Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7.

FBXW7 is an E3 ubiquitin ligase that targets proteins for proteasome-mediated degradation and is mutated in various cancer types. Here, we use CRISPR base editors to introduce different FBXW7 hotspot mutations in human colon organoids. Functionally, FBXW7 mutation reduces EGF dependency of organoid growth by ~10,000-fold. Combined transcriptomic and proteomic analyses revealed increased EGFR protein stability in FBXW7 mutants. Two distinct phosphodegron motifs reside in the cytoplasmic tail of EGFR. Mutations in these phosphodegron motifs occur in human cancer. CRISPR-mediated disruption of the phosphodegron motif at T693 reduced EGFR degradation and EGF growth factor dependency. FBXW7 mutant organoids showed reduced sensitivity to EGFR-MAPK inhibitors. These observations were further strengthened in CRC-derived organoid lines and validated in a cohort of patients treated with panitumumab. Our data imply that FBXW7 mutations reduce EGF dependency by disabling EGFR turnover.

SMYD4 monomethylates PRMT5 and forms a positive feedback loop to promote hepatocellular carcinoma progression.

Both lysine and arginine methyltransferases are thought to be promising therapeutic targets for malignant tumors, yet how these methyltransferases function in malignant tumors, especially hepatocellular carcinoma (HCC), has not been fully elucidated. Here, we reported that SMYD4, a lysine methyltransferase, acts as an oncogene in HCC. SMYD4 was highly upregulated in HCC and promoted HCC cell proliferation and metastasis. Mechanistically, PRMT5, a well-known arginine methyltransferase, was identified as a SMYD4-binding protein. SMYD4 monomethylated PRMT5 and enhanced the interaction between PRMT5 and MEP50, thereby promoting the symmetrical dimethylation of H3R2 and H4R3 on the PRMT5 target gene promoter and subsequently activating DVL3 expression and inhibiting expression of E-cadherin, RBL2, and miR-29b-1-5p. Moreover, miR-29b-1-5p was found to inversely regulate SMYD4 expression in HCC cells, thus forming a positive feedback loop. Furthermore, we found that the oncogenic effect of SMYD4 could be effectively suppressed by PRMT5 inhibitor in vitro and in vivo. Clinically, high coexpression of SMYD4 and PRMT5 was associated with poor prognosis of HCC patients. In summary, our study provides a model of crosstalk between lysine and arginine methyltransferases in HCC and highlights the SMYD4-PRMT5 axis as a potential therapeutic target for the treatment of HCC.

Application of noninvasive sampling technique in mitochondrial genome intraspecific phylogeny of the endangered butterfly, Teinopalpus aureus (Lepidoptera: Papilionidae).

The butterfly genus of Teinopalpus, endemic to Asia, embodies a distinct species of mountain-dwelling butterflies with specific habitat requirements. These species are rare in the wild and hold high conservation and research value. Similar to other protected species, the genetic analysis of the rare Teinopalpus aureus poses challenges due to the complexity of sampling. In this study, we successfully extracted DNA and amplified mitochondrial genomic DNA from various noninvasive sources such as larval feces, larval exuviae, larval head capsules, pupal exuviaes, and filamentous gland secretions, all integral parts of butterfly metamorphosis. This was conducted as part of a research initiative focused on the artificial conservation of T. aureus population in Jinggang Shan Nature Reserve. Our findings illustrated the successful extraction of DNA from multiple noninvasive sources, achieved through modified DNA extraction methodologies. Although the DNA concentration obtained from noninvasive samples was lower than that from muscle tissues of newly dead larvae during rearing, all samples met the requirements for PCR amplification and sequencing, yielding complete circular sequences. These sequences are pivotal for both interspecific and intraspecific genetic relationship analysis. Our methods can be extended to other insects, especially scarce species.

Increased co-expression of PD1 and TIM3 is associated with poor prognosis and immune microenvironment heterogeneity in gallbladder cancer.

