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Abstract The shift of cytokine profile from anti‐ to pro‐inflammatory is the most recognizable sign of labor, although the underlying mechanism remains elusive. Here, we report that the epithelial sodium channel (ENaC) is upregulated and activated in the uterus at labor in mice. Mechanical activation of ENaC results in phosphorylation of CREB and upregulation of pro‐inflammatory cytokines as well as COX‐2/PGE2 in uterine epithelial cells. ENaC expression is also upregulated in mice with RU486‐induced preterm labor as well as in women with preterm labor. Interference with ENaC attenuates mechanically stimulated uterine contractions and significantly delays the RU486‐induced preterm labor in mice. Analysis of a human transcriptome database for maternal–fetus tissue/blood collected at onset of human term and preterm births reveals significant and positive correlation of ENaC with labor‐associated pro‐inflammatory factors in labored birth groups (both term and preterm), but not in non‐labored birth groups. Taken together, the present finding reveals a pro‐inflammatory role of ENaC in labor at term and preterm, suggesting it as a potential target for the prevention and treatment of preterm labor.

Glucagon, produced by islet α cells, functions to increase blood glucose. Abnormal glucose levels are often seen in cystic fibrosis (CF), a systematic disease caused by mutations of the CF transmembrane conductance regulator (CFTR), and in polycystic ovarian syndrome (PCOS), an endocrine disorder featured with hyperandrogenism affecting 5–10% women of reproductive age. Here, we explored the role of CFTR in glucagon production in α cells and its possible contribution to glucagon disturbance in CF and PCOS. We found elevated fasting glucagon levels in CFTR mutant (DF508) mice compared to the wildtypes. Glucagon and prohormone convertase 2 (PC2) were also upregulated in CFTR inhibitor-treated or DF508 islets, as compared to the controls or wildtypes, respectively. Dihydrotestosterone (DHT)-induced PCOS rats exhibited significantly lower fasting glucagon levels with higher CFTR expression in α cells compared to that of controls. Treatment of mouse islets or αTC1-9 cells with DHT enhanced CFTR expression and reduced the levels of glucagon and PC2. The inhibitory effect of DHT on glucagon production was blocked by CFTR inhibitors in mouse islets, and mimicked by overexpressing CFTR in αTC1-9 cells with reduced phosphorylation of the cAMP/Ca2+ response element binding protein (p-CREB), a key transcription factor for glucagon and PC2. These results revealed a previously undefined role of CFTR in suppressing glucagon production in α-cells, defects in which may contribute to glucose metabolic disorder seen in CF and PCOS.

Clear cell renal cell carcinoma (ccRCC) accounts for 80% of renal cell carcinomas (RCCs), and its morbidity and prognosis are unfavorable. Surgical resection is the first-line treatment for ccRCC, but the oncogenesis of ccRCC is very complex. With the development of high-throughput sequencing technology, it is necessary to analyze the transcriptome to determine more effective treatment methods. The tumor microenvironment (TME) is composed of tumor cells, various immune-infiltrating cells, fibroblasts, many cytokines, and catalysts. It is a complex system with a dynamic balance that plays an essential role in tumor growth, invasion, and metastasis. Previous studies have confirmed that potassium channels can affect the immune system, especially T lymphocytes that require potassium channel activation. However, the effect of potassium channels on the TME of ccRCC remains to be studied. Therefore, this study aims to construct a prognostic signature for ccRCC patients based on potassium ion channel-related genes (PCRGs), assess patient risk scores, and divide patients into high- and low-risk groups based on the cutoff value. In addition, we investigated whether there were differences in immune cell infiltration, immune activator expression, somatic mutations, and chemotherapeutic responses between the high- and low-risk groups. Our results demonstrate that the PCRG signature can accurately assess patient prognosis and the tumor microenvironment and predict chemotherapeutic responses. In summary, the PCRG signature could serve as an auxiliary tool for the precision treatment of ccRCC.

