PcEiger links the Imd/Relish pathway to ROS production in the intestine of the red swamp crayfish.

In the arthropod gut, commensal microbiota maintain the immune deficiency (Imd)/Relish pathway for expression of antimicrobial peptides, whereas pathogenic bacteria induce dual oxidase 2 (Duox2) for production of extracellular microbicidal reactive oxygen species (ROS). The Imd/Relish pathway and the Duox2/ROS system are regarded as independent systems. Here, we report that these two systems are bridged by the tumor necrosis factor (TNF) ortholog PcEiger in the red swamp crayfish Procambarus clarkii. PcEiger expression is induced by commensal bacteria or the Imd/Relish pathway. PcEiger knockdown alters bacterial abundance and community composition due to variations in the oxidative status of the intestine. PcEiger induces Duox2 expression and ROS production by regulating the activity of the transcription factor Atf2. Moreover, PcEiger mediates regulation of the Duox2/ROS system by commensal bacteria and the Imd/Relish pathway. Our findings suggest that the Imd/Relish pathway regulates the Duox2/ROS system via PcEiger in P. clarkii, and they provide insights into the crosstalk between these two important mechanisms for arthropod intestinal immunity.

Expected Eight-Week Prenatal Versus Twelve-Week Perinatal Tenofovir Alafenamide Prophylaxis to Prevent Mother-To-Child Transmission of Hepatitis B Virus: A Multicenter, Prospective, Open-label, Randomized Controlled Trial.

INTRODUCTION: The course of maternal antiviral prophylaxis to prevent mother-to-child transmission of hepatitis B virus (HBV-MTCT) varies greatly, and it has not been demonstrated in a randomized controlled study. METHODS: In this multicenter, open-label, randomized controlled trial, eligible pregnant women with HBV DNA of 5.3-9.0 log10 IU/mL who received tenofovir alafenamide fumarate (TAF) from the first day of 33 gestational weeks to delivery (expected eight-week) or to four-week postpartum (expected twelve-week) were randomly enrolled at a 1:1 ratio and followed until six-month postpartum. All infants received standard immunoprophylaxis (hepatitis B immunoglobulin and vaccine). The primary endpoint was the safety of mothers and infants. The secondary endpoint was infants' HBV-MTCT rate at seven months of age. RESULTS: Among 119 and 120 intention-to-treat pregnant women, 115 and 116 women were followed until delivery, and 110 and 112 per-protocol mother-infant dyads in two groups completed the study. Overall, TAF was well tolerated, no one discontinued therapy due to adverse events (0/239, 0%, 95% confidence interval [CI] 0%-1.6%), and no infant had congenital defects or malformations at delivery (0/231, 0%, 95% CI 0%-1.6%). The infants' physical development at birth (n=231) and at seven months (n=222) were normal. Furthermore, 97.0% (224/231, 95% CI 93.9%-98.5%) of women achieved HBV DNA <5.3 log10 IU/mL at delivery. The intention-to-treat and per-protocol infants' HBV-MTCT rates were 7.1% (17/239, 95% CI 4.5%-11.1%) and 0% (0/222, 95% CI 0%-1.7%) at seven months of age. Comparatively, 15.1% (18/119, 95% CI 9.8%-22.7%) versus 18.3% (22/120, 95% CI 12.4%-26.2%) of women in the two groups had mildly elevated alanine aminotransferase levels at three-month and six-month postpartum, respectively (P=0.507); notably, no one experienced alanine aminotransferase flare (0% [0/119, 95% CI 0%-3.1%] versus 0% [0/120, 0%-3.1%]). DISCUSSION: Maternal TAF prophylaxis to prevent HBV-MTCT is generally safe and effective, and expected eight-week prenatal duration is feasible. ClinicalTrials.gov, NCT04850950.

Small immune effectors coordinate peptidoglycan-derived immunity to regulate intestinal bacteria in shrimp.