BACKGROUND: The effectiveness of immune checkpoint inhibitors in treating gallbladder cancer (GBC) remains unsatisfactory. Recently, several new immune checkpoints have been identified. However, investigations exploring these immune checkpoints in GBC are limited. In this study, we aim to investigate the expression patterns and clinical implications of various immune checkpoints, and further characterize the spatial and quantitative heterogeneity of immune components in GBC. METHODS: We employed single and multiplex immunohistochemistry to evaluate the expression of five immune checkpoint markers and four immune cell markers in the primary tumor core, hepatic invasion margin, and liver metastasis. Subsequently, we analyzed their interrelationships and their prognostic significance. RESULTS: We observed a robust positive correlation between PD1/TIM3 expression in GBC (R = 0.614, P < 0.001). The co-expression of PD1/TIM3 exhibited a synergistic effect in predicting poor prognosis among postoperative GBC patients. Further analysis revealed that the prognostic significance of PD1/TIM3 was prominent in the subgroup with high infiltration of CD8 + T cells (P < 0.001). Multiplex immunohistochemistry reveals that PD1 + TIM3 + FOXP3 + cells constitute a significant proportion of FOXP3 + TILs in GBC tissue. Moreover, the co-high expression of PD1 and TIM3 is positively correlated with the accumulation of CD8 + TILs at the hepatic invasion margin. Lastly, our findings indicated reduced expression levels of immune checkpoints and diminished immune cell infiltration in liver metastases compared to primary tumors. CONCLUSIONS: Increased co-expression of PD1/TIM3 is associated with poor prognosis in GBC patients and is related to the heterogeneity of immune microenvironment between GBC primary tumor and its hepatic invasion margin or liver metastases, which may be a potential target for future immunotherapy of GBC.

Proteasomal inhibitors induce myeloma cell pyroptosis via the BAX/GSDME pathway.

Proteasomes are overexpressed in multiple myeloma (MM) and proteasomal inhibitors (PIs) have been widely used for the treatment of MM. PIs are reported to induce MM cell apoptosis but impair necroptosis. In the present study, we found that PIs MG132 and bortezomib induce MM cell pyroptosis, a novel type of cell death, in a GSDME-dependent manner. Lack of GSDME totally blocks PI-induced pyroptosis. Interestingly, we found that Caspase-3/6/7/9 are all involved in pyroptosis triggered by PIs because the specific inhibitor of each caspase ablates GSDME activation. PIs markedly reduce mitochondrial membrane potential. Moreover, PIs disrupt the interaction of Bcl-2 and BAX, induce cytochrome c release from mitochondria to cytosol and activate GSDME. Furthermore, we found that overexpression of an N-terminal portion of GSDME suffices to release cytochrome c from mitochondria and to activate Caspase-3/9, suggesting N-GSDME might penetrate the mitochondrial membrane. Consistent with Bcl-2 inhibition, BAX can induce MM cell pyroptosis in a GSDME-dependent manner. In accordance with these findings, inhibition of Bcl-2 synergizes with PIs to induce MM cell pyroptosis. Therefore, the present study indicates that PIs trigger MM cell pyroptosis via the mitochondrial BAX/GSDME pathway and provides a rationale for combined treatment of MM with Bcl-2 and proteasome inhibitors to increase therapeutic efficiency via induction of pyroptosis.

Estimation of gastric cancer burden attributable to Helicobacter pylori infection in Asia.

