Moderate UV Exposure Enhances Learning and Memory by Promoting a Novel Glutamate Biosynthetic Pathway in the Brain.

Sunlight exposure is known to affect mood, learning, and cognition. However, the molecular and cellular mechanisms remain elusive. Here, we show that moderate UV exposure elevated blood urocanic acid (UCA), which then crossed the blood-brain barrier. Single-cell mass spectrometry and isotopic labeling revealed a novel intra-neuronal metabolic pathway converting UCA to glutamate (GLU) after UV exposure. This UV-triggered GLU synthesis promoted its packaging into synaptic vesicles and its release at glutamatergic terminals in the motor cortex and hippocampus. Related behaviors, like rotarod learning and object recognition memory, were enhanced after UV exposure. All UV-induced metabolic, electrophysiological, and behavioral effects could be reproduced by the intravenous injection of UCA and diminished by the application of inhibitor or short hairpin RNA (shRNA) against urocanase, an enzyme critical for the conversion of UCA to GLU. These findings reveal a new GLU biosynthetic pathway, which could contribute to some of the sunlight-induced neurobehavioral changes.

METTL3-mediated upregulation of FAM135B promotes EMT of esophageal squamous cell carcinoma via regulating the Wnt/ß-catenin pathway.

Family with sequence similarity 135 member B (FAM135B) is a novel driver gene in esophageal squamous cell carcinoma (ESCC). However, little is known regarding its biological functions and mechanisms in ESCC. Here, we identified that the high expression of FAM135B was associated with lymph node metastasis and infiltrating development of ESCC. Elevated FAM135B expression promoted ESCC migration and invasion in vitro and lung metastasis in vivo. Furthermore, epithelial-mesenchymal transition (EMT)-related pathways were enriched in ESCC samples with high levels of FAM135B and FAM135B positively regulated EMT markers. Mechanistically, we observed that FAM135B interacted with the intermediate domain of TRAF2 and NCK-interacting kinase (TNIK), activating the Wnt/ß-catenin signaling pathway. The facilitation of TNIK on ESCC migration and invasion was reversed by FAM135B siRNA. In addition, the N6-methyladenosine (m6A) modification positively regulated FAM135B expression, with methyltransferase like 3 (METTL3) acting as its substantial m6A writer. The pro-EMT effects of METTL3 overexpression were reversed by silencing FAM135B. Collectively, these findings illustrate the critical role of ABCDE in ESCC progression and provide new insights into the upstream and downstream mechanisms of FAM135B.NEW & NOTEWORTHY This study reveals for the first time that the novel cancer-related gene, FAM135B, promotes ESCC metastasis both in vitro and in vivo. Besides, we substantiate FAM135B's action on the ß-catenin pathway through interacting with TNIK, thereby elucidating the promotional effect of FAM135B on ESCC EMT. Furthermore, we provide initial evidence demonstrating that METTL3-mediated m6A modification upregulates the expression of FAM135B in ESCC cells.

Factors influencing passage of time judgment in individuals' daily lives: evidence from the experience sampling and diary methods.

People often express feeling that time passes quickly or slowly in their daily lives, which is termed passage of time judgment (PoTJ). Past studies have shown that PoTJ is affected by emotional valence and arousal; however, few studies have verified the effects of alertness, attention to time, and time expectation on PoTJ and whether the effects are stable over different time periods. Using the experience sampling method (ESM) and diary method, the present study collected data from 105 participants and examined for the first time whether alertness, attention to time, and time expectation affect PoTJ based on daily life data, as well as whether above factors, emotional valence, and arousal are stable over different time periods. All participants answered a questionnaire five times a day on their in-the-day PoTJ and related factors regarding the last 30 min, and answered the same questionnaire once a day at 23:00 regarding the of-the-day PoTJ. The results showed that alertness and time expectation, as well as emotional valence and arousal, predicted an individual's in-the-day PoTJ over a shorter period (i.e., the last 30 min); in contrast, only time expectation and emotional arousal predicted of-the-day PoTJ over a longer period (i.e., the past day). These results suggest that, alertness and time expectation are important factors influencing PoTJ, in addition to emotional state. Of-the-day PoTJ correlates most strongly with the mean and latest in-the-day PoTJ, implying that overall perception of time passage is influenced by both cumulative temporal experience and recent temporal experience.

