Single-cell and spatial transcriptomics reveals that PTPRG activates the m6A methyltransferase VIRMA to block mitophagy-mediated neuronal death in Alzheimer's disease.

Neuronal death is one of the key pathologies in Alzheimer's disease (AD). How neuronal death begins in AD is far from clear, so clarifying this process may help develop effective therapies. This study collected single-cell RNA sequencing data of 85 AD samples and 83 control samples, covering the prefrontal cortex, internal olfactory cortex, superior parietal lobe, superior frontal gyrus, caudal internal olfactory cortex, somatosensory cortex, hippocampus, superior frontal cortex and peripheral blood mononuclear cells. Additionally, spatial transcriptomic data of coronal sections from 6 AppNL-G-F AD mice and 6 control C57Bl/6 J mice were acquired. The main single-cell and spatial transcriptomics results were experimentally validated in wild type and 5 × FAD mice. We found that the microglia subpopulation Mic_PTPRG can communicate with specific types of neurons (especially excitatory ExNeu_PRKN_VIRMA and inhibitory InNeu_PRKN_VIRMA neuronal subpopulations) and cause them to express PTPRG during AD progression. Within neurons, PTPRG binds and upregulates the m6A methyltransferase VIRMA, thus inhibiting translation of PRKN mRNA to prevent the clearance of damaged mitochondria in neurons through suppressing mitophagy. As the disease progresses, the energy and nutrient metabolic pathways in neurons are reprogrammed, leading to their death. Consistently, we determined that PTPTRG can physically interact with VIRMA in mouse brains and PRKN is significantly upregulated in 5 × FAD mouse brain. Altogether, our findings demonstrate that PTPRG activates the m6A methyltransferase VIRMA to block mitophagy-mediated neuronal death in AD, which is a potential pathway, through which microglia and neuronal PTPRG modify neuronal connections in the brain during AD progression.

Probabilistic Estimation of Airborne Micro- and Nanoplastic Intake in Humans.

Little research exists on the magnitude, variability, and uncertainty of human exposure to airborne micro- and nanoplastics (AMNPs), despite their critical role in human exposure to MNPs. We probabilistically estimate the global intake of AMNPs through three main pathways: indoor inhalation, outdoor inhalation, and ingestion during indoor meals, for both children and adults. The median inhalation of AMPs is 1,207.7 (90% CI, 42.5-8.48 × 104) and 1,354.7 (90% CI, 47.4-9.55 × 104) N/capita/day for children and adults, respectively. The annual intake of AMPs is 13.18 mg/capita/a for children and 19.10 mg/capita/a for adults, which is approximately one-fifth and one-third of the mass of a standard stamp, assuming a consistent daily intake of medians. The majority of AMP number intake occurs through inhalation, while the ingestion of deposited AMPs during meals contributes the most in terms of mass. Furthermore, the median ANP intake through outdoor inhalation is 9,638.1 N/day (8.23 × 10-6 µg/d) and 5,410.6 N/day (4.62 × 10-6 µg/d) for children and adults, respectively, compared to 5.30 × 105 N/day (5.79 × 10-4 µg/d) and 6.00 × 105 N/day (6.55 × 10-4 µg/d) via indoor inhalation. Considering the increased toxicity of smaller MNPs, the significant number of ANPs inhaled warrants great attention. Collaborative efforts are imperative to further elucidate and combat the current MPN risks.

Efficacy and safety of high-intensity focused ultrasound combined with suction curettage for the treatment of caesarean scar pregnancy: a systematic review and single-arm meta-analysis.

PURPOSE: Caesarean scar pregnancy (CSP) presents a significant clinical challenge owing to the associated risks of uterine scar rupture, severe haemorrhage and adverse maternal outcomes. This study aimed to assess the safety and efficacy of combining high-intensity focused ultrasound (HIFU) with suction curettage for treating CSP. METHODS: We conducted a comprehensive search in four databases, namely PubMed, Web of Science, Embase and Cochrane Library, to identify published studies evaluating the use of HIFU combined with suction curettage to treat CSP. Intraoperative blood loss, treatment success rate, and reproductive results were the primary outcomes assessed. RESULTS: A total of 18 studies involving 1251 patients with CSP, all of whom received preoperative HIFU therapy were included. The average hospital stay was 6.22 days, the intraoperative blood loss was 26.29 ml and the incidence of adverse events was 15.60%, including abdominal or lower limb pain, fever, vaginal bleeding, haematuria and vomiting. Furthermore, post-treatment follow-up showed that serum ß-human chorionic gonadotropin levels were rapidly normalized (average of 25.48 days) and menstruation returned (average of 33.03 days). The treatment had a remarkable success rate of 97.60% and a subsequent pregnancy rate of 68.70%. CONCLUSION: While the combination of HIFU and suction-curettage may induce common adverse effects such as lower abdominal or limb pain, these reactions typically do not necessitate therapeutic intervention. Additionally, the size of the gestational sac is a determinant of the procedure's success. In conclusion, HIFU combined with suction curettage demonstrates promising clinical efficacy, safety and favourable reproductive outcomes in managing CSP.