Small antibacterial effectors, including lysozymes, lectins, and antimicrobial peptides, are key regulators of intestinal immunity. However, whether there is coordination among them during regulation is an interesting, but largely unknown, issue. In the present study, we revealed that small effectors synergistically regulate peptidoglycan-derived intestinal immunity in the kuruma shrimp, Marsupenaeus japonicus. A C-type lysozyme (LysC) was screened as a responsive factor for the intestine-bacteria interaction. LysC functions to restrict intestinal bacteria, mainly by cleaving Photobacterium damselae peptidoglycan to generate muropeptides which are powerful stimulators that induce anti-lipopolysaccharides factor B1 (AlfB1), an effective bactericidal peptide. The muropeptides also induce a C-type lectin (Ctl24), which recognizes peptidoglycan and coats bacteria. By counteracting LysC-mediated muropeptide release and AlfB1's bactericidal activity, Ctl24 prevents the continuous elimination of intestinal bacteria. Therefore, this study demonstrates a mechanism by which small immune effectors coordinate to achieve intestinal homeostasis, and provides new insights into peptidoglycan-derived intestinal immunity in invertebrates.

Effects of SARS-COV-2 infection during the frozen-thawed embryo transfer cycle on embryo implantation and pregnancy outcomes.

STUDY QUESTION: Does severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the frozen-thawed embryo transfer (FET) cycle affect embryo implantation and pregnancy rates? SUMMARY ANSWER: There is no evidence that SARS-CoV-2 infection of women during the FET cycle negatively affects embryo implantation and pregnancy rates. WHAT IS KNOWN ALREADY: Coronavirus disease 2019 (COVID-19), as a multi-systemic disease, poses a threat to reproductive health. However, the effects of SARS-CoV-2 infection on embryo implantation and pregnancy following fertility treatments, particularly FET, remain largely unknown. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study, included women who underwent FET cycles between 1 November 2022 and 31 December 2022 at an academic fertility centre. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who tested positive for SARS-CoV-2 during their FET cycles were included in the COVID-19 group, while those who tested negative during the same study period were included in the non-COVID-19 group. The primary outcome was ongoing pregnancy rate. Secondary outcomes included rates of implantation, biochemical pregnancy, clinical pregnancy, early pregnancy loss, and ongoing pregnancy. Multivariate logistic regression models were applied to adjust for potential confounders including age, body mass index, gravidity, vaccination status, and endometrial preparation regimen. Subgroup analyses were conducted by time of infection with respect to transfer (prior to transfer, 1-7 days after transfer, or 8-14 days after transfer) and by level of fever (no fever, fever <39°C, or fever ≥39°C). MAIN RESULTS AND THE ROLE OF CHANCE: A total of 243 and 305 women were included in the COVID-19 and non-COVID-19 group, respectively. The rates of biochemical pregnancy (58.8% vs 62.0%, P = 0.46), clinical pregnancy (53.1% vs 54.4%, P = 0.76), implantation (46.4% vs 46.2%, P = 0.95), early pregnancy loss (24.5% vs 26.5%, P = 0.68), and ongoing pregnancy (44.4% vs 45.6%, P = 0.79) were all comparable between groups with or without infection. Results of logistic regression models, both before and after adjustment, revealed no associations between SARS-CoV-2 infection and rates of biochemical pregnancy, clinical pregnancy, early pregnancy loss, or ongoing pregnancy. Moreover, neither the time of infection with respect to transfer (prior to transfer, 1-7 days after transfer, or 8-14 days after transfer) nor the level of fever (no fever, fever <39°C, or fever ≥39°C) was found to be related to pregnancy rates. LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study is subject to possible selection bias. Additionally, although the sample size was relatively large for the COVID-19 group, the sample sizes for certain subgroups were relatively small and lacked adequate power, so these results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: The study findings suggest that SARS-CoV-2 infection during the FET cycle in females does not affect embryo implantation and pregnancy rates including biochemical pregnancy, clinical pregnancy, early pregnancy loss, and ongoing pregnancy, indicating that cycle cancellation due to SARS-CoV-2 infection may not be necessary. Further studies are warranted to verify these findings. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the National Key Research and Development Program of China (2023YFC2705500, 2019YFA0802604), National Natural Science Foundation of China (82130046, 82101747), Shanghai leading talent program, Innovative research team of high-level local universities in Shanghai (SHSMU-ZLCX20210201, SHSMU-ZLCX20210200, SSMU-ZLCX20180401), Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital Clinical Research Innovation Cultivation Fund Program (RJPY-DZX-003), Science and Technology Commission of Shanghai Municipality (23Y11901400), Shanghai Sailing Program (21YF1425000), Shanghai's Top Priority Research Center Construction Project (2023ZZ02002), Three-Year Action Plan for Strengthening the Construction of the Public Health System in Shanghai (GWVI-11.1-36), and Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161413). The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Functional cure induced by tenofovir alafenamide plus peginterferon-alpha-2b in young children with chronic hepatitis B: a case series study.