High-pressure (HP) and ultrahigh-temperature (UHT) granulites with a high geothermal gradient (greater than 500 °C/GPa) are prominent features of Paleoproterozoic orogenic belts and may represent paired metamorphic belts present during the early stages of plate tectonics. Understanding their pressure-temperature-time (P-T-t) paths and metamorphic evolutionary relationships could provide valuable constraints on the tectonic processes of Paleoproterozoic orogenic belts. Here, we describe garnet mafic and clinopyroxene-orthopyroxene (Cpx-Opx) granulites from the Diebusige area of the Alxa Block in the western part of the Khondalite Belt, North China Craton. Through detailed petrographic, phase equilibrium modeling, and Ti-in-amphibole thermometric studies, we obtained the preserved peak mineral assemblages of two types of mafic granulites: garnet + clinopyroxene + amphibole + plagioclase + quartz + ilmenite, and clinopyroxene + orthopyroxene + plagioclase + amphibole + garnet (rare) + ilmenite. The preserved peak P-T conditions were determined to be 850-890 °C/11.4-13.2 kbar (HP granulite-facies) and 950-970 °C/8.2-9.2 kbar (UHT conditions), with thermal gradients of ~70 °C/kbar (moderate differential temperature/differential pressure, dT/dP) and ~110 °C/kbar (high dT/dP), respectively. Using sensitive high-resolution ion microprobe U-Pb dating and rare earth element analysis of zircons, we found that the garnet mafic granulite recorded an HP granulite-facies metamorphic age of ca. 1.95 Ga and a retrograde cooling age of ca. 1.8 Ga, while the Cpx-Opx granulite recorded a consistent retrograde cooling age of ca. 1.8 Ga. By combining these results with the metamorphic evolution and timing (ca. 1.92-1.91 Ga) of UHT rocks from the Khondalite Belt, we suggest that the garnet (HP) mafic and Cpx-Opx (UHT) granulites may represent different stages of the same metamorphic event, shedding light on the processes involved in the collision and subsequent exhumation of Paleoproterozoic orogenic belts. [ABSTRACT FROM AUTHOR]

Insight into the formation of Archean trondhjemite-tonalite-granodiorite (TTG) and sanukitoids is essential for understanding Archean crustal evolution and tectonic styles; however, their exact source and petrogenesis are still open to debate. Detailed chemical compositions of minerals, whole-rocks and whole-rock Sm-Nd isotopes, zircon U-Pb ages and Hf-O isotopes of the Zhulagou (ZLG) diorites and mafic enclaves from the Yinshan Block of the North China Craton are used to investigate the petrogenesis of the diorites and related geological processes. The ZLG diorites, which formed at ~2520 Ma, have moderate SiO2 (59.4-65.5wt %) and Mg# (49-52), high Al2O3 (15.6-20.6wt %), Cr (90.4-438 ppm), Ni (15.0-95.9 ppm), Sr (436-882 ppm) and Ba (237-1206 ppm) contents, and also fractionated rare earth element patterns (REE; LaN/YbN=9.1-40.5) and depleted high field strength elements (HFSE) such as Nb, Ta and Ti, similar to Archean sanukitoids. The diorites may contain cumulus plagioclase and do not represent pristine melts, as indicated by their high Al2O3 contents and positive Eu and Sr anomalies. They have evolved whole-rock Nd isotope compositions [εNd(t)= 1.0-2.3, TDM=2.8-2.7 Ga], variable zircon εHf(t) (-1.6 toβ6.0) and high zircon δ18O (~9.060.4&, 2SD) values, indicating that the parental magma was most probably produced by partial melting of 2.8-2.7 Ga mafic crust. The high-δ18O character of the zircons was probably inherited from the magma source of hydrated metabasalts, which had elevated δ18O owing to previous low-temperature alteration, rather than resulting from granulite-facies metamorphism or wall-rock contamination. Coeval mafic enclaves (~2525 Ma) in the diorites are dominantly composed of clinopyroxene, amphibole and orthopyroxene. They have low SiO2 (46.5-50.3wt %) and high CaO (8.3-12.3wt %), Cr (647-1946 ppm) and Ni (197-280 ppm) contents, convex light REE patterns, and similar Nd isotope compositions to the host diorites. In addition, clinopyroxene and amphibole in the mafic enclaves have major and trace element compositions similar to those of the diorites. These observations collectively indicate that the mafic enclaves probably represent cumulates from the diorite magma. The diorites and enclaves experienced regional granulitefacies metamorphism at ~2500 Ma, soon after their emplacement. The late Archean large-scale crustal anatexis and high-grade metamorphism within the Yinshan Block of the NCC probably occurred at the root of a continental arc. [ABSTRACT FROM AUTHOR]