Plasmonic couplings in Ag-Au heterodimers.

The plasmonic coupling between silver (Ag) and gold (Au) nanoparticles (NPs) under four polarization modes was examined: a longitudinal mode (L-mode), where the electric field of a linearly polarized incident light parallels the dimer axis, and three transverse modes (T-modes), where the electric field of the light is perpendicular to the dimer axis. The coupling was studied using the discrete dipole approximation followed by an in-house postprocessing code that determines the extinction (Qext), absorption (Qabs), and near-field (Qnf) spectra from the individual NPs as well as the whole system. In agreement with the literature results, the extinction/absorption spectra of the whole dimer have two peaks, one near the Ag localized surface plasmon resonance (LSPR) region and the other at the Au LSPR region, with the peak at Ag LSPR being reduced in all modes and the peak at Au LSPR being red-shifted and increased in the L-mode but not in the T-modes. It is further shown that the scattering at the Ag LSPR region is reduced and becomes less than the isolated Ag NPs, but the absorption at the Ag LSPR is increased and becomes greater than the isolated Ag NPs for the 50 nm Ag-Au heterodimer. This suggests that the scattering from Ag NPs is being reabsorbed by the neighboring Au NPs due to the interband electronic transition in Au at that wavelength range. The Qext from the individual NP in the heterodimer shows the presence of the Fano profile on the Au NP but not on the Ag NP. This phenomenon was further investigated by using a dielectric particle (DP) placed near the Ag or Au NPs. The Fano profile appears in the absorbing DP spectra placed near either Ag or Au NPs. However, the Fano profile is masked upon further increases in the refractive index value of the DP particle. This explains the absence of a Fano profile on the Ag NPs in the Ag-Au heterodimer. The large near-field enhancement on both Ag and Au NPs at the Au plasmonic wavelength in the L-mode for large NPs was investigated through a DP-Au system. The large enhancement was shown to arise from a large imaginary component of the DP refractive index and a small real component. Through examination of both the near- and far-field properties of the individual NPs as well as the whole system and examinations of DP-Ag and DP-Au systems, our study provides a new understanding of the couplings between Ag and Au NPs.

Lanthanum interferes with the fundamental rhythms of stomatal opening, expression of related genes, and evapotranspiration in Arabidopsis thaliana.

The accumulation of rare earth elements (REEs) in the global environment poses a threat to plant health and ecosystem stability. Stomata located on leaves serve as the primary site for plant responses to REE-related threats. This study focused on lanthanum [La(III)], a prevalent REE in the atmospheric environment. Using interdisciplinary techniques, it was found that La(III) (≤80 µM) interfered with the fundamental rhythms of stomatal opening, related gene expression, and evapotranspiration in plants. Specifically, when exposed to low concentrations of La(III) (15 and 30 µM), the expression levels of six genes were increased, stomatal opening was enhanced, and the evapotranspiration rate was accelerated. The interference on stomatal rhythms was enhanced with higher concentrations of La(III) (60 and 80 µM), increasing the expression levels of six genes, stomatal opening, and evapotranspiration rate. To counter the interference of low concentrations of La(III) (15 and 30 µM), plants accelerated nutrient replenishment through La(III)-induced endocytosis, which the redundant nutrients enhanced photosynthesis. However, replenished nutrients failed to counter the disruption of plant biological rhythms at higher concentrations of La(III) (60 and 80 µM), thus inhibiting photosynthesis due to nutrient deficit. The interference of La(III) on these biological rhythms negatively affected plant health and ecosystem stability.

Investigations on the EPR g factors and local structures for the orthorhombic and tetragonal Cu2+ centers in Pb[Zr0.54Ti0.46]O3.