BACKGROUND: Helicobacter pylori causes large burden of gastric cancer (GC) in Asia. We aimed to comprehensively quantify the burden of GC attributable to H. pylori infection in Asia. METHODS: We searched related articles from January 1998 to December 2020 to obtain the prevalence and relative risks (or odds ratio) of GC associated with H. pylori in Asia. The burden of GC attributable to H. pylori infection was quantified by Population Attributable Fraction (PAF) and Disability-adjusted life-years (DALYs). RESULTS: We quantified the burden of GC attributable to H. pylori infection with 415.6 thousand DALYs and 38.03% PAF through the five included Asian countries in 2019. The study found that the burden had obvious regional differences. The DALYs ranged from 298.9 thousand in China to 1.9 thousand in Malaysia, and the PAFs were between 58.00% in Japan and 30.89% in China. The average prevalence of H. pylori in the included general population was estimated to be 56.29%. CONCLUSIONS: Helicobacter pylori poses a huge disease burden of GC to the population, and its eradication should receive attention, especially in the countries with high incidence of and mortality due to GC.

Intravenous lidocaine improves postoperative cognition in patients undergoing laparoscopic colorectal surgery: a randomized, double-blind, controlled study.

BACKGROUND: The risk of postoperative cognitive dysfunction(POCD) in laparoscopic surgery should not be overlooked. Intravenous lidocaine can reduce perioperative inflammatory response in patients undergoing laparoscopic surgery, while the effect of intraoperative intravenous lidocaine on postoperative cognitive function in patients undergoing laparoscopic colorectal cancer surgery has not been well studied. We investigated whether intraoperative lidocaine improves postoperative cognitive function after laparoscopic radical resection for colorectal cancer. METHODS: We conducted a prospective, randomized double blinded controlled trial to investigate the effect of intravenous lidocaine on rapid postoperative recovery in patients undergoing laparoscopic radical resection of colorectal cancer. The patients were randomly assigned to receive either intravenous lidocaine or saline. The primary outcome was cognitive dysfunction defined by a decrease from pre- to postoperative ≥ 2 of the Mini-Mental State Examination (MMSE) score, at the 3rd and the 7th postoperative days. Secondary outcomes were the MMSE raw score and parameters of the patients' postoperative recovery such as agitation and length of stay in the post-anaesthesia care unit (PACU), length of hospital stay, markers of inflammation (white blood cell count and CRP), and incidence of complications. RESULTS: Seventy-three patients in the lidocaine group and 77 patients in the control group completed the trial. The rate of cognitive dysfunction was lower in the lidocaine group than that in the control group, both at the 3rd (18.57% vs. 63.64% for each group respectively; RR = 0.26, 95%CI = 0.19-0.32; p < 0.0001) and at the 7th postoperative day (12.33% vs. 53.25% for each group respectively; RR = 0.28, 95%CI = 0.22-0.35; P < 0.001). The postoperative MMSE scores were also higher in the lidocaine group than in the control group both at the 3rd (median 25 vs. 24 respectively) and at the 7th postoperative day (26 vs. 24 respectively). Also, patients in the lidocaine group displayed a lower white blood cell count than the control group at the 1st postoperative day (8.5 ± 2.7 vs. 10.4 ± 3.3; p < 0. 001). No differences were evidenced for the other secondary outcomes. CONCLUSIONS: Intraoperative intravenous lidocaine can significantly improve postoperative cognitive function in patients undergoing laparoscopic radical resection of colorectal cancer. TRIAL REGISTRATION: Chinese Clinical Trial Registry (16/1/2022, registration number: ChiCTR2200055683).

The phonon scattering mechanism and its effect on the temperature dependent thermal and thermoelectric properties of a silver nanowire.

In this work, the electron-phonon, phonon-phonon, and phonon structure scattering mechanisms and their effect on the thermal and thermoelectric properties of a silver nanowire (AgNW) is investigated in the temperature range of 10 to 300 K. The electron-phonon scattering rate decreases with the increase of temperature. The phonon-phonon scattering rate increases with temperature and becomes greater than the electron-phonon scattering rate when the temperature is higher than the Debye temperature (223 K). The rate of phonon structure scattering is constant. The total phonon scattering rate decreases with temperature when the temperature is lower than about 150 K, and increases when the temperature is higher than 150 K. Correspondingly, the temperature dependent variation trend of the lattice thermal conductivity is opposite diametrically to that of the total phonon scattering rate. The thermoelectric properties of the AgNW are strongly coupled with the thermal conductivity via the phonon and electron transition. The thermoelectric properties of the material are quantified by the figure of merit (ZT). The ZT value of the AgNW is greater than that of bulk silver in the corresponding temperature range, and this difference increases with temperature. The order of the ZT of the AgNW is about 13 times greater than that of bulk silver at room temperature. The large increase of the ZT value of the AgNW is mainly due to the enhanced electron scattering and phonon scattering mechanisms in the AgNW.