Bimetallic Cu11Ag3 Nanotips for Ultrahigh Yield Rate of Nitrate-to-Ammonium.

Electrochemical reduction of nitrate to ammonia (NRA) offers a sustainable approach for NH3 production and NO3- removal but suffers from low NH3 yield rate (<1.20 mmol h-1 cm-2). We present bimetallic Cu11Ag3 nanotips with tailored local environment and tip-enhanced effects, which achieve an ultrahigh NH3 yield rate of 2.36 mmol h-1 cm-2 at a low applied potential of -0.33 V vs. RHE, a high Faradic efficiency (FE) of 98.8%, and long-term operation stability at 1800 mg-N L-1 NO3-, outperforming most of the recently reported catalysts. At a NO3- concentration as low as 15 mg-N L-1, it still delivers a high FE of 86.9% and an NH3 selectivity of 93.8%. Operando ATR-FTIR spectra, finite-element method, and DFT calculations reveal that the Cu11Ag3 exhibits reduced adsorption energy barrier of *N intermediates, favorable water dissociation for *H generation and high energy barrier for H2 formation, while its tip-enhanced enrichment promoting NO3- accumulation.

Live-Cell Imaging of Endogenous RNA with a Genetically Encoded Fluorogenic Allosteric Aptamer.

Imaging and tracking tools for natural cellular RNA with improved biocompatibility, specificity, and sensitivity are critical to understanding RNA function and providing insights into disease therapeutics. We developed a new genetically encoded sensor using fluorogenic allosteric aptamer (FaApt) for the sensitive imaging of the localization and dynamics of RNA targets in live cells. Target RNAs can be specifically recognized with our sensor by forming perfectly complementary duplexes, which in turn can induce allosteric structural changes of the sensor to refold the native conformation of fluorogenic RNA aptamers. We demonstrated the ability of the sensor to monitor the effect of tumor necrosis factor and small-molecule inhibitor on the expression abundance of CXCL1 and survivin mRNA in human cancer cells, respectively. The asymmetrical distribution of endogenous Squint mRNA was confirmed in developing zebrafish embryos through microinjection of FaApt probes. This study provides an effective molecular tool for sensitive imaging and tracking endogenous RNA in living cells. Due to the high specificity and small size of our sensor system, it is expected to be applied to early diagnosis of RNA marker-related diseases and real-time evaluation of the treatment process.

Prognostic factors and adjuvant systemic therapy for patients with HER2-positive T1N0 breast cancer: evidence from a real-world study with long-term follow-up.

PURPOSE: The optimal adjuvant systemic treatment and potential prognostic factors for patients with T1N0 HER2-positive breast cancer are still unclear. We conducted a real-world study in this relatively low-risk population to identify the clinical-pathological factors of potential prognostic value and to compare the efficacy of different adjuvant strategies. METHODS: We included patients with HER2-positive T1N0 breast cancer of infiltrating ductal carcinoma (IDC) histology treated at the Cancer Hospital, Chinese Academy of Medical Sciences from April 2010 to April 2017. We performed Cox multivariate analysis to identify the potential prognostic factors for invasive disease-free survival (IDFS). We also compared survival outcomes of (1) patients treated with adjuvant chemotherapy alone, or chemotherapy plus trastuzumab, or observation; (2) patients receiving adjuvant anthracycline-based and non-anthracycline regimens, both combined with trastuzumab. Inverse probability of treatment weighting (IPTW) propensity score was used to reduce selection bias. RESULTS: Overall, 692 consecutive patients were included, with a median follow-up of 78.0 months for IDFS. Age ≤ 40, T1c, ER + PR + , and adjuvant trastuzumab were identified as independent prognostic factors. For adjuvant treatment, compared with observation and chemotherapy alone, chemotherapy plus trastuzumab could significantly benefit patients (HR = 2.70, P = 0.034; HR = 3.95, P < 0.001). Meanwhile, compared with observation, chemotherapy alone did not significantly benefit patients (HR = 1.37, P = 0.424). For the comparison of anthracycline-based versus non-anthracycline regimens when combined with trastuzumab, patients in both groups had similar IDFS (HR = 1.74, P = 0.242). CONCLUSIONS: HER2-positive T1N0 IDC patients could benefit from adjuvant chemotherapy plus trastuzumab. Age ≤ 40, T1c, ER + PR + , and adjuvant trastuzumab are independent prognostic factors for this population.