The defect models of the orthorhombical and tetragonal Cu2+ centers in Pb[Zr0.54Ti0.46]O3 are attributed to Cu2+ ions occupying the sixfold coordinated octahedral Ti4+ site with and without charge compensation, respectively. The electron paramagnetic resonance (EPR) g factors gi (i = x, y, z) of the Cu2+ centers in Pb[Zr0.54Ti0.46]O3 are theoretically studied by using the perturbation formulas of a 3d9 ion under orthorhombically and tetragonally elongated octahedra. Based on the calculation, the impurity off-center displacements are about 0.253 and 0.162 Å for the orthorhombical and tetragonal Cu2+ centers, respectively. Meanwhile, the planar Cu2+-O2- bonds are found to experience the relative variation ΔR (≈0.102 Å) along the a- and b-axes for the orthorhombical Cu2+ center due to the Jahn-Teller (JT) effect. The theoretical EPR g factors based on the above local structures agree well with the observed values.

Deep Learning-Based Fish Detection Using Above-Water Infrared Camera for Deep-Sea Aquaculture: A Comparison Study.

Long-term, automated fish detection provides invaluable data for deep-sea aquaculture, which is crucial for safe and efficient seawater aquafarming. In this paper, we used an infrared camera installed on a deep-sea truss-structure net cage to collect fish images, which were subsequently labeled to establish a fish dataset. Comparison experiments with our dataset based on Faster R-CNN as the basic objection detection framework were conducted to explore how different backbone networks and network improvement modules influenced fish detection performances. Furthermore, we also experimented with the effects of different learning rates, feature extraction layers, and data augmentation strategies. Our results showed that Faster R-CNN with the EfficientNetB0 backbone and FPN module was the most competitive fish detection network for our dataset, since it took a significantly shorter detection time while maintaining a high AP50 value of 0.85, compared to the best AP50 value of 0.86 being achieved by the combination of VGG16 with all improvement modules plus data augmentation. Overall, this work has verified the effectiveness of deep learning-based object detection methods and provided insights into subsequent network improvements.

Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

BACKGROUND: Mutations in colony-stimulating factor 1 receptor (CSF1R) are known to cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), which has been recently demonstrated as a primary microgliopathy characterized by cognitive impairment. Although the molecular mechanism underlying CSF1R-mediated microgliopathy remains unclear, therapeutic strategies have generally targeted modulation of microglial function. In particular, the microglial inhibitor, minocycline, has been shown to attenuate learning and memory deficits in several neurodegenerative diseases. The objectives of this study were to investigate the pathogenic mechanisms underlying ALSP and to explore the therapeutic effects of minocycline in an in vivo model of ALSP. We hypothesized that inhibiting microglial activation via minocycline could reverse the behavior and pathological defects in ALSP model mice. METHODS: We generated a Csf1r haploinsufficiency mouse model of ALSP using CRISPR/Cas9 genome editing and conducted electrophysiological recordings of long-term potentiation (LTP) and behavioral tests to validate the recapitulation of clinical ALSP characteristics in 8- to 11-month-old mice. RNA-sequencing was used to explore enriched gene expression in the molecular pathogenesis of ALSP. Microglial activation was assessed by immunofluorescent detection of Iba1 and CD68 in brain sections of male ALSP mice and pro-inflammatory activation and phagocytosis were assessed in Csf1r+/- microglia. Therapeutic effects were assessed by behavioral tests, histological analysis, and morphological examination after four weeks of intraperitoneal injection with minocycline or vehicle control in Csf1r+/- mice and wild-type control littermates. RESULTS: We found that synaptic function was reduced in LTP recordings of neurons in the hippocampal CA1 region, while behavioral tests showed impaired spatial and cognitive memory specifically in male Csf1r+/- mice. Increased activation, pro-inflammatory cytokine production, and enhanced phagocytic capacity were also observed in Csf1r+/- microglia. Treatment with minocycline could suppress the activation of Csf1r+/- microglia both in vitro and in vivo. Notably, the behavioral and pathological deficits in Csf1r+/- mice were partially rescued by minocycline administration, potentially due to inhibition of microglial inflammation and phagocytosis in Csf1r+/- mice. CONCLUSIONS: Our study shows that CSF1R deficiency results in aberrant microglial activation, characterized by a pro-inflammatory phenotype and enhanced phagocytosis of myelin. Our results also indicate that microglial inhibition by minocycline can ameliorate behavioral impairment and ALSP pathogenesis in CSF1R-deficient male mice, suggesting a potential therapeutic target for CSF1R-related leukoencephalopathy. Collectively, these data support that minocycline confers protective effects against CSF1R-related microgliopathy in male ALSP model mice.

