1) in colorectal cancer (CRC) was awaited to be elucidated. Clinical specimen and data on ACTA2-AS1 expression in colon adenocarcinoma (COAD) were collected, followed by in situ hybridization. Transfected CRC cell viability, proliferation, migration, and invasion were determined with Cell Counting Kit-8, colony formation, Scratch, and Transwell assays, respectively. Relative expressions of ACTA2-AS1, PCNA, Bcl-2, MMP-2 and MMP-9 were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. ACTA2-AS1 expression was downregulated in CRC. Overexpressed ACTA2-AS1 repressed the cell viability, proliferation, migration and invasion, increased cleaved caspase-3 level yet decreased PCNA, Bcl-2, MMP-2 and MMP-9 levels. ACTA2-AS1 silencing, however, did oppositely. Collectively, ACTA2-AS1 inhibits the viability, proliferation, migration and invasion of CRC cells to effectively suppress the progression of CRC.

CACNA1I, a schizophrenia risk gene, encodes a subtype of voltage-gated T-type calcium channel CaV3.3. We previously reported that a patient-derived missense de novo mutation (R1346H) of CACNA1I impaired CaV3.3 channel function. Here, we generated CaV3.3-RH knock-in animals, along with mice lacking CaV3.3, to investigate the biological impact of R1346H (RH) variation. We found that RH mutation altered cellular excitability in the thalamic reticular nucleus (TRN), where CaV3.3 is abundantly expressed. Moreover, RH mutation produced marked deficits in sleep spindle occurrence and morphology throughout non-rapid eye movement (NREM) sleep, while CaV3.3 haploinsufficiency gave rise to largely normal spindles. Therefore, mice harboring the RH mutation provide a patient derived genetic model not only to dissect the spindle biology but also to evaluate the effects of pharmacological reagents in normalizing sleep spindle deficits. Importantly, our analyses highlighted the significance of characterizing individual spindles and strengthen the inferences we can make across species over sleep spindles. In conclusion, this study established a translational link between a genetic allele and spindle deficits during NREM observed in schizophrenia patients, representing a key step toward testing the hypothesis that normalizing spindles may be beneficial for schizophrenia patients.

Carbonatitic magmatism in subduction zones provides extremely valuable information on the cycling, behavior and storage of deep carbon within the Earth. It may also shed light on insights into crust-mantle interaction and mantle metasomatism within subduction zones. Origin of carbonatite has long been debated: all hypotheses need to reflect the different mineral assemblages and geochemical compositions of carbonatites and their diverse tectonic settings. Here we present a petrological, geochronological, geochemical and isotopic study of carbonatite bodies associated with orogenic peridotites, which occur as stocks or dykes with widths of tens to hundreds of meters in the Luliangshan region, North Qaidam, northern Tibet, China. On the basis of modal olivine (Ol) content, the studied samples were subdivided into two groups: Ol-poor carbonatite and Ol-rich carbonatite. Zircon grains from the Ol-poor carbonatite show detrital features, and yield a wide age spectrum between 400 Ma and 1000 Ma with a pronounced peak at ca. 410–430 Ma. By contrast, oscillatory zoned zircons and inherited cores show two relatively small Neoproterozoic age peaks at ca. 920 and 830 Ma. Zircon grains from the Ol-rich carbonatite sample are also distributed in a wide spectrum between 400 and 1000 Ma, with a pronounced peak at ca. 440 Ma and a slightly inferior peak at ca. 410 Ma. The oscillatory zoned zircons and inherited cores exhibit a smaller Neoproterozoic age peak at ca. 740 Ma. The pronounced peaks ranging from 430 to 410 Ma are consistent with the deep subduction and mantle metasomatic events recorded in associated ultramafic rocks. Both groups of carbonatites are characterized by enrichment of light rare earth elements (LREEs) with high (La/Yb)N values and pronounced negative Eu anomalies. They show high 87Sr/86Sr values (0.708156–0.709004), low 143Nd/144Nd values (0.511932–0.512013) and high δ18OV-SMOW values (+17.9 to +21.3‰). This geochemical and isotopic evidence suggests that these carbonatites were derived from remobilized sedimentary carbonate rocks. We propose that the primary carbonatite magma was formed by partial melting of sedimentary carbonates with mantle contributions. Sedimentary carbonates were subducted into the shallow upper mantle where they melted and formed diapirs that moved upwards through the hot mantle wedge. The case presented provides a rare example of carbonatite originating from sedimentary carbonates with mantle contributions and relevant information on the mantle metasomatism within a subduction zone.