A new deuterium-labeled compound [2,3,4,6,6'-2 H5 ]-D-glucose for deuterium magnetic resonance metabolic imaging.

Deuterium (2 H) magnetic resonance imaging is an emerging approach for noninvasively studying glucose metabolism in vivo, which is important for understanding pathogenesis and monitoring the progression of many diseases such as tumors, diabetes, and neurodegenerative diseases. However, the synthesis of 2 H-labeled glucose is costly because of the expensive raw substrates and the requirement for extreme reaction conditions, making the 2 H-labeled glucose rather expensive and unaffordable for clinic use. In this study, we present a new deuterated compound, [2,3,4,6,6'-2 H5 ]-D-glucose, with an approximate 10-fold reduction in production costs. The synthesis route uses cheaper raw substrate methyl-α-D-glucopyranoside, relies on mild reaction conditions (80°C), and has higher deuterium labeling efficiency. Magnetic resonance spectroscopy (MRS) and mass spectroscopy experiments confirmed the successful deuterium labeling in the compound. Animal studies demonstrated that the substrate could describe the glycolytic metabolism in a glioma rat model by quantifying the downstream metabolites through 2 H-MRS on an ultrahigh field system. Comparison of the glucose metabolism characteristics was carried out between [2,3,4,6,6'-2 H5 ]-D-glucose and commercial [6,6'-2 H2 ]-D-glucose in the animal studies. This cost-effective compound will help facilitate the clinical translation of deuterium magnetic resonance imaging, and enable this powerful metabolic imaging modality to be widely used in both preclinical and clinical research and applications.

The aptamer-based RNA-PROTAC.

RNA-binding proteins (RBPs) dysfunction has been implicated in a number of diseases, and RBPs have traditionally been considered to be undruggable targets. Here, targeted degradation of RBPs is achieved based on the aptamer-based RNA-PROTAC, which consists of a genetically encoded RNA scaffold and a synthetic heterobifunctional molecule. The target RBPs can bind to their RNA consensus binding element (RCBE) on the RNA scaffold, while the small molecule can recruit E3 ubiquitin ligase to the RNA scaffold in a non-covalent manner, thereby inducing proximity-dependent ubiquitination and subsequent proteasome-mediated degradation of the target protein. Different RBPs targets, including LIN28A and RBFOX1, have been successfully degraded by simply replacing the RCBE module on the RNA scaffold. In addition, the simultaneous degradation of multiple target proteins has been realized by inserting more functional RNA oligonucleotides into the RNA scaffold.

Renal sarcoidosis presenting with chronic kidney disease and hypercalcemia.

Sarcoidosis is a multisystem inflammatory disease that most frequently affects the lungs, lymph nodes, eyes, and skin. Renal involvement is clinically rare. We describe a 72-year-old male who presented with chronic kidney disease and elevated serum calcium and angiotensin-converting enzyme. Renal biopsy pathology showed chronic granulomatous interstitial nephritis. Renal function was significantly improved after glucocorticoid therapy. This case emphasizes that chronic kidney disease and hypercalcemia can be clues for renal sarcoidosis. Early renal biopsy and projective treatment is beneficial for renal outcome.

Antibacterial Indole Diketopiperazine Alkaloids from the Deep-Sea Cold Seep-Derived Fungus Aspergillus chevalieri.