Prenatal diagnosis of type A fetal interrupted aortic arch by four-dimensional echocardiography with HD-flow STIC: A case report.

Interrupted aortic arch (IAA) is a rare complex congenital heart disease characterized by interrupted continuity between ascending aorta and descending aorta. Prenatal diagnosis of IAA by echocardiography is not uncommonly reported despite its rarity. However, employing four-dimensional ultrasound HD-flow imaging and spatiotemporal image correlation (STIC) in diagnosis of this condition has seldom been reported. We report a case of fetal IAA prenatally diagnosed by two-dimensional echocardiography and HD-flow STIC.

Enantioselective Radical Carbocyanation of 1,3-Dienes via Photocatalytic Generation of Allylcopper Complexes.

1,3-Dienes are readily available feedstocks that are widely used in the laboratory and industry. However, the potential of converting 1,3-dienes into value-added products, especially chiral products, has not yet been fully exploited. By synergetic photoredox/copper catalysis, we achieve the first visible-light-induced, enantioselective carbocyanation of 1,3-dienes by using carboxylic acid derivatives and trimethylsilyl cyanide. Under mild and neutral conditions, a diverse range of chiral allyl cyanides are produced in generally good efficiency and with high enantioselectivity from bench-stable and user-safe chemicals. Moreover, preliminary results also confirm that this success can be expanded to 1,3-enynes and the four-component carbonylative carbocyanation of 1,3-dienes and 1,3-enynes.

CMOS monolithic photodetector with a built-in 2-dimensional light direction sensor for laser diode based underwater wireless optical communications.

Underwater wireless optical communications (UWOC) are considered an emerging high-speed wireless network for underwater applications and compete with underwater radio frequency (RF) communications and underwater acoustic communications (UAC). Even though the utilization of laser diodes (LDs) enhances the -3dB modulation bandwidth extraordinarily from a few tens of MHz to GHz, LDs have the features of high collimation and narrow spectrum. Without the point-to-point optical alignment, the performance of the LD-based UWOC system drops exponentially because the received optical power determines the signal-to-noise ratio (SNR) of the UWOC system. To achieve a high-performance and reliable UWOC link based on LDs requires focusing optics and an alignment system. In this paper, we demonstrated a CMOS monolithic photodetector with a built-in 2-dimensional light direction sensor for the UWOC link by using a 450 nm LD and none-return-to-zero on-off keying (NRZ-OOK) modulation method. Employing this innovative technique, the field of view (FOV) was enlarged to 120°, and data rates up to 110 Mb/s at a bit error rate (BER) of 2.3×10-10 were obtained. The establishment of a proposed UWOC physical link showed enhanced communication performance for more practical and robust wireless communication applications.

Variant of SNPs at lncRNA NEAT1 contributes to gastric cancer susceptibility in Chinese Han population.