Radiomics Nomogram Based on Dual-Sequence MRI for Assessing Ki-67 Expression in Breast Cancer.

BACKGROUND: Radiomics has been extensively applied in predicting Ki-67 in breast cancer (BC). However, this is often confined to the exploration of a single sequence, without considering the varying sensitivity and specificity among different sequences. PURPOSE: To develop a nomogram based on dual-sequence MRI derived radiomic features combined with clinical characteristics for assessing Ki-67 expression in BC. STUDY TYPE: Retrospective. POPULATION: 227 females (average age, 51 years) with 233 lesions and pathologically confirmed BC, which were divided into the training set (n = 163) and test set (n = 70). FIELD STRENGTH/SEQUENCE: 3.0-T, T1-weighted dynamic contrast-enhanced MRI (DCE-MRI) and apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI (EPI sequence). ASSESSMENT: The regions of interest were manually delineated on ADC and DCE-MRI sequences. Three radiomics models of ADC, DCE-MRI, and dsMRI (combined ADC and DCE-MRI sequences) were constructed by logistic regression and the radiomics score (Radscore) of the best model was calculated. The correlation between Ki-67 expression and clinical characteristics such as receptor status, axillary lymph node (ALN) metastasis status, ADC value, and time signal intensity curve was analyzed, and the clinical model was established. The Radscore was combined with clinical predictors to construct a nomogram. STATISTICAL TESTS: The independent sample t-test, Mann-Whitney U test, Chi-squared test, Interclass correlation coefficients (ICCs), single factor analysis, least absolute shrinkage and selection operator (LASSO), logistic regression, receiver operating characteristics, Delong test, Hosmer_Lemeshow test, calibration curve, decision curve. A P-value <0.05 was considered statistically significant. RESULTS: In the test set, the prediction efficiency of the dsMRI model (AUC = 0.862) was higher than ADC model (AUC = 0.797) and DCE-MRI model (AUC = 0.755). With the inclusion of estrogen receptor (ER) and ALN metastasis, the nomogram displayed quality improvement (AUC = 0.876), which was superior to the clinical model (AUC = 0.787) and radiomics model. DATA CONCLUSION: The nomogram based on dsMRI radiomic features and clinical characteristics may be able to assess Ki-67 expression in BC. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

Deep Learning-Based Acceleration of Compressed Sensing for Noncontrast-Enhanced Coronary Magnetic Resonance Angiography in Patients With Suspected Coronary Artery Disease.

BACKGROUND: The clinical application of coronary MR angiography (MRA) remains limited due to its long acquisition time and often unsatisfactory image quality. A compressed sensing artificial intelligence (CSAI) framework was recently introduced to overcome these limitations, but its feasibility in coronary MRA is unknown. PURPOSE: To evaluate the diagnostic performance of noncontrast-enhanced coronary MRA with CSAI in patients with suspected coronary artery disease (CAD). STUDY TYPE: Prospective observational study. POPULATION: A total of 64 consecutive patients (mean age ± standard deviation [SD]: 59 ± 10 years, 48.4% females) with suspected CAD. FIELD STRENGTH/SEQUENCE: A 3.0-T, balanced steady-state free precession sequence. ASSESSMENT: Three observers evaluated the image quality for 15 coronary segments of the right and left coronary arteries using a 5-point scoring system (1 = not visible; 5 = excellent). Image scores ≥3 were considered diagnostic. Furthermore, the detection of CAD with ≥50% stenosis was evaluated in comparison to reference standard coronary computed tomography angiography (CTA). Mean acquisition times for CSAI-based coronary MRA were measured. STATISTICAL TESTS: For each patient, vessel and segment, sensitivity, specificity, and diagnostic accuracy of CSAI-based coronary MRA for detecting CAD with ≥50% stenosis according to coronary CTA were calculated. Intraclass correlation coefficients (ICCs) were used to assess the interobserver agreement. RESULTS: The mean MR acquisition time ± SD was 8.1 ± 2.4 minutes. Twenty-five (39.1%) patients had CAD with ≥50% stenosis on coronary CTA and 29 (45.3%) patients on MRA. A total of 885 segments on the CTA images and 818/885 (92.4%) coronary MRA segments were diagnostic (image score ≥3). The sensitivity, specificity, and diagnostic accuracy were as follows: per patient (92.0%, 84.6%, and 87.5%), per vessel (82.9%, 93.4%, and 91.1%), and per segment (77.6%, 98.2%, and 96.6%), respectively. The ICCs for image quality and stenosis assessment were 0.76-0.99 and 0.66-1.00, respectively. DATA CONCLUSION: The image quality and diagnostic performance of coronary MRA with CSAI may show good results in comparison to coronary CTA in patients with suspected CAD. EVIDENCE LEVEL: 1. TECHNICAL EFFICACY: 2.