A large body of fungal secondary metabolites has been discovered to exhibit potent antibacterial activities with distinctive mechanisms and has the potential to be an untapped resource for drug discovery. Here, we describe the isolation and characterization of five new antibacterial indole diketopiperazine alkaloids, namely 24,25-dihydroxyvariecolorin G (1), 25-hydroxyrubrumazine B (2), 22-chloro-25-hydroxyrubrumazine B (3), 25-hydroxyvariecolorin F (4), and 27-epi-aspechinulin D (5), along with the known analogue neoechinulin B (6) from a fungal strain of deep-sea cold seep-derived Aspergillus chevalieri. Among these compounds, 3 and 4 represented a class of infrequently occurring fungal chlorinated natural products. Compounds 1-6 showed inhibitory activities against several pathogenic bacteria with MIC values ranging from 4 to 32 µg/mL. It was revealed that compound 6 could induce structural damage to the Aeromonas hydrophila cells based on the observation by scanning electron microscopy (SEM), which led to the bacteriolysis and death of A. hydrophila, suggesting that neoechinulin B (6) might be a potential alternative to novel antibiotics development.

Colletotrichum horii and Colletotrichum fioriniae Causing Anthracnose on Star Anise (Illicium verum) in China.

Star anise (Illicium verum) is an important economic and medical plant widely cultivated in Guangxi province, China. Its fruit can be used as spice and medicine (Wang et al. 2011). In recent years, anthracnose led to a serious decline in the production of star anise in Guangxi. In 2021, a survey conducted in CenwangLaoshan Reserve of Guangxi (24°21'N; 106°27'E) showed that the 2500 ha planting area had disease incidence greater than 80%. The leaf symptoms initially appeared as small spots, then expanded to round spots, finally becoming withered with grayish-white centers, surrounded by dark brown margins. Sometimes, small black acervuli were observed in the later stage. To explore the pathogen, infected leaves were collected and cut into small pieces (about 5 mm2) from the edge of the lesion, disinfected with 75% ethanol for 10 s, 1% NaClO for 1 min, washed with sterilized water and incubated on potato dextrose agar (PDA) plates at 28 °C in the dark. Ten single-spore isolates were obtained from the cultures. After 7 days on PDA at 28 °C, the colonies of 7 isolates were white with abundant aerial hyphae, gray-black with white-gray margins, and the other 3 isolates were light gray on the upper surface, and pink or orange on the underside. Representative isolates BS3-4 and BS3-1 were selected from 3 isolates and 7 isolates, respectively. Conidia of BS3-4 and BS3-1 were both hyaline, cylindrical, aseptate, smooth, apex obtuse, base truncate, and no significant differences (P > 0.05) in size between BS3-1 (13.22 to 5.38 × 3.89 to 1.99 µm) (n = 50) and BS3-4 (12.04 to 4.34 × 3.48 to 1.64 µm) (n = 50). These morphological characteristics were consistent with the Colletotrichum ssp. (Damm et al. 2012). The species identification of BS3-4 and BS3-1 was performed based on DNA sequence analysis. Genomic DNA was extracted as a template. Partial sequences of the rDNA internal transcribed spacer (ITS), actin gene (ACT), ß-tubulin2 (TUB2) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were amplified and sequenced (Weir et al. 2012). The sequences were deposited in GenBank (ITS:OQ062642-43; ACT:OQ067614-15; GAPDH:OQ067616-17;TUB2：OQ067618-19). Based on the concatenated sequences of the 4 genes (ITS-ACT- GAPDH -TUB2) of BS3-4 and BS3-1 as well as sequences of other Colletotrichum spp. obtained from GenBank, the Maximum likelihood (ML) tree which produced with IQ-TREE (Minh et al. 2020) revealed that the isolate BS3-1 was Colletotrichum horii, and BS3-4 was Colletotrichum fioriniae. Pathogenicity was confirmed on healthy leaves of 1-year-old star anise seedlings (cultivar Dahong), and the leaves were wounded by sterilized toothpicks, and were inoculated with 10 µl of conidial suspensions of BS3-1 and BS3-4 (106 conidia/ml). Control seedlings were inoculated with sterilized distilled water. Five leaves per plant and 3 plants per treatment were selected. All inoculated seedlings were maintained in the greenhouse (12/12h light/dark, 25 ± 2℃, 90% relative humidity). Wound sites inoculated with BS3-1 and BS3-4 both turned greenish-brown after 2 days and then turned light brown with water-soaked spots. Black (BS3-1) or orange (BS3-4) dots of acervuli developed after 6 days. The lesion diameter of BS3-1 (14.4 mm) was larger than that of BS3-4 (8.1 mm). No symptoms were observed on controls. BS3-1 and BS3-4 were re-isolated from inoculated leaves, fulfilling Koch's postulates. Anthracnose of star anise caused by C.horii has been reported in China (Liao et al. 2017). However, to our knowledge, this is the first report of C.fioriniae infecting star anise in China. Accurate pathogen identification in this study could provide a reference for the control of anthracnose on star anise.