BACKGROUND AND AIMS: Data on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α. METHODS: In this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored. RESULTS: As of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment. CONCLUSIONS: TAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB.

Clinical impact of sarcopenia for overweight or obese patients with colorectal cancer.

BACKGROUND: Sarcopenia, overweight and obesity are all dynamic changes in body composition, which may have a negative effect on the prognosis for patients with colorectal cancer. The aim of this study was to investigate the predictive role of sarcopenia on overweight or obese patients with colorectal cancer. METHODS: We conducted an observative study on the population of overweight or obese patients with colorectal cancer who underwent curative surgeries in two centers between 2015 and 2021. They were grouped by the presence of sarcopenia. Propensity score match analysis was used to balance the baseline of clinicopathologic characteristics of the two groups. Then, the postoperative outcomes between the two groups were compared. Independent risk factors were evaluated for complications using univariate and multivariate analysis. RESULTS: Of 827 patients enrolled, 126 patients were matched for analysis. Patients with sarcopenia had a higher incidence of total complication and medical complications, a higher rate of laparoscopic surgery performed and higher hospitalization costs. Old age (≥65 years, P = 0.012), ASA grade (III, P = 0.008) and sarcopenia (P = 0.036) were independent risk factors for total complications. ASA grade (III, P = 0.002) and sarcopenia (P = 0.017) were independent risk factors for medical complications. CONCLUSIONS: Sarcopenia was prevalent among overweight or obese patients with colorectal cancer and was associated with negative postoperative outcomes. Early recognition of changes in body composition could help surgeons be well prepared for surgical treatment for overweight or obese patients.

Effects of immunosuppressive therapy on renal prognosis in primary membranous nephropathy.

BACKGROUND: Immunosuppressive therapy plays a crucial role in treating membranous nephropathy, with previous studies highlighting its benefits for patients with primary membranous nephropathy (PMN). Guidelines suggest that the management of membranous nephropathy should be tailored to individual risk levels. However, there is a lack of real-world studies examining the effects of immunosuppressive therapy on renal outcomes in PMN patients. This study aimed to investigate the relationship between immunosuppressive therapy and renal prognosis in PMN patients. METHODS: This was a real-world retrospective study including patients diagnosed with PMN in Shenzhen Second People's Hospital and Hechi People's Hospital. Univariate and multivariate Cox regression analysis and Kaplan-Meier survival analysis were used. RESULTS: After propensity score-matching, 464 PMN patients were included and they were assigned to conservative and immunosuppressive group in a 1:1 ratio. Immunosuppressive therapy was the protective factor of renal composite outcome (HR = 0.65, p < 0.01). Separately, the effect was significant in moderate- and high-risk but not in low-risk patients. Key influencing factors including age, blood pressure, albumin and total cholesterol levels, with slight differences among patients at different risk. CONCLUSIONS: This study demonstrates the efficacy of immunosuppressive therapy in non-low-risk PMN patients. The key factors affecting renal prognosis in patients with different risk levels are emphasized to help provide individualized treatment.

Investigation of the mechanisms behind ochratoxin A-induced cytotoxicity in human astrocytes and the protective effects of N-acetylcysteine.