Thermal ionization mass spectrometry (TIMS) allows excellent precision for determining Sr isotope ratios in natural water samples. Traditionally, a chemical separation procedure using cation exchange resin has been employed to obtain a high purity Sr fraction from natural water, which makes sample preparation time-consuming. In this study, we present a rapid and precise method for the direct determination of the Sr isotope ratio of natural water using TIMS equipped with amplifiers with two 1012 Ω resistors. To eliminate the 87Rb isobaric interference, Re ribbons are used as filaments, providing a significant advantage over W ribbons in the inhibition of Rb+ emission, based on systematically examining a series of NIST SRM987 standard doping with various amounts of Rb using Re and W ribbons. To validate the applicability of our method, twenty-two natural water samples, including different water types (rain, snow, river, lake and drinking water), that show a large range in Sr content variations (2.54-922.8 ppb), were collected and analyzed from North and South China. Analytical results show good precision (0.003-0.005%, 2 RSE) and the method was further validated by comparative analysis of the same water with and without chemical separation. The method is simple and rapid, eliminates sample preparation time, and prevents potential contamination during complicated sample-preparation procedures. Therefore, a high sample throughput inherent to the TIMS can be fully utilized. [ABSTRACT FROM AUTHOR]

Polycystic ovarian syndrome (PCOS) is one of the most frequent causes of female infertility, featured by abnormal hormone profile, chronic oligo/anovulation, and presence of multiple cystic follicles in the ovary. However, the mechanism underlying the abnormal folliculogenesis remains obscure. We have previously demonstrated that CFTR, a cAMP-dependent Cl- and HCO3- conducting anion channel, is expressed in the granulosa cells and its expression is downregulated in PCOS rat models and human patients. In this study, we aimed to investigate the possible involvement of downregulation of CFTR in the impaired follicle development in PCOS using two rat PCOS models and primary culture of granulosa cells. Our results indicated that the downregulation of CFTR in the cystic follicles was accompanied by reduced expression of proliferating cell nuclear antigen (PCNA), in rat PCOS models. In addition, knockdown or inhibition of CFTR in granulosa cell culture resulted in reduced cell viability and downregulation of PCNA. We further demonstrated that CFTR regulated both basal and FSH-stimulated granulosa cell proliferation through the HCO3-/sAC/PKA pathway leading to ERK phosphorylation and its downstream target cyclin D2 (Ccnd2) upregulation. Reduced ERK phosphorylation and CCND2 were found in ovaries of rat PCOS model compared with the control. This study suggests that CFTR is required for normal follicle development and that its downregulation in PCOS may inhibit granulosa cell proliferation, resulting in abnormal follicle development in PCOS. [ABSTRACT FROM AUTHOR]