Detection of Cancer Marker Flap Endonuclease 1 Using One-Pot Transcription-Powered Clustered Regularly Interspaced Short Palindromic Repeat/Cas12a Signal Expansion.

As a critical functional protein in DNA replication and genome stability, flap endonuclease 1 (FEN1) has been considered a promising biomarker and druggable target for multiple cancers. We report here a transcription-powered clustered regularly interspaced short palindromic repeat (CRISPR)/Cas12a signal expansion platform for rapid and sensitive detection of FEN1. In this method, the probe cleavage by FEN1 generated a free 5' flap single-stranded DNA which could hybridize with the single-stranded T7 promoter-bearing template and trigger the extension. Then, the CRISPR guide RNA (crRNA) transcribed from the extended template activated the collateral DNase activity of Cas12a, releasing the fluorophore from the quenched DNA signal probe to report the FEN1 detection result. The high specificity for FEN1 was validated by comparing with other repair-relevant proteins. The limit of detection (LOD) could be as low as 0.03 mU, which is sensitive enough to detect the FEN1 activity in biological samples. In addition, the inhibition assay of FEN1 was also successfully achieved with this platform, proving its potential in inhibitor screening. In summary, this study provides a novel biosensor for FEN1 activity analysis and provides new insights into the development of CRISPR-based biosensors for non-nucleic acid targets.

Association between polymorphisms of ABCB1 and prognosis in esophageal squamous cell carcinoma patients treated with taxane.

BACKGROUND: In China, most esophageal cancer patients are squamous cell carcinomas and are treated with taxane-containing regimens; however, few studies have examined taxane pharmacokinetics genes and esophageal squamous cell carcinoma (ESCC) prognosis. METHODS: In total, 227 pathologically confirmed ESCC patients receiving chemotherapy with taxane were included in the analysis. We genotyped seven SNPs (rs1045642, rs2032582 and rs3213619 of ABCB1; rs2231137 and rs2231142 of ABCG2; and ABCC1 rs246221 and ABCC2 rs3740066) and analyzed their relationship with overall survival. RESULTS: With a retrospective cohort study design, by Cox regression and semi-Bayesian shrinkage, in the genetic recessive model, the variant homozygote of ABCB1 rs1045642 was inversely associated with survival (semi-Bayesian shrinkage crude hazard ratio = 1.82, 95% confidence interval = 1.00, 3.31; p = 0.0482). CONCLUSIONS: Because of inherent defects of the research itself, the finding that the ABCB1 rs1045642 variant was related to poor prognosis in ESCC patients treated with taxane-containing regimens needs to be tested in a larger population and by using more genetic and molecular mechanism experiments.

Updated efficacy of adjuvant epirubicin plus cyclophosphamide followed by taxanes versus carboplatin plus taxanes in early triple-negative breast cancer in phase 2 trial: 8.1-year median follow-up.