BACKGROUND: The long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) has been implicated in many tumors risk including gastric cancer. However, the association of single nucleotide polymorphisms (SNPs) at NEAT1 with gastric cancer risk has not been studied. The aim of this study was to investigate the association between SNPs in NEAT1 and gastric cancer susceptibility. METHODS: In this study, four SNPs in lncRNA NEAT1 were selected for genotyping in 484 gastric cancer patients and 484 controls in Chinese Han population. Quantitative real-time PCR (qRT-PCR) was conducted to evaluate the potential function of rs3825071. Attributable risk percentage (ARP) and population attributable risk percentage (PARP) were used to assess the epidemiological effect. RESULTS: In the dominant model (GG), the genotypes AG + AA of rs3825071 and rs7943779 were associated with an increased risk of gastric cancer (OR = 1.72, 95%CI = 1.27-2.32 and OR = 1.63, 95%CI = 1.19-2.22). Individuals harboring ≥ 3 risk alleles have higher risk of gastric cancer (OR = 1.88, 95% CI = 1.26-2.80, P = 0.002). ARP and PARP associated with gastric cancer were 42.53% and 10.88% for rs3825071, and were 33.78% and 6.26% for rs7943779, respectively. Furthermore, compared with the genotype GG of rs3825071, the genotypes AG and AA had higher expression of NEAT1. CONCLUSIONS: We found that the genetic variations in NEAT1 were significantly associated with risk of gastric cancer. The G > A variant of rs3825071 may confer gastric cancer susceptibility by changed biological effects to increase the expression of NEAT1.

Clinical differences in chest CT characteristics between the progression and remission stages of patients with COVID-19 pneumonia.

INTRODUCTION: Computed tomography (CT) can be effective for the early screening and diagnosis of COVID-19. This study aimed to investigate the distinctive CT characteristics of two stages of the disease (progression and remission). METHODS: We included all COVID-19 patients admitted to Wenzhou Central Hospital from January to February, 2020. Patients underwent multiple chest CT scans at intervals of 3-10 days. CT features were recorded, such as the lesion lobe, distribution characteristics (subpleural, scattered or diffused), shape of the lesion, maximum size of the lesion, lesion morphology (ground-glass opacity, GGO) and consolidation features. When consolidation was positive, the boundary was identified to determine its clarity. RESULTS: The ratios of some representative features differed between the remission stage and the progression phase, such as round-shape lesion (8.0% vs 34.4%), GGO (65.0% vs 87.5%), consolidation (62.0% vs 31.3%), large cable sign (59.0% vs 9.4%) and crazy-paving sign (20.0% vs 50.0%). Using these features, we pooled all the CT data (n = 132) and established a logistic regression model to predict the current development stage. The variables consolidation, boundary feature, large cable sign and crazy-paving sign were the most significant factors, based on a variable named "prediction of progression or remission" (PPR) that we constructed. The ROC curve showed that PPR had an AUC of 0.882 (cutoff value = 0.66, sensitivity = 0.75, specificity = 0.875). CONCLUSION: CT characteristics, in particular, round shape, GGO, consolidation, large cable sign, and crazy-paving sign, may increase the recognition of the intrapulmonary development of COVID-19.

DPYSL2 as potential diagnostic and prognostic biomarker linked to immune infiltration in lung adenocarcinoma.

BACKGROUND: Dihydropyrimidinase like 2 (DPYSL2) has been linked to tumor metastasis. However, the function of DPSY2L in lung adenocarcinoma (LUAD) is yet to be explored. METHODS: Herein, we assessed DPYSL2 expression in various tumor types via online databases such as Oncomine and Tumor Immune Estimation Resource (TIMER). Further, we verified the low protein and mRNA expressions of DPYSL2 in LUAD via the ULCAN, The TCGA and GEPIA databases. We applied the ROC curve to examine the role of DPYSL2 in diagnosis. The prognostic significance of DPYSL2 was established through the Kaplan-Meier plotter and the Cox analyses (univariate and multivariate). TIMER was used to explore DPYSL2 expression and its connection to immune infiltrated cells. Through Gene Set Enrichment Analysis, the possible mechanism of DPYSL2 in LUAD was investigated. RESULTS: In this study, database analysis revealed lower DPYSL2 expression in LUAD than in normal tissues. The ROC curve suggested that expression of DPYSL2 had high diagnostic efficiency in LUAD. The DPYSL2 expression had an association with the survival time of LUAD patients in the Kaplan-Meier plotter and the Cox analyses. The results from TIMER depicted a markedly positive correlation of DPYSL2 expression with immune cells infiltrated in LUAD, such as macrophages, dendritic cells, CD4+ T cells, and neutrophils. Additionally, many gene markers for the immune system had similar positive correlations in the TIMER analysis. In Gene Set Enrichment Analysis, six immune-related signaling pathways were associated with DPYSL2. CONCLUSIONS: In summary, DPYSL2 is a novel biomarker with diagnostic and prognostic potential for LUAD as well as an immunotherapy target. HIGHLIGHTS: 1. Expression of DPYSL2 was considerably lower in LUAD than in normal tissues. 2. Investigation of multiple databases showed a high diagnostic value of DPYSL2 in LUAD. 3. DPYSL2 can independently predict the LUAD outcomes. 4. Immune-related mechanisms may be potential ways for DPYSL2 to play a role in LUAD.