In the northern West Qinling orogen (WQO), granulite-facies metamorphic rocks are recognized within the Qinling Complex. These rocks are composed of amphibole-bearing two-pyroxene granulite and garnet-sillimanite gneiss with widespread migmatitization. We investigate three granulite-facies samples and one leucosome sample from the Qinling Complex, which are suitable for U-Pb analyses of zircon and monazite. SHRIMP and LA-ICPMS U-Pb age dating of zircon and monazite from two pelitic granulites provides weighted mean ages of 430±4 Ma (MSWD=0.88) and 433±4 Ma (MSWD=0.27), respectively. Based on the petrographic characteristics and zircon CL imagery, we postulated a ca. 430 Ma metamorphic timing for the pelitic granulites. LA-ICPMS zircon U-Pb data from an amphibole two-pyroxene granulite sample reports two weighted mean age groups: 424±3 Ma (MSWD=0.45) and 402±3 Ma (MSWD=1.4), which were interpreted as granulite-facies metamorphic and retrograde ages, respectively. LA-ICPMS U-Pb dating of zircons from the leucosome sample yields a weighted mean age of 426±2 Ma (MSWD=0.3), which is interpreted as the crystallization age of the leucosome. These data indicate that the West QOB experienced early Paleozoic granulite-facies metamorphism and anatexis similar to the East QOB. However, it remains unclear whether the early Paleozoic granulite facies metamorphism resulted from an arc setting created by the northward subduction of the Shangdan ocean or from a continental collisional orogenic event.

The Qinling Orogen, which was formed by long-lived subduction and collision between the North and South China blocks, can be divided into the South Qinling orogenic belt (SQOB) and the North Qinling orogenic belt (NQOB) by the Shangdan suture zone. Orogen-scale shear zones developed on the boundaries within the NQOB can be used to enhance our understanding of collisional orogeny that occurred during the Paleozoic in the Qinling Orogen. Previous studies have identified several ductile shear zones on boundaries between different lithotectonic units in the eastern NQOB. However, ductile shear zones related to orogenic processes in the western NQOB have attracted relatively little attention. Herein, we present structural and chronological data for the ductile shear zones in the Tianshui region, western NQOB. Three sub-parallel ductile shear zones (DSZ-1, DSZ-2, and DSZ-3) are recognised in the southern Qinling Complex or as boundaries between the Qinling Complex and adjacent lithotectonic units in the Huamiao area, Tianshui City. Microstructural and fabric analyses indicate that these shear zones have kinematics of transpressive sinistral strike-slip. Zircon U-Pb and 40Ar-39Ar dating data suggest that these ductile shear zones experienced a prolonged period of deformation from 420 to 370 Ma during exhumation, which was related to oblique convergence between the SQOB and the NQOB. Combining with the synchronous Xinyang-Yuanlong dextral shear zone in the northern Qinling Complex, we suggest that the transpressive sinistral shearing and dextral transpressive ductile shearing on both sides of the Qinling Complex subjected it to orogen-parallel oblique-slip extrusion during the middle Paleozoic. Our results, together with previously published data in the eastern NQOB, indicate the occurrence of orogen-scale strike-slip shearing along the whole NQOB during the Paleozoic orogeny.

Cathodoluminiscence imagery of zircons revealing 206Pb/238U ages and Th/U ratios (Table S1) and analysis of biotite from mylonitized paragneiss yielding Ar–Ar plateau and isochron ages (Table S2)

Cells rely on autophagy to clear misfolded proteins and damaged organelles to maintain cellular homeostasis. In this study we use the new autophagy inhibitor PIK-III to screen for autophagy substrates. PIK-III is a selective inhibitor of VPS34 that binds a unique hydrophobic pocket not present in related kinases such as PI(3)Kα. PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. By performing ubiquitin-affinity proteomics on PIK-III-treated cells we identified substrates including NCOA4, which accumulates in ATG7-deficient cells and co-localizes with autolysosomes. NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion. Interestingly, Ncoa4(-/-) mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells. Taken together, the results of this study provide a new mechanism for selective autophagy of ferritin and reveal a previously unappreciated role for autophagy and NCOA4 in the control of iron homeostasis in vivo.