BACKGROUND: Paclitaxel/docetaxel after doxorubicin plus cyclophosphamide (ECT) is considered as an adjuvant chemotherapy and improves the survival of early triple-negative breast cancer (TNBC) patients. We aim to assess whether carboplatin plus taxanes (TP) is non-inferior to ECT in prolonging the survival time. METHODS: TNBC patients were randomized (1:1) to receive ECT (90 mg/m2 epirubicin + 600 mg/m2 cyclophosphamide followed by 75 mg/m2 docetaxel or 175 mg/m2 paclitaxel every 3 weeks, n = 154) or TP (75 mg/m2 docetaxel or 175 mg/m2 paclitaxel + carboplatin AUC 5 every 3 weeks, n = 154). These expression of SPARC, PD-L1, and BRCA were studied. Patients were followed up for disease-free survival (DFS), overall survival (OS), and safety. RESULTS: We recruited 308 TNBC patients (median follow-up of 97.6 months). The median DFS and OS were not reached; the 8-year DFS rate of ECT and TP arms was 78.4% and 81.7%, respectively, while the 8-year OS rate were 87.2% and 89.1%, respectively. In the SPARC (> 50%) subgroup analysis, the TP arm had longer DFS (P = 0.049) and a tendency with better OS (P = 0.06) than ECT arm. No significant differences were observed in the DFS and OS between the ECT arm and TP arm in TNBC with SPARC (≤ 50%), PD-L1 (-) PD-L1 (+), and BRCA mutation or BRCA wild (all P values > 0.05). CONCLUSION: TP showed non-inferiority for DFS and OS compared with ECT in early TNBC. TP may be an effective alternative chemotherapy for TNBC patients whom the standard ECT regimen is not being used. TRAIL REGISTRATION: ClinicalTrials.gov identifier NCT01150513.

Combined analysis of receptor expression reflects inter-and intra-tumor heterogeneity in HR+/HER2+ breast cancer.

BACKGROUND: Hormone receptor-positive and human epidermal growth factor receptor 2-positive (HR+/HER2+ breast cancer comprise approximately 5-10% of all invasive breast cancers. However, the lack of knowledge regarding the complexity of tumor heterogeneity in HR+/HER2+ disease remains a barrier to more accurate therapies. This study aimed to describe the tumor heterogeneity of HR+/HER2+ breast cancer and to establish a novel indicator to identify the HER2-enriched subtype in patients with HR+/HER2+ breast cancer. METHODS: First of all, a comprehensive analysis was performed on HR+/HER2+ breast cancer samples from the TCGA (n = 141) and METABRIC (n = 104) databases. We determined the distribution of PAM50 intrinsic subtypes within the two cohorts and compared the somatic mutational profile and RNA expression features between HER2-enriched and non-HER2-enriched subtypes. From this, we constructed a novel marker termed rH/E, which was calculated as ERBB2 expression quantity/(ESR1 expression quantity + 1). Secondly, we performed multiplex immunofluorescence (mIF) to evaluate HER2 and estrogen receptor (ER) expression simultaneously in the third cohort, enrolling 43 cases of early HR+/HER2+ breast cancer from Cancer Hospital, Chinese Academy of Medical Sciences (CAMS). When using mIF, rH/E was adjusted to prH/E, which was calculated as HER2-positive cells%/(ER-positive cells + 1)%. RESULTS: All four main intrinsic subtypes were identified in HR+/HER2+ breast cancer, of which the luminal B subtype was the most common, followed by the HER2-enriched and luminal A subtypes. Significantly increased TP53 and ERBB3 and decreased PIK3CA somatic mutation frequency were observed in the HER2-enriched subtype compared with the non-HER2-enriched subtype. In addition, the HER2-enriched subtype was characterized by significantly higher ERBB2 and lower ESR1 expression. We then constructed a marker termed rH/E to reflect the relative expression of ERBB2 to ESR1 in each patient. rH/E discriminates the HER2-enriched subtype from the better than the expression of ERBB2 or ESR1 alone. In the CAMS cohort, we observed four subtypes of tumor cells: ER+/HER2-, ER+/HER2+, ER-/HER2+, and ER-/HER2-. Tumor cell diversity was common, with 86% of patients having all four subtypes of tumor cells. Moreover, prH/E showed a significant prognostic association in the CAMS cohort. CONCLUSIONS: This study furthers our understanding of the complexity of tumor heterogeneity in HR+/HER2+ breast cancer, and suggests that the combined analysis of ERBB2 and ESR1 expression may contribute to identifying patients with specific subtypes in this population.