Severe cervical inflammation and high-grade squamous intraepithelial lesions: a cross-sectional study.

PURPOSE: Inflammation has been reported as a facilitator in cervical oncogenesis, but the correlation between inflammation and cytological abnormality remains uncertain. The aim of this study was to investigate the correlation between inflammation and cytological abnormality. METHODS: ThinPrep cytological test (TCT) was used to detect cervical cytological abnormalities and inflammation degrees of 46,255 women in this prospective cross-sectional study. Histopathological examination was used to define the cervical intraepithelial neoplasia (CIN) in patients with cervical cytological abnormalities. RESULTS: The study revealed that 8.87% (4102/46,255) of TCT results had cytological abnormalities. The 4102 included cases were classified as the case group, including atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL). Women with negative intraepithelial lesion or malignancy (NILM) were classified as the control group. About 88.83% (3644/4102) of women with cytological abnormalities showed inflammations. The rate of severe inflammation was significantly higher in the case group than the control group (23.86% vs. 2.0%, P = 0.000). Our results also showed that patients with severe inflammation had a significantly increasing incidence of cytological abnormality by 12.598 times and elevated the risk of HSIL by 756.47 times, compared to the inflammation negative group. CONCLUSION: Severe inflammation was positively related to HSIL. Patients with severe cervical inflammation should be given more follow-ups and regular examinations and treated more carefully than those with mild or no inflammation.

[Role of Puerariae Lobatae Radix in Gegen Decoction for treatment of primary dysmenorrhea].

This study aimed to explore the characteristic role of Puerariae Lobatae Radix(PLR) in Gegen Decoction for the treatment of primary dysmenorrhea(PD). Estrogen(E_2) was combined with oxytocin to establish a mouse model of PD. The mice were randomly divided into a normal group, a model group, a Gegen Decoction group, a PLR-free Gegen Decoction group, a PLR group, and a positive drug group(ibuprofen). Writhing response times and writhing incubation of mice in each group were tested by behavio-ral assessment, and the serum levels of prostaglandin F_(2α)(PGF_(2α)), prostaglandin E_2(PGE_2), E_2, and progesterone(PROG) were detected by ELISA kits. Western blot method was adopted to detect cyclooxygenase-2(COX-2) and estrogen receptor alpha(ER_α) expression levels in uterine tissues. Doppler ultrasound was employed to detect changes in uterine artery blood flow in mice, including peak systolic blood flow velocity(maximum velocity), end-diastolic velocity(minimum velocity), peak systolic blood flow velocity/end-diastolic velocity(S/D), pulsatility index(PI), and resistive index(RI). Histopathological changes in the uterus were detected by HE staining. Based on the oxytocin-induced isolated uterine contraction model, the effects of Gegen Decoction, PLR-free Gegen Decoction, and PLR on the amplitude, frequency, and activity of isolated uterine contraction were compared to investigate the role of PLR in Gegen Decoction for the treatment of PD. The results showed that compared with the Gegen Decoction group, the PLR-free Gegen Decoction improved the indicators of PD except for E_2 content, ER_α expression, and uterine artery blood flow. PLR could significantly down-regulate the serum content of E_2 and the protein expression of uterine ER_α, and improve the uterine artery blood flow. The data suggested that PLR, as the sovereign drug of Gegen Decoction, might function in Gegen Decoction for the treatment of PD by mediating E_(2 )and improving the uterine artery blood flow.