Hepatitis C Virus Clearance Cascade - United States, 2013-2022.

Approximately 2.4 million adults were estimated to have hepatitis C virus (HCV) infection in the United States during 2013-2016 (1). Untreated, hepatitis C can lead to advanced liver disease, liver cancer, and death (2). The Viral Hepatitis National Strategic Plan for the United States calls for ≥80% of persons with hepatitis C to achieve viral clearance by 2030 (3). Characterizing the steps that follow a person's progression from testing to viral clearance and subsequent infection (clearance cascade) is critical for monitoring progress toward national elimination goals. Following CDC guidance (4), a simplified national laboratory results-based HCV five-step clearance cascade was developed using longitudinal data from a large national commercial laboratory throughout the decade since highly effective hepatitis C treatments became available. During January 1, 2013-December 31, 2021, a total of 1,719,493 persons were identified as ever having been infected with HCV. During January 1, 2013-December 31, 2022, 88% of those ever infected were classified as having received viral testing; among those who received viral testing, 69% were classified as having initial infection; among those with initial infection, 34% were classified as cured or cleared (treatment-induced or spontaneous); and among those persons, 7% were categorized as having persistent infection or reinfection. Among the 1.0 million persons with evidence of initial infection, approximately one third had evidence of viral clearance (cured or cleared). This simplified national HCV clearance cascade identifies substantial gaps in cure nearly a decade since highly effective direct-acting antiviral (DAA) agents became available and will facilitate the process of monitoring progress toward national elimination goals. It is essential that increased access to diagnosis, treatment, and prevention services for persons with hepatitis C be addressed to prevent progression of disease and ongoing transmission and achieve national hepatitis C elimination goals.

Prediction of postoperative reintervention risk for uterine fibroids using clinical-imaging features and T2WI radiomics before high-intensity focused ultrasound ablation.

OBJECTIVE: To predict the risk of postoperative reintervention for uterine fibroids using clinical-imaging features and T2WI radiomics before high-intensity focused ultrasound (HIFU) ablation. METHODS: Among patients with uterine fibroids treated with HIFU from 2019 to 2021, 180 were selected per the inclusion and exclusion criteria (42 reintervention and 138 non-reintervention). All patients were randomly assigned to either the training (n = 125) or validation (n = 55) cohorts. Multivariate analysis was used to determine independent clinical-imaging features of reintervention risk. The Relief and LASSO algorithm were used to select optimal radiomics features. Random forest was used to construct the clinical-imaging model based on independent clinical-imaging features, the radiomics model based on optimal radiomics features, and the combined model incorporating the above features. An independent test cohort of 45 patients with uterine fibroids tested these models. The integrated discrimination index (IDI) was used to compare the discrimination performance of these models. RESULTS: Age (p < .001), fibroid volume (p = .001) and fibroid enhancement degree (p = .001) were identified as independent clinical-imaging features. The combined model had AUCs of 0.821 (95% CI: 0.712-0.931) and 0.818 (95% CI: 0.694-0.943) in the validation and independent test cohorts, respectively. The predictive performance of the combined model was 27.8% (independent test cohort, p < .001) and 29.5% (independent test cohort, p = .001) better than the clinical-imaging and radiomics models, respectively. CONCLUSION: The combined model can effectively predict the risk of postoperative reintervention for uterine fibroids before HIFU ablation. It is expected to help clinicians to develop accurate, personalized treatment and management plans. Future studies will need to be prospectively validated.

Development and validation of a combined model based on dual-sequence MRI radiomics for predicting the efficacy of high-intensity focused ultrasound ablation for hysteromyoma.