Summary Biliary epithelial cells (BECs) form bile ducts in the liver and are facultative liver stem cells that establish a ductular reaction (DR) to support liver regeneration following injury. Liver damage induces periportal LGR5+ putative liver stem cells that can form BEC-like organoids, suggesting that RSPO-LGR4/5-mediated WNT/β-catenin activity is important for a DR. We addressed the roles of this and other signaling pathways in a DR by performing a focused CRISPR-based loss-of-function screen in BEC-like organoids, followed by in vivo validation and single-cell RNA sequencing. We found that BECs lack and do not require LGR4/5-mediated WNT/β-catenin signaling during a DR, whereas YAP and mTORC1 signaling are required for this process. Upregulation of AXIN2 and LGR5 is required in hepatocytes to enable their regenerative capacity in response to injury. Together, these data highlight heterogeneity within the BEC pool, delineate signaling pathways involved in a DR, and clarify the identity and roles of injury-induced periportal LGR5+ cells.

Cleidocranial dysplasia (CCD) is an autosomal dominant human disorder characterized by abnormal bone development that is mainly due to defective intramembranous bone formation by osteoblasts. Here, we describe a mouse strain lacking the E3 ubiquitin ligase RNF146 that shows phenotypic similarities to CCD. Loss of RNF146 stabilized its substrate AXIN1, leading to impairment of WNT3a-induced β-catenin activation and reduced Fgf18 expression in osteoblasts. We show that FGF18 induces transcriptional coactivator with PDZ-binding motif (TAZ) expression, which is required for osteoblast proliferation and differentiation through transcriptional enhancer associate domain (TEAD) and runt-related transcription factor 2 (RUNX2) transcription factors, respectively. Finally, we demonstrate that adipogenesis is enhanced in Rnf146-/- mouse embryonic fibroblasts. Moreover, mice with loss of RNF146 within the osteoblast lineage had increased fat stores and were glucose intolerant with severe osteopenia because of defective osteoblastogenesis and subsequent impaired osteocalcin production. These findings indicate that RNF146 is required to coordinate β-catenin signaling within the osteoblast lineage during embryonic and postnatal bone development.

Bone undergoes continuous remodeling due to balanced bone formation and resorption mediated by osteoblasts and osteoclasts, respectively. Osteoclasts arise from the macrophage lineage, and their differentiation is dependent on RANKL, a member of the TNF family of cytokines. Here, we have provided evidence that RANKL controls the expression of 3BP2, an adapter protein that is required for activation of SRC tyrosine kinase and simultaneously coordinates the attenuation of β-catenin, both of which are required to execute the osteoclast developmental program. We found that RANKL represses the transcription of the E3 ubiquitin ligase RNF146 through an NF-κB-related inhibitory element in the RNF146 promoter. RANKL-mediated suppression of RNF146 results in the stabilization of its substrates, 3BP2 and AXIN1, which consequently triggers the activation of SRC and attenuates the expression of β-catenin, respectively. Depletion of RNF146 caused hypersensitivity to LPS-induced TNF-α production in vivo. RNF146 thus acts as an inhibitory switch to control osteoclastogenesis and cytokine production and may be a control point underlying the pathogenesis of chronic inflammatory diseases.

LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/β-catenin signalling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/β-catenin signalling gradient, but the instructive mechanism controlling its spatiotemporal regulation is not known. We have now identified the RSPO–LGR4/5–ZNRF3/RNF43 module as a master regulator of Wnt/β-catenin-mediated metabolic liver zonation. Liver-specific LGR4/5 loss of function (LOF) or RSPO blockade disrupted hepatic Wnt/β-catenin signalling and zonation. Conversely, pathway activation in ZNRF3/RNF43 LOF mice or with recombinant RSPO1 protein expanded the hepatic Wnt/β-catenin signalling gradient in a reversible and LGR4/5-dependent manner. Recombinant RSPO1 protein increased liver size and improved liver regeneration, whereas LGR4/5 LOF caused the opposite effects, resulting in hypoplastic livers. Furthermore, we show that LGR4+ hepatocytes throughout the lobule contribute to liver homeostasis without zonal dominance. Taken together, our results indicate that the RSPO–LGR4/5–ZNRF3/RNF43 module controls metabolic liver zonation and is a hepatic growth/size rheostat during development, homeostasis and regeneration.

R-spondin proteins strongly potentiate Wnt signalling and function as stem-cell growth factors. Despite the biological and therapeutic significance, the molecular mechanism of R-spondin action remains unclear. Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6. Inhibition of ZNRF3 enhances Wnt/β-catenin signalling and disrupts Wnt/planar cell polarity signalling in vivo. Notably, R-spondin mimics ZNRF3 inhibition by increasing the membrane level of Wnt receptors. Mechanistically, R-spondin interacts with the extracellular domain of ZNRF3 and induces the association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. These data suggest that R-spondin enhances Wnt signalling by inhibiting ZNRF3. Our study provides new mechanistic insights into the regulation of Wnt receptor turnover, and reveals ZNRF3 as a tractable target for therapeutic exploration.