Thermal ionization mass spectrometry and multiple-collector inductively coupled plasma mass spectrometry are considered to be "gold standards" for the determination of the isotope ratios of Sr-Nd and Hf in geological samples because of the extremely high precision and accuracy of these methods. However, the sample throughputs are hindered by time-consuming and tedious chemical procedures. Three-step ion exchange resin separation is traditionally employed to purify Sr-Nd-Hf from matrix elements. In this study, a one-step Sr-Nd-Hf separation scheme was developed to process geological samples. The separation scheme is based on the combined use of conventional AG50W-X12 cationexchange resin and LN Spec extraction chromatographic material without any intervening evaporation step. The protocol not only prevents cross-contamination during operation using multiple-stage ion exchange resins but also significantly improves the efficiency of sample preparation. The stability of our chemical procedure was demonstrated by replicate measurements of 87Sr/86Sr, 143Nd/144Nd, and 176Hf/177Hf ratios in six international reference materials of silicate rocks. The analytical results obtained for these standard rocks compare well with the published data. The external reproducibility (2 SD, n = 10) of a BCR-2 standard sample was ±0.000018 for 87Sr/86Sr, ±0.000010 for 143Nd/144Nd, and ±10.000014 for 176Hf/177Hf. [ABSTRACT FROM AUTHOR]

Sm–Nd isotopic system is a powerful tracer and dating tool in geochemistry and cosmochemistry. Thermal ionization mass spectrometry (TIMS) is the benchmark method for obtaining high precision Nd isotope ratios. Traditionally, a two-step separation was employed in order to obtain high purity Nd fraction, which makes the sample preparation time-consuming. In this study, we present a new method to directly obtain precise and accurate Nd isotope ratios of geological samples without Sm–Nd separation. The key point is to well correct isobaric interferences of 144Sm on 144Nd for this method. The accurate intensity of 144Sm can be obtained using 147Sm/144Sm ratio of 4.87090 and mass discrimination factor of Sm (βSm), which is achieved using 147Sm/149Sm ratio of 1.08583 with Russell equation. Consequently, the real intensity of 144Nd was achieved, then also raw 146Nd/144Nd, 143Nd/144Nd ratios. Finally, 143Nd/144Nd ratio is normalized using 146Nd/144Nd ratio of 0.7219 following exponential law. The accuracy of this method is validated by replicating TIMS measurements for thirteen international reference materials of silicate rock, spanning a wide range of Sm/Nd from 0.13 to 0.46 and bulk compositions. The measured 143Nd/144Nd ratios of the rock standards are in good agreement with the reported values of within error of ±0.004%. Our new method shortens the analytical procedure and significantly improves sample throughput which greatly contributes to those studies requiring a large dataset and quick analysis. [ABSTRACT FROM AUTHOR]

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) plays a critical role in electrolyte and fluid transport in epithelial cells, and women with cystic fibrosis (CF), caused by CFTR gene mutations, have a higher incidence of infertility. METHODS: In the present study, we investigated the expression of CFTR in porcine oviduct and its functional role in oviductal HCO3- secretion and embryo development with RT-PCR, western blot, patch-clamp, short-circuit current (Isc), pH measurement and embryo culture. RESULTS: RT-PCR and western blot analysis showed the expression of CFTR mRNA and protein in the oviduct with its localization demonstrated by immunohistochemstry. The whole-cell patch-clamp recording revealed a forskolin (FSK)-activated current with electrophysiological and pharmacological characteristics of CFTR. The Isc measurement showed that FSK-stimulated an increase in the Isc, which could be significantly reduced by CFTR inhibitor or removal of both CO2 and HCO3-. pH measurement showed a FSK stimulated alkalization at the apical surface, which could be inhibited by CFTR inhibitor, indicating CFTR-mediated HCO3- secretion. Mouse embryo development from 2-cell to morula or blastocyst stage was significantly inhibited in the absence of HCO3- or when co-cultured with HCO3- secretiondeficient CFTR mutant cells as compared with the wild-type. RT-PCR, western blot and immunostaining showed the expression of soluble adenylate cyclase (sAC), the known HCO3- sensor, in embryos. Treatment with its inhibitors, 2-hydroxyestradiol and KH7, prevented the HCO3- dependent embryo development. CONCLUSION: The present results suggest that CFTR-mediated oviductal HCO3- secretion may be vital for sAC-dependent early embryo development, a defect of which may contribute to the reduced fertility seen in women with CF. [ABSTRACT FROM AUTHOR]