Late-Stage Dehydroxyazidation of Alcohols Promoted by Trifunctional Hypervalent Azido-Iodine(III) Reagents.

The development of convenient new methods for the synthesis of organic azides is highly desirable. Herein, we report a practical method for dehydroxyazidation of alcohols via an SN 2 pathway involving PPh3 and trifunctional benziodazolone-based hypervalent azido-iodine(III) reagents, which function as an electrophilic center, an azido source, and a base. This mild, chemoselective method was used for late-stage azidation of structurally complex alcohols, as well as for a new synthetic route to the antiepileptic drug rufinamide. The reaction mechanism was also investigated both experimentally and computationally.

Frame-shifted proteins of a given gene retain the same function.

Frameshift mutations are generally considered to be lethal because it could result in radical changes of the protein sequence behind. However, the protein of frameshift mutants of a type I toxin (ibsc) was found to be still toxic to bacteria, retaining the similar function as wild-type protein to arrest the cellular growth by impairing the membrane's integrity. Additionally, we have verified that this observation is not an individual event as the same phenomenon had been found in other toxins subsequently. After analyzing the coding sequence of these genes, we proposed a hypothesis to search this kind of hidden gene, through which a dihydrofolate reductase-encoding gene (dfrB3) was found out. Like the wild-type reductase, both +1 and -1 frame-shifted proteins of dfrB3 gene were also proved to catalyze the reduction of dihydrofolate to tetrahydrofolate by using NADPH.

Percutaneous Transhepatic Papillary Balloon Dilation versus Endoscopic Retrograde Cholangiopancreatography for Common Bile Duct Stones: A Multicenter Prospective Study.

Background Endoscopic retrograde cholangiopancreatography (ERCP) is recommended by major guidelines for the removal of common bile duct (CBD) stones but is technically challenging in patients with low cardiopulmonary reserve and anatomic abnormalities of the upper gastrointestinal (GI) tract. Purpose To compare percutaneous transhepatic papillary balloon dilation (PTPBD) with ERCP for CBD stone removal. Materials and Methods Participants with one to three CBD stones (largest stone ≤30 mm) and without intrahepatic bile duct or gallbladder stones were eligible for this prospective cohort study. PTPBD was recommended in participants with low cardiopulmonary reserve or definitive anatomic abnormalities of the upper GI tract. Otherwise, both procedures were offered without preference. Follow-up, including abdominal CT, was conducted at 1-week and 1-, 3- and 6-month follow-up, and every 6 months thereafter. US and MR cholangiopancreatography were conducted if recurrence could not be confirmed with CT. Technical success rate was the primary outcome. Results A total of 531 participants were analyzed: there were 360 undergoing PTPBD (median age, 76 years; interquartile range [IQR], 64-82 years; 163 men) and 171 undergoing ERCP (median age, 66 years; IQR, 57-74 years; 94 men). The technical success rate was 99% (355 of 360) in the PTPBD group and 98% (167 of 171) in the ERCP group (relative risk, 1.02; P = .12). The incidence of overall complications was 4% (13 of 360) for PTPBD and 8% (13 of 171) for ERCP (relative risk, 0.27; 95% CI: 0.12, 0.61; P < .001). The PTPBD group showed a longer fluoroscopy time and a higher radiation exposure, with adjusted differences of 28.7 minutes (95% CI: 22.2, 35.2) and 384.3 mGy (95% CI: 296.5, 472), respectively. A propensity score-matching analysis (n = 123 per group) indicated that PTPBD had a slightly higher technical success rate and significantly fewer complications. Conclusion When compared with endoscopic retrograde cholangiopancreatography, percutaneous transhepatic papillary balloon dilation has a similar technical success rate and fewer perioperative complications but a higher radiation exposure. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by van Sonnenberg and Mueller in this issue.