OBJECTIVES: To determine the value of dual-sequence magnetic resonance imaging (MRI)-based radiomics in predicting the efficacy of high-intensity focused ultrasound (HIFU) ablation for hysteromyoma. METHODS: A total of 142 patients with 172 hysteromyomas (95 hysteromyomas from the sufficient ablation group, and 77 hysteromyomas from the insufficient ablation group) were enrolled in the study. The clinical-radiological model was constructed with independent clinical-radiological risk factors, the radiomics model was constructed based on the optimal radiomics features of hysteromyoma from dual sequences, and the two groups of features were incorporated to construct the combined model. A fivefold cross validation procedure was adopted to validate these models. A nomogram was constructed, applying the combined model in the training cohort. The models were assessed with receiver operating characteristic (ROC) curves and integrated discrimination improvement (IDI). An independent test cohort comprising 40 patients was used to evaluate the performance of the optimal model. RESULTS: Among the three models, the average areas under the ROC curves (AUC) of the radiomics model and combined model were 0.803 (95% confidence interval (CI): 0.726-0.881) and 0.841 (95% CI: 0.772-0.909), which were better than the clinical-radiological model in the training cohort. The IDI showed that the combined model had the best prediction accuracy. The combined model also showed good discrimination in both the validation cohort (AUC = 0.834) and the independent test cohort (AUC = 0.801). CONCLUSION: The combined model based on the dual-sequence MRI radiomics is the most promising tool from our study to assist clinicians in predicting HIFU ablation efficacy.

Perioperative, function, and positive surgical margin in extraperitoneal versus transperitoneal single port robot-assisted radical prostatectomy: a systematic review and meta-analysis.

BACKGROUND: Extraperitoneal and transperitoneal approaches are two common modalities in single-port (SP) robot-assisted radical prostatectomy (RARP), but differences in safety and efficacy between the two remain controversial. This study aimed to compare the perioperative, function, and positive surgical margin of extraperitoneal with transperitoneal approaches SP-RARP. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, this study is registered with PROSPERO (CRD 42023409667). We systematically searched databases including PubMed, Embase, Web of Science, and Cochrane Library to identify relevant studies published up to February 2023. Stata 15.1 software was used to analyze and calculate the risk ratio (RR) and weighted mean difference (WMD). RESULTS: A total of five studies, including 833 participants, were included in this study. The SP-TPRP group is superior to the SP-EPRP group in intraoperative blood loss (WMD: - 43.92, 95% CI - 69.81, - 18.04; p = 0.001), the incidence of postoperative Clavien-Dindo grade II and above complications (RR: 0.55, 95% CI - 0.31, 0.99; p = 0.04), and postoperative continence recovery (RR: 1.23, 95% CI 1.05, 1.45; p = 0.04). Conversely, the hospitalization stays (WMD: 7.88, 95% confidence interval: 0.65, 15.1; p = 0.03) for the SP-EPRP group was shorter than that of the SP-TPRP group. However, there was no significant difference in operation time, postoperative pain score, total incidence of postoperative complications, and positive surgical margin (PSM) rates between the two groups (p > 0.05). CONCLUSIONS: This study demonstrates that both extraperitoneal and extraperitoneal SP-RARP approaches are safe and effective. SP-TPRP is superior to SP-EPRP in postoperative blood loss, the incidence of postoperative Clavien-Dindo grade II and above complications, and postoperative continence recovery, but it is accompanied by longer hospital stays.

Odorant-Binding Proteins and Chemosensory Proteins in Spodoptera frugiperda: From Genome-Wide Identification and Developmental Stage-Related Expression Analysis to the Perception of Host Plant Odors, Sex Pheromones, and Insecticides.