Melilotus extract has been used as a folk medicine in inflammation-related therapy. This study was undertaken to determine the potential benefits of this herbal extract in treating postoperative ecchymosis and edema after simultaneous rhinoplasty and blepharoplasty.Augmentation rhinoplasty and double-eyelid blepharoplasty were performed in one procedure by the same surgeon on 46 patients.Postoperative edema and ecchymosis were evaluated independently by two investigators checking the upper eyelid, lower eyelid, and paranasal area at postoperative days 1, 4, and 7. Our data showed that the patients receiving melilotus extract (n = 16) had lower scores not only in upper-eyelid and lower-eyelid ecchymosis, but also in paranasal ecchymosis at postoperative day 7 when compared with those in the control group. No significant difference in postoperative ecchymosis was detected in the group receiving dexamethasone treatment (n = 16) when compared with the control group (n = 14) at postoperative days 1, 4, and 7. The mean scores of upper-eyelid, lower-eyelid, and paranasal edema at postoperative days 1 and 4 were significantly lower in the group receiving dexamethasone treatment (n = 16) than that in the control group. Although the scores of eyelid edema reduction in the patients receiving melilotus extract showed no difference when compared with the control group, paranasal edema was reduced much more at postoperative days 4 and 7 when compared with the control group.We suggest the appropriate use of melilotus extract based on its beneficial effects on the postoperative results after simultaneous rhinoplasty and blepharoplasty.

In this report, we analyse the effects of osmotic shock on signal transduction in CHO cells. We demonstrate that at least three different kinase cascades are switched on upon osmotic shock, namely PKA, AMPK, and MLTK. Whereas PKA from cells treated with forskolin activated stress kinase p38, PKA from cells treated with sorbitol did not activate p38, although the enzyme is activated in both cases as analysed in vitro using a specific peptide target. Further, osmolar shock activated AMPK but treatment of the cells with the AMPK activator 5-amino-4-imidazolecarboxamide (AICAr) did not result in p38 activation, strongly suggesting that AMPK is not involved in stress kinase activation. Transfection of CHO cells with dominant negative recombinants of MLTKα resulted in inhibition of sorbitol-mediated p38 activation, indicating that the mixed-lineage kinase is involved in the activation of p38 by sorbitol. Finally, in CHO cells overexpressing wild-type MLTKα, no activation of AMPK of PKA could be demonstrated, indicating that the activated kinase cascades are not involved in a cross-talk process.

Cytosolic phospholipase A(2) (cPLA(2)) is an enzyme involved in the formation of proinflammatory mediators by catalyzing the release of arachidonic acid, thereby mediating eicosanoid biosynthesis. Using HaCaT keratinocytes as a model system, we present experimental evidence that in these cells, cPLA(2) is constitutively phosphorylated and that the degree of phosphorylation dramatically increases in cells under hyperosmotic stress induced by sorbitol. In parallel, a rapid release of arachidonic acid followed by prostaglandin E(2) formation was detected. Elucidating the mechanism of cPLA(2) upregulation, we observed that it is mediated via epidermal growth factor receptor (EGFR) activation, since tyrphostin AG1478, a selective inhibitor of EGFR tyrosine kinase, completely inhibited cPLA(2) phosphorylation. Furthermore, addition of PD98059, which is an inhibitor of MEK1 activation, but not of SB203580, which is an inhibitor of p38 stress kinase, inhibited cPLA(2) phosphorylation, indicating that the ras-raf-MEK cascade is the major signalling pathway involved in cPLA(2) phosphorylation. In addition, depletion of the cells from intracellular calcium does not prevent sorbitol-elicited cPLA(2) phosphorylation, suggesting that this process is independent of the presence of calcium. Together, our results demonstrate that hyperosmotic stress phosphorylates cPLA(2) in human keratinocytes by an EGFR-mediated process.