[Herbal textual research on Chuanxiong Rhizoma in Chinese classical prescriptions].

Fourteen classical prescriptions in the Catalog of 100 Ancient Classical Prescriptions(First Batch) promulgated in 2018 contain Chuanxiong Rhizoma, which reveals the high medicinal value and wide application of Chuanxiong Rhizoma. This paper systematically reviews the ancient herbal books and modern literature to explore the name, origin, genuine producing area, medicinal part, harvesting, and processing of Chuanxiong Rhizoma, thus facilitating the development of classical prescriptions containing Chuan-xiong Rhizoma. It is confirmed that Chuanxiong Rhizoma, formerly known as "Xiongqiong" in Chinese, was first called "Chuanxiong" in late Tang Dynasty, which has been gradually accepted as its official name due to the rise of the status of Chuanxiong Rhizoma produced in Sichuan. The main original plant of Chuanxiong Rhizoma in past dynasties has always been deemed to be Ligusticum chuan-xiong(Umbellifera), whose rhizome serves as the medicinal part. In general, it is best harvested in summer but the harvesting time can vary with different growth environments. Since the Song Dynasty, Sichuan province has been recognized as the genuine producing area of Chuanxiong Rhizoma in light of the high yield and good quality. It is suggested that Chuanxiong Rhizoma from Sichuan be used preferentially in the development of classical prescriptions. There are multiple processing methods of Chuanxiong Rhizoma recorded in ancient medical classics, and the raw(after purifying and slicing) or wine-processed or stir-fried Chuanxiong Rhizoma is still in use today. In the development of classical prescriptions containing Chuanxiong Rhizoma, Chuanxiong Rhizoma is advised to be processed in accordance with current processing standards if the specific processing method is described in the medical classics. If not, the raw Chuanxiong Rhizoma is preferred and then processed following the processing standards of Chuanxiong Rhizoma decoction pieces in Chinese Pharmacopoeia.

Interferon Lambda Promotes Paneth Cell Death Via STAT1 Signaling in Mice and Is Increased in Inflamed Ileal Tissues of Patients With Crohn's Disease.

BACKGROUND & AIMS: Interferon lambda (IFNL) is expressed at high levels by intestinal epithelial cells (IECs) and mucosal immune cells in response to infection and inflammation. We investigated whether IFNL might contribute to pathogenesis of Crohn's disease (CD). METHODS: We obtained serum samples and terminal ileum biopsies from 47 patients with CD and 16 healthy individuals (controls). We measured levels of IFNL by enzyme-linked immunosorbent assay and immunohistochemistry and location of expression by confocal microscopy. Activation of IFNL signaling via STAT1 was measured in areas of no, mild, moderate, and severe inflammation and correlated with Paneth cell homeostasis and inflammation. IFNL expression and function were studied in wild-type mice and mice with intestinal epithelial cell-specific (ΔIEC) disruption or full-body disruption of specific genes (Mlkl-/-, Stat1ΔIEC, Casp8ΔIEC, Casp8ΔIECRipk3-/-, Casp8ΔIECTnfr-/-, Casp8ΔIECMlkl-/-, and Nod2-/- mice). Some mice were given tail vein injections of a vector encoding a secreted form of IFNL. Intestinal tissues were collected from mice and analyzed by immunohistochemistry and immunoblots. We generated 3-dimensional small intestinal organoids from mice and studied the effects of IFNL and inhibitors of STAT-signaling pathway. RESULTS: Patients with CD had significant increases in serum and ileal levels of IFNL compared with controls. Levels of IFNL were highest in ileum tissues with severe inflammation. High levels of IFNL associated with a reduced number of Paneth cells and increased cell death at the crypt bottom in inflamed ileum samples. Intestinal tissues from the ileum of wild-type mice injected with a vector expressing IFNL had reduced numbers of Paneth cells. IFNL-induced death of Paneth cells in mice did not occur via apoptosis, but required Mixed Lineage Kinase Domain Like (MLKL) and activation of Signal transducer and activator of transcription 1 (STAT1). In organoids, inhibitors of Janus kinase (JAK) signaling via STAT1 (glucocorticoids, tofacitinib, or filgotinib) reduced expression of proteins that mediate cell death and prevented Paneth cell death. CONCLUSIONS: Levels of IFNL are increased in serum and inflamed ileal tissues from patients with CD and associated with a loss of Paneth cells. Expression of a secreted form of IFNL in mice results in loss of Paneth cells from intestinal tissues, via STAT1 and MLKL, controlled by caspase 8. Strategies to reduce IFNL or block its effects might be developed for treatment of patients with CD affecting the terminal ileum.