Ochratoxin A (OTA) is a type of mycotoxin commonly found in raw and processed foods. It is essential to be aware of this toxin, as it can harm your health if consumed in high quantities. OTA can induce toxic effects in various cell models. However, a more comprehensive understanding of the harmful effects of OTA on human astrocytes is required. This study evaluated OTA's neurotoxic effects on the Gibco® Human Astrocyte (GHA) cell line, its underlying mechanisms, and the antioxidant N-acetylcysteine (NAC) ability to prevent them. OTA exposure within 5-30 µM has induced concentration-dependent cytotoxicity. In the OTA-treated cells, the levels of reactive oxygen species (ROS) were found to be significantly increased, while the glutathione (GSH) contents were found to decrease considerably. The western blotting of OTA-treated cells has revealed increased Bax, cleaved caspase-9/caspase-3 protein levels, and increased Bax/Bcl-2 ratio. In addition, exposure to OTA has resulted in the induction of antioxidant responses associated with the protein expressions of Nrf2, HO-1, and NQO1. On the other hand, the pretreatment with NAC has partially alleviated the significant toxic effects of OTA. In conclusion, our findings suggest that oxidative stress and apoptosis are involved in the OTA-induced cytotoxicity in GHA cells. NAC could act as a protective agent against OTA-induced oxidative damage.

Time domain turbo equalization based on vector approximate message passing for multiple-input multiple-output underwater acoustic communications.

This paper proposes a high-performance receiver for underwater acoustic communications based on time reversal processing for multiple-input multiple-output (MIMO) systems. The receiver employs the vector approximate message passing (VAMP) algorithm as a soft equalizer in turbo equalization. By performing self-iteration between the inner soft slicer and the inner soft equalizer, the VAMP algorithm achieves near-optimal performance. Furthermore, an iterative channel-estimation-based soft successive interference cancellation method is incorporated to suppress co-channel interference in the MIMO system. Additionally, the introduction of passive time reversal technology can combine multiple channels into a single channel, which greatly reduces the computational complexity of the MIMO system, especially for large MIMO systems. The effectiveness of the proposed receiver is verified using experimental data collected in Songhua Lake, China in 2019. The results demonstrate that the proposed receiver significantly reduces the complexity of the traditional parallel-VAMP receiver without sacrificing performance and outperforms other receivers of the same type. Moreover, our experimental results also verify that the VAMP-turbo outperforms the generalized approximate message passing (GAMP)-turbo in terms of bit error rate and convergence performance.

Robust symbol detection for single-carrier underwater acoustic communication in impulsive noise environment.

This paper addresses robust underwater acoustic communication in the presence of impulsive noise. We propose a single-carrier iterative symbol detection method, which combines variational Bayesian inference (VBI) and vector approximate message passing (VAMP) for impulsive noise cancellation. Unlike existing methods, we model the measurements as a combination of two components: clean data without impulsive noise and impulse-noise-induced outliers. A set of binary indicator variables is used to identify outliers automatically. Under the proposed mixed model, we derive a VBI-based symbol detection method that can alternatively detect communication symbols and impulsive noise, and compensate for the impulsive noise when detecting communication symbols. To further improve detection performance, we integrate the VAMP into the VBI framework for communication symbols detection. Additionally, to reduce the overall complexity of the communication system, we propose a channel estimation method based on damped generalized approximate message passing. Simulation and experimental results show that the proposed detection method outperforms existing methods in terms of robustness and bit error rate.

A Combined Filtering Method for ZigBee Indoor Distance Measurement.

Indoor distance measurement technology utilizing Zigbee's Received Signal Strength Indication (RSSI) offers cost-effective and energy-efficient advantages, making it widely adopted for indoor distance measurement applications. However, challenges such as multipath effects, signal attenuation, and signal blockage often degrade the accuracy of distance measurements. Addressing these issues, this study proposes a combined filtering approach integrating Kalman filtering, Dixon's Q-test, Gaussian filtering, and mean filtering. Initially, the method evaluates Zigbee's transmission power, channel, and other parameters, analyzing their impact on RSSI values. Subsequently, it fits a signal propagation loss model based on actual measured data to understand the filtering algorithm's effect on distance measurement error. Experimental results demonstrate that the proposed method effectively improves the conversion relationship between RSSI and distance. The average distance measurement error, approximately 0.46 m, substantially outperforms errors derived from raw RSSI data. Consequently, this method offers enhanced distance measurement accuracy, making it particularly suitable for indoor positioning applications.