Effective use of conditional Cre recombinase- loxP gene modification requires Cre-expressing mouse strains with defined patterns of expression. To assess the in vivo functionality of Cre-expressing mice, we have engineered an improved reporter strain for monitoring Cre-mediated excisions. The β-galactosidase-neomycin phosphotransferase fusion gene (βgeo)-trapped ROSA26 locus was modified by gene targeting such that βgeo is expressed only after Cre-mediated excision of loxP -flanked DNA sequences. βgeo from the excised ROSA26 allele is expressed ubiquitously in embryos and adult mice. By mating the reporter strain with Cre-expressing transgenic mice, we have shown that the loxP -flanked ROSA26 allele is accessible to Cre during early embryogenesis, as well as in a specific hematopoietic lineage (T lymphocytes). This improved reporter strain should facilitate monitoring in vivo Cre-mediated excision events in a variety of experimental contexts.

In this thesis, a detail study on channel characterization and modeling of the propagation within waveguide-like structures, namely; the lift shaft and the cargo hull of a merchant ship is performed. These channels are studied for military applications such as urban warfare and battlefield communication network onboard ships. For urban areas, although the environment can be different from one to the next, high-rise buildings with lift shafts can be commonly found. Due to the boxed shaped hollow structure of the lift shaft, guiding effect associated with the lift shaft channel can be a reliable link. The propagation mechanisms along a lift shaft in an urban area are examined based on experimental study and verified by ray-tracing simulation results. The signal variations caused by the opening/closing of the lift door and movement of the lift car are modeled in detail. On board the ship, the aim is to establish communication between two key locations, the bridge room on the top and the engine control room at the bottom. These are crucial locations in terms of trying to take control over the ship. Therefore, the knowledge of wave propagation mechanisms between these locations within the ship is required. In this study, a series of experimental work has been conducted along the lift shaft onboard a merchant ship. Waveguide-like effect and signal variations associated with the lift shaft channel is examined and compared with the results obtained from urban area. Moreover, the waveguide-like effect along the cargo hull of the merchant ship is studied based on experimental and simulation results. Small-scale channel characteristics are analyzed based on the guiding effect. Finally, besides the direct propagation in VHF band, a relay system is proposed to enable the wideband propagation between the two key locations in the military UHF band and popular ISM band. As the analogues waveguide effect of the cargo hull can ensure the communication quality, the relay system is suggested to be deployed inside the cargo hull. DOCTOR OF PHILOSOPHY (EEE)

We report the isolation of bcl-x, a bcl-2-related gene that can function as a bcl-2-independent regulator of programmed cell death (apoptosis). Alternative splicing results in two distinct bcl-x mRNAs. The protein product of the larger mRNA, bcl-xL, is similar in size and predicted structure to Bcl-2. When stably transfected into an IL-3-dependent cell line, bcl-xL inhibits cell death upon growth factor withdrawal at least as well as bcl-2. Surprisingly, the second mRNA species, bcl-xS, encodes a protein that inhibits the ability of bcl-2 to enhance the survival of growth factor-deprived cells. In vivo, bcl-xS mRNA is expressed at high levels in cells that undergo a high rate of turnover, such as developing lymphocytes. In contrast, bcl-xL is found in tissues containing long-lived postmitotic cells, such as adult brain. Together these data suggest that bcl-x plays an important role in both positive and negative regulation of programmed cell death.

Reporter mouse strains are important tools for monitoring Cre recombinase-mediated excision in vivo. In practice, excision may be incomplete in a given population due to threshold level or variegated expression of Cre. Hence, it is desirable in many experimental contexts to isolate cells that have undergone excision to assess the consequences of gene ablation. To generate alternative reporter mice, an enhanced green fluorescent protein (EGFP) gene was targeted to the retroviral-trapped ROSA26 locus. Upon Cre-mediated excision of “Stop” sequences, EGFP was expressed ubiquitously during embryogenesis and in adult tissues (including T cells, B cells, and myeloid cells). Using this new reporter strain, separation of excised from nonexcised cells in vitro was achieved in thymocytes in a noninvasive manner based on activated EGFP expression. This new EGFP reporter strain should facilitate a variety of conditional gene-targeting experiments, including the functional studies of hematopoietic cells in lineage-specific knockout mice.

To investigate the association between quality of life (QOL) and sociodemographic factors, clinical seizure factors, depression and anxiety in patients suffering from epilepsy.We examined 141 consecutive patients with epilepsy (mean age 25.8±9.6, 61.7% male). All patients completed the Self-Rating Depression Scale, Self-Rating Anxiety Scale, WHOQOL-BREF and QOLIE-31(Chinese version). Multiple linear regression analyses were applied to investigate factors impact on QOL.The results revealed that scores on two domains of the WHOQOL-BREF (i.e., physical and psychological domains, P0.05) were significantly lower in the epilepsy group compared with the control group. Multiple regression analyses showed that anxiety, depression and course explained approximately 40% of the variance in patients' QOL. Anxiety was consistently the strongest predictor of lower scores on almost all QOL domains. In addition, the severity of depressive symptoms was significantly associated with lower scores across many QOL domains.Our findings suggest that QOLIE scores might be substantially affected by the presence and severity of anxiety symptoms and, to a lesser degree, of depressive symptoms and prolonged course of illness. In contrast, clinical seizure variables had a weaker association with QOL. Healthcare professionals should be aware of the significance of patients' emotional state and of the role it plays in their QOL.