Epstein-Barr virus activates F-box protein FBXO2 to limit viral infectivity by targeting glycoprotein B for degradation.

Epstein-Barr virus (EBV) is a human cancer-related virus closely associated with lymphoid and epithelial malignancies, and EBV glycoprotein B (gB) plays an essential role in viral entry into both B cells and epithelial cells by promoting cell-cell fusion. EBV gB is exclusively modified with high-mannose-linked N-glycans and primarily localizes to the endoplasmic reticulum (ER) with low levels on the plasma membrane (PM). However, the mechanism through which gB is regulated within host cells is largely unknown. Here, we report the identification of F-box only protein 2 (FBXO2), an SCF ubiquitin ligase substrate adaptor that preferentially binds high-mannose glycans and attenuates EBV infectivity by targeting N-glycosylated gB for degradation. gB possesses seven N-glycosylation sites, and FBXO2 directly binds to these high-mannose moieties through its sugar-binding domain. The interaction promotes the degradation of glycosylated gB via the ubiquitin-proteasome pathway. Depletion of FBXO2 not only stabilizes gB but also promotes its transport from the ER to the PM, resulting in enhanced membrane fusion and viral entry. FBXO2 is expressed in epithelial cells but not B cells, and EBV infection up-regulates FBXO2 levels. In summary, our findings highlight the significance of high-mannose modification of gB and reveal a novel host defense mechanism involving glycoprotein homeostasis regulation.

Proposed a self-absorption internal standard model to detect element concentrations of complex constituent material with a single emission line of element in laser plasmas.

Laser induced plasmas (LIPs) method is a highly regarded approach to evaluate the chemical composition of materials. But the strong self-absorption of the radiation seriously affects its accuracy. Meanwhile, the model based on self-absorption phenomenon makes its application very difficult. In this work, a self-absorption internal standard (SAIS) model is proposed for detection of the multi-element concentrations of complex constituent material with a single emission line of the element in laser plasmas. A typical LIPs experiment system is set up to generate plasmas, and the soil is selected as a test sample. The average electron temperature (0.975 eV) and electron density (1.44×1018 cm-3) are determined by the Boltzmann plot and emission lines Stark broadening, respectively. The plasmas are diagnosed as in local thermodynamic equilibrium condition. The emission lines selected to calculate the concentration of sample contain a wide set of kt values (0.575×10-30∼37.2×10-30 m3). Then, the concentrations of some elements are calculated by the model using single emission line of each element. It is found that the concentrations of the five elements (Ti, Fe, Mg, Al, Si) calculated by SAIS model are relatively consistent with the results of the traditional chemical testing methods. This indicated that the SAIS model is an effective and neat method for multi-element concentrations detection of complex constituent materials.