Enhanced Indoor Positioning Using RSSI and Time-Distributed Auto Encoder-Gated Recurrent Unit Model.

This study presents a novel approach to indoor positioning leveraging radio frequency identification (RFID) technology based on received signal strength indication (RSSI). The proposed methodology integrates Gaussian Kalman filtering for effective signal preprocessing and a time-distributed auto encoder-gated recurrent unit (TAE-GRU) model for precise location prediction. Addressing the prevalent challenges of low accuracy and extended localization times in current systems, the proposed method significantly enhances the preprocessing of RSSI data and effectively captures the temporal relationships inherent in the data. Experimental validation demonstrates that the proposed approach achieves a 75.9% improvement in localization accuracy over simple neural network methods and markedly enhances the speed of localization, thereby proving its practical applicability in real-world indoor localization scenarios.

Enhancing UWB Indoor Positioning Accuracy through Improved Snake Search Algorithm for NLOS/LOS Signal Classification.

Non-line-of-sight (NLOS) errors significantly impact the accuracy of ultra-wideband (UWB) indoor positioning, posing a major barrier to its advancement. This study addresses the challenge of effectively distinguishing line-of-sight (LOS) from NLOS signals to enhance UWB positioning accuracy. Unlike existing research that focuses on optimizing deep learning network structures, our approach emphasizes the optimization of model parameters. We introduce a chaotic map for the initialization of the population and integrate a subtraction-average-based optimizer with a dynamic exploration probability to enhance the Snake Search Algorithm (SSA). This improved SSA optimizes the initial weights and thresholds of backpropagation (BP) neural networks for signal classification. Comparative evaluations with BP, Particle Swarm Optimizer-BP (PSO-BP), and Snake Optimizer-PB (SO-BP) models-performed using three performance metrics-demonstrate that our LTSSO-BP model achieves superior stability and accuracy, with classification accuracy, recall, and F1 score values of 90%, 91.41%, and 90.25%, respectively.

ELF5 drives angiogenesis suppression though stabilizing WDTC1 in renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is a common malignant tumor of the urinary system. Angiogenesis is a main contributing factor for tumorigenesis. E74-like transcription factor 5 (ELF5) has been verified to participate in the progression of different cancers and can regulate angiogenesis. This study was aimed to explore the functions of ELF5 in RCC. METHODS: Bioinformatics tools were used to predict the expression of ELF5 in RCC. RT-qPCR was applied for testing ELF5 expression in RCC cells. Cell behaviors were evaluated by colony formation, CCK-8, and transwell assays. The tube formation assay was used for determining angiogenesis. Methylation-specific PCR (MSP) was utilized for measuring the methylation level of ELF5 in RCC cells. ChIP and luciferase reporter assays were applied for assessing the binding of ELF5 and ubiquitin-specific protease 3 (USP3). Co-IP and GST pull-down were utilized for detecting the interaction of WD40 and tetratricopeptide repeats 1 (WDTC1) and USP3. Ubiquitination level of WDTC1 was determined by ubiquitination assay. RESULTS: ELF5 was lowly expressed in RCC cells and tissues. High expression of ELF5 expression notably suppressed RCC cell proliferative, migratory, and invasive capabilities, and inhibited angiogenesis. The tumor growth in mice was inhibited by ELF5 overexpression. ELF5 was highly methylated in RCC samples, and DNA methyltransferases (DNMTs) can promote hypermethylation level of ELF5 in RCC cells. ELF5 was further proved to transcriptionally activate USP3 in RCC. Moreover, USP3 inhibited WDTC1 ubiquitination. ELF5 can promote USP3-mediated WDTC1 stabilization. Additionally, WDTC1 silencing reversed the functions of ELF5 overexpression on RCC progression. CONCLUSION: Downregulation of ELF5 due to DNA hypermethylation inhibits RCC development though the USP3/WDTC1axis in RCC.