Channel sounding on board a merchant ship is performed between the cargo hull and the bridge room. Power delay profiles for 3 different spread bandwidths (5MHz, 10MHz and 20MHZ) have been analyzed. From the periodicity and increasing amplitude of the multipath peaks, it can be concluded that the metallic cargo hull forms a structure analogous to the waveguide. The large RMS delay spread found again confirms the waveguide propagation mechanism and the complexity of the metallic merchant ship structure. The small coherence bandwidth shows wideband transmission on board a ship is not feasible.

Trimethylation on H3K27 (H3K27me3) mediated by the Polycomb repressive complex 2 (PRC2) has been linked to embryonic stem (ES) cell identity and pluripotency. EZH2, the catalytic subunit of PRC2, has been reported as the sole histone methyltransferase which methylates H3K27 and mediates transcriptional silencing. Analysis of Ezh2−/− ES cells suggests existence of additional enzyme(s) catalyzing H3K27 methylation. We have identified EZH1, a homolog of EZH2 that is physically present in a non-canonical PRC2 complex, as an H3K27 methyltransferase in vivo and in vitro. EZH1 colocalizes with the H3K27me3 mark on chromatin, and preferentially preserves this mark on development-related genes in Ezh2−/− ES cells. Depletion of Ezh1 in cells lacking Ezh2 abolishes residual methylation on H3K27 and derepresses H3K27me3 target genes, demonstrating a role of EZH1 in safeguarding ES cell identity. Ezh1 partially complements Ezh2 in executing pluripotency during ES cell differentiation, suggesting that cell fate transitions require epigenetic specificity.

Succinate acts as an extracellular mediator signaling through the G protein-coupled receptor GPR91. Here we show that dendritic cells had high expression of GPR91. In these cells, succinate triggered intracellular calcium mobilization, induced migratory responses and acted in synergy with Toll-like receptor ligands for the production of proinflammatory cytokines. Succinate also enhanced antigen-specific activation of human and mouse helper T cells. GPR91-deficient mice had less migration of Langerhans cells to draining lymph nodes and impaired tetanus toxoid-specific recall T cell responses. Furthermore, GPR91-deficient allografts elicited weaker transplant rejection than did the corresponding grafts from wild-type mice. Our results suggest that the succinate receptor GPR91 is involved in sensing immunological danger, which establishes a link between immunity and a metabolite of cellular respiration.

This paper studies the small-scale multipath propagation characteristics of a typical outdoor urban environment. Wideband channel sounding measurements are performed and findings are presented. Channel sounding is carried out at UHF band (250, 300, 350, 400 MHz) for static transmit and receive antennas. The power delay profile, mean delay spread, RMS delay spread, as well as coherence bandwidth have been estimated. The results show that the outdoor urban environment at UHF frequencies is a rich scattering environment, where spatial diversity can be applied.

In eukaryotes, Suv39h H3K9 trimethyltransferases are required for pericentric heterochromatin formation and function. In early mouse preimplantation embryos, however, paternal pericentric heterochromatin lacks Suv39h-mediated H3K9me3 and downstream marks. Here we demonstrate Ezh2-independent targeting of maternally provided polycomb repressive complex 1 (PRC1) components to paternal heterochromatin. In Suv39h2 maternally deficient zygotes, PRC1 also associates with maternal heterochromatin lacking H3K9me3, thereby revealing hierarchy between repressive pathways. In Rnf2 maternally deficient zygotes, the PRC1 complex is disrupted, and levels of pericentric major satellite transcripts are increased at the paternal but not the maternal genome. We conclude that in early embryos, Suv39h-mediated H3K9me3 constitutes the dominant maternal transgenerational signal for pericentric heterochromatin formation. In absence of this signal, PRC1 functions as the default repressive back-up mechanism. Parental epigenetic asymmetry, also observed along cleavage chromosomes, is resolved by the end of the 8-cell stage--concurrent with blastomere polarization--marking the end of the maternal-to-embryonic transition.