Fibroblast Growth Factor 19-Mediated Up-regulation of SYR-Related High-Mobility Group Box 18 Promotes Hepatocellular Carcinoma Metastasis by Transactivating Fibroblast Growth Factor Receptor 4 and Fms-Related Tyrosine Kinase 4.

BACKGROUND AND AIMS: The poor prognosis of patients with hepatocellular carcinoma (HCC) is mainly attributed to its high rate of metastasis and recurrence. However, the molecular mechanisms underlying HCC metastasis need to be elucidated. The SRY-related high-mobility group box (SOX) family proteins, which are a group of highly conserved transcription factors, play important roles in cancer initiation and progression. Here, we report on a role of SOX18, a member of the SOX family, in promoting HCC invasion and metastasis. APPROACH AND RESULTS: The elevated expression of SOX18 was positively correlated with poor tumor differentiation, higher tumor-node-metastasis (TNM) stage, and poor prognosis. Overexpression of SOX18 promoted HCC metastasis by up-regulating metastasis-related genes, including fibroblast growth factor receptor 4 (FGFR4) and fms-related tyrosine kinase 4 (FLT4). Knockdown of both FGFR4 and FLT4 significantly decreased SOX18-mediated HCC invasion and metastasis, whereas the stable overexpression of FGFR4 and FLT4 reversed the decrease in cell invasion and metastasis that was induced by inhibition of SOX18. Fibroblast growth factor 19 (FGF19), which is the ligand of FGFR4, up-regulated SOX18 expression. A mechanistic investigation indicated that the up-regulation of SOX18 that was mediated by the FGF19-FGFR4 pathway relied on the phosphorylated (p)-fibroblast growth factor receptor substrate 2/p-glycogen synthase kinase 3 beta/ß-catenin pathway. SOX18 knockdown significantly reduced FGF19-enhanced HCC invasion and metastasis. Furthermore, BLU9931, a specific FGFR4 inhibitor, significantly reduced SOX18-mediated HCC invasion and metastasis. In human HCC tissues, SOX18 expression was positively correlated with FGF19, FGFR4, and FLT4 expression, and patients that coexpressed FGF19/SOX18, SOX18/FGFR4, or SOX18/FLT4 had the worst prognosis. CONCLUSIONS: We defined a FGF19-SOX18-FGFR4 positive feedback loop that played a pivotal role in HCC metastasis, and targeting this pathway may be a promising therapeutic option for the clinical management of HCC.

Anisotropic c-f Hybridization in the Ferromagnetic Quantum Critical Metal CeRh_{6}Ge_{4}.

Heavy fermion compounds exhibiting a ferromagnetic quantum critical point have attracted considerable interest. Common to two known cases, i.e., CeRh_{6}Ge_{4} and YbNi_{4}P_{2}, is that the 4f moments reside along chains with a large interchain distance, exhibiting strong magnetic anisotropy that was proposed to be vital for the ferromagnetic quantum criticality. Here, we report an angle-resolved photoemission study on CeRh_{6}Ge_{4} in which we observe sharp momentum-dependent 4f bands and clear bending of the conduction bands near the Fermi level, indicating considerable hybridization between conduction and 4f electrons. The extracted hybridization strength is anisotropic in momentum space and is obviously stronger along the Ce chain direction.The hybridized 4f bands persist up to high temperatures, and the evolution of their intensity shows clear band dependence. Our results provide spectroscopic evidence for anisotropic hybridization between conduction and 4f electrons in CeRh_{6}Ge_{4}, which could be important for understanding the electronic origin of the ferromagnetic quantum criticality.