Smooth Muscle Overexpression of PGC1α Attenuates Atherosclerosis in Rabbits.

[Figure: see text].

An integrated PK/PD model investigating the impact of tumor size and systemic safety on animal survival in SW1990 pancreatic cancer xenograft.

Survival is one of the most important endpoints in cancer therapy, and parametric survival analysis could comprehensively reveal the overall result of disease progression, drug efficacy, toxicity as well as their interactions. In this study we investigated the efficacy and toxicity of dexamethasone (DEX) combined with gemcitabine (GEM) in pancreatic cancer xenograft. Nude mice bearing SW1990 pancreatic cancer cells derived tumor were treated with DEX (4 mg/kg, i.g.) and GEM (15 mg/kg, i.v.) alone or in combination repeatedly (QD, Q3D, Q7D) until the death of animal or the end of study. Tumor volumes and net body weight (NBW) were assessed every other day. Taking NBW as a systemic safety indicator, an integrated pharmacokinetic/pharmacodynamic (PK/PD) model was developed to quantitatively describe the impact of tumor size and systemic safety on animal survival. The PK/PD models with time course data for tumor size and NBW were established, respectively, in a sequential manner; a parametric time-to-event (TTE) model was also developed based on the longitudinal PK/PD models to describe the survival results of the SW1990 tumor-bearing mice. These models were evaluated and externally validated. Only the mice with good tumor growth inhibition and relatively stable NBW had an improved survival result after DEX and GEM combination therapy, and the simulations based on the parametric TTE model showed that NBW played more important role in animals' survival compared with tumor size. The established model in this study demonstrates that tumor size was not always the most important reason for cancer-related death, and parametric survival analysis together with safety issues was also important in the evaluation of oncology therapies in preclinical studies.

Involvement of oxidative stress-related apoptosis in chlorpyrifos-induced cytotoxicity and the ameliorating potential of the antioxidant vitamin E in human glioblastoma cells.

Organophosphate pesticides (OPs), which are among the most widely used synthetic chemicals for the control of a wide variety of pests, are however associated with various adverse reactions in animals and humans. Chlorpyrifos, an OP, has been shown to cause various health complications due to ingestion, inhalation, or skin absorption. The mechanisms underlying the adverse effect of chlorpyrifos on neurotoxicity have not been elucidated. Therefore, we aimed to determine the mechanism of chlorpyrifos-induced cytotoxicity and to examine whether the antioxidant vitamin E (VE) ameliorated these cytotoxic effects using DBTRG-05MG, a human glioblastoma cell line. The DBTRG-05MG cells were treated with chlorpyrifos, VE, or chlorpyrifos plus VE and compared with the untreated control cells. Chlorpyrifos induced a significant decrease in cell viability and caused morphological changes in treated cultures. Furthermore, chlorpyrifos led to the increased production of reactive oxygen species (ROS) accompanied by a decrease in the level of reduced glutathione. Additionally, chlorpyrifos induced apoptosis by upregulating the protein levels of Bax and cleaved caspase-9/caspase-3 and by downregulating the protein levels of Bcl-2. Moreover, chlorpyrifos modulated the antioxidant response by increasing the protein levels of Nrf2, HO-1, and NQO1. However, VE reversed the cytotoxicity and oxidative stress induced by chlorpyrifos treatment in DBTRG-05MG cells. Overall, these findings suggest that chlorpyrifos causes cytotoxicity through oxidative stress, a process that may play an important role in the development of chlorpyrifos-associated glioblastoma.

G protein ßγ translocation to the Golgi apparatus activates MAPK via p110γ-p101 heterodimers.

The Golgi apparatus (GA) is a cellular organelle that plays a critical role in the processing of proteins for secretion. Activation of G protein-coupled receptors at the plasma membrane (PM) induces the translocation of G protein ßγ dimers to the GA. However, the functional significance of this translocation is largely unknown. Here, we study PM-GA translocation of all 12 Gγ subunits in response to chemokine receptor CXCR4 activation and demonstrate that Gγ9 is a unique Golgi-translocating Gγ subunit. CRISPR-Cas9-mediated knockout of Gγ9 abolishes activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), two members of the mitogen-activated protein kinase family, by CXCR4. We show that chemically induced recruitment to the GA of Gßγ dimers containing different Gγ subunits activates ERK1/2, whereas recruitment to the PM is ineffective. We also demonstrate that pharmacological inhibition of phosphoinositide 3-kinase γ (PI3Kγ) and depletion of its subunits p110γ and p101 abrogate ERK1/2 activation by CXCR4 and Gßγ recruitment to the GA. Knockout of either Gγ9 or PI3Kγ significantly suppresses prostate cancer PC3 cell migration, invasion, and metastasis. Collectively, our data demonstrate a novel function for Gßγ translocation to the GA, via activating PI3Kγ heterodimers p110γ-p101, to spatiotemporally regulate mitogen-activated protein kinase activation by G protein-coupled receptors and ultimately control tumor progression.

Rab43 GTPase directs postsynaptic trafficking and neuron-specific sorting of G protein-coupled receptors.

G protein-coupled receptors (GPCRs) are important modulators of synaptic functions. A fundamental but poorly addressed question in neurobiology is how targeted GPCR trafficking is achieved. Rab GTPases are the master regulators of vesicle-mediated membrane trafficking, but their functions in the synaptic presentation of newly synthesized GPCRs are virtually unknown. Here, we investigate the role of Rab43, via dominant-negative inhibition and CRISPR-Cas9-mediated KO, in the export trafficking of α2-adrenergic receptor (α2-AR) and muscarinic acetylcholine receptor (mAChR) in primary neurons and cells. We demonstrate that Rab43 differentially regulates the overall surface expression of endogenous α2-AR and mAChR, as well as their signaling, in primary neurons. In parallel, Rab43 exerts distinct effects on the dendritic and postsynaptic transport of specific α2B-AR and M3 mAChR subtypes. More interestingly, the selective actions of Rab43 toward α2B-AR and M3 mAChR are neuronal cell specific and dictated by direct interaction. These data reveal novel, neuron-specific functions for Rab43 in the dendritic and postsynaptic targeting and sorting of GPCRs and imply multiple forward delivery routes for different GPCRs in neurons. Overall, this study provides important insights into regulatory mechanisms of GPCR anterograde traffic to the functional destination in neurons.

Tenofovir Alafenamide for Pregnant Chinese Women With Active Chronic Hepatitis B: A Multicenter Prospective Study.

BACKGROUND & AIMS: Data on long-term tenofovir alafenamide (TAF) therapy for pregnant women with active chronic hepatitis B (CHB) (immune clearance and reactivation phases, currently and previously diagnosed) and their infants are lacking. METHODS: Pregnant women with active CHB treated with TAF and tenofovir disoproxil fumarate (TDF) were enrolled in this multicenter prospective study, and infants received immunoprophylaxis. The primary outcomes were rates of adverse (safety) events in pregnant women and defects in infants and fetuses. The secondary outcomes were virologic responses in pregnant women, infants' safety, hepatitis B surface antigen (HBsAg) status, and growth conditions. RESULTS: One hundred three and 104 pregnant women were enrolled and 102 and 104 infants were born in the TAF and TDF groups, respectively. In the TAF group, the mean age, gestational age, alanine aminotransferase level, and viral loads at treatment initiation were 29.3 years, 1.3 weeks, 122.2 U/L, and 5.1 log10 IU/mL, respectively. TAF was well-tolerated, and the most common adverse event was nausea (29.1%) during a mean of 2 years of treatment. Notably, 1 (1.0%) TAF-treated pregnant woman underwent induced abortion due to noncausal fetal cleft lip and palate. No infants in either group had birth defects. In the TAF group, the hepatitis B e antigen seroconversion rate was 20.7% at postpartum month 6, infants had normal growth parameters, and no infants were positive for HBsAg at 7 months. The TDF group had comparable safety and effectiveness profiles. CONCLUSIONS: TAF administered throughout or beginning in early pregnancy is generally safe and effective for pregnant women with active CHB and their infants.