Spodoptera frugiperda is a worldwide generalist pest with remarkable adaptations to environments and stresses, including developmental stage-related behavioral and physiological adaptations, such as diverse feeding preferences, mate seeking, and pesticide resistance. Insects' odorant-binding proteins (OBPs) and chemosensory proteins (CSPs) are essential for the chemical recognition during behavioral responses or other physiological processes. The genome-wide identification and the gene expression patterns of all these identified OBPs and CSPs across developmental stage-related S. frugiperda have not been reported. Here, we screened for genome-wide SfruOBPs and SfruCSPs, and analyzed the gene expression patterns of SfruOBPs and SfruCSPs repertoires across all developmental stages and sexes. We found 33 OBPs and 22 CSPs in the S. frugiperda genome. The majority of the SfruOBP genes were most highly expressed in the adult male or female stages, while more SfruCSP genes were highly expressed in the larval or egg stages, indicating their function complementation. The gene expression patterns of SfruOBPs and SfruCSPs revealed strong correlations with their respective phylogenic trees, indicating a correlation between function and evolution. In addition, we analyzed the chemical-competitive binding of a widely expressed protein, SfruOBP31, to host plant odorants, sex pheromones, and insecticides. Further ligands binding assay revealed a broad functional related binding spectrum of SfruOBP31 to host plant odorants, sex pheromones, and insecticides, suggesting its potential function in food, mate seeking, and pesticide resistance. These results provide guidance for future research on the development of behavioral regulators of S. frugiperda or other environmentally friendly pest-control strategies.

Acute Endoplasmic Reticulum Stress Suppresses Hepatic Gluconeogenesis by Stimulating MAPK Phosphatase 3 Degradation.

Drug-induced liver injury (DILI) is a widespread and harmful disease, and is closely linked to acute endoplasmic reticulum (ER) stress. Previous reports have shown that acute ER stress can suppress hepatic gluconeogenesis and even leads to hypoglycemia. However, the mechanism is still unclear. MAPK phosphatase 3 (MKP-3) is a positive regulator for gluconeogenesis. Thus, this study was conducted to investigate the role of MKP-3 in the suppression of gluconeogenesis by acute ER stress, as well as the regulatory role of acute ER stress on the expression of MKP-3. Results showed that acute ER stress induced by tunicamycin significantly suppressed gluconeogenesis in both hepatocytes and mouse liver, reduced glucose production level in hepatocytes, and decreased fasting blood glucose level in mice. Additionally, the protein level of MKP-3 was reduced by acute ER stress in both hepatocytes and mouse liver. Mkp-3 deficiency eliminated the inhibitory effect of acute ER stress on gluconeogenesis in hepatocytes. Moreover, the reduction effect of acute ER stress on blood glucose level and hepatic glucose 6-phosphatase (G6pc) expression was not observed in the liver-specific Mkp-3 knockout mice. Furthermore, activation of protein kinase R-like ER kinase (PERK) decreased the MKP-3 protein level, while inactivation of PERK abolished the reduction effect of acute ER stress on the MKP-3 protein level in hepatocytes. Taken together, our study suggested that acute ER stress could suppress hepatic gluconeogenesis by stimulating MKP-3 degradation via PERK, at least partially. Thus, MKP-3 might be a therapeutic target for DILI-related hypoglycemia.

N-glycosylation of CD82 at Asn157 is required for suppressing migration and invasion by reversing EMT via Wnt/ß-catenin pathway in colon cancer.

CD82, a tetraspanin superfamily member, has been identified to be glycosylated at three specific residues (Asn129, Asn157, and Asn198). However, CD82 post-translational modification and its effect on colorectal cancer (CRC) metastasis remain unclear. Here, we constructed various deficient mutants of CD82 N-glycosylation in SW620 cells and demonstrated that the Asn157 site is necessary for CD82 glycosylation in CRC cells migration and LN-dependent adhesion in vitro. Furthermore, we found that CD82 N-glycosylation at the Asn157 site leads to lower expression levels of vimentin and claudin-1 but higher expression levels of E-cadherin, which are the EMT markers; also, there are lower expression levels of phospho-GSK3ß and less ß-catenin transportation to the nucleus. These findings suggest that CD82 N-glycosylation at the Asn157 site inhibits EMT by down-regulating the Wnt/ß-catenin pathway. Moreover, we reported that CD82 with N-glycosylation at a single site of the Asn157 reduces lung metastases in vivo. The results indicate that N-glycosylation of CD82 at the Asn157 site regulates CRC metastasis and adhesion. These observations suggest that the N-glycosylation of CD82 might be a potential therapeutic target for CRC.

Genome-scale transcriptomic insights into the gene co-expression network of seed abortion in triploid Siraitia grosvenorii.

BACKGROUND: Siraitia grosvenorii (Swingle) C. Jeffrey, also known as Luohanguo or monk fruit, is a famous traditional Chinese medicine ingredient with important medicinal value and broad development prospects. Diploid S. grosvenorii has too many seeds, which will increase the utilization cost of active ingredients. Thus, studying the molecular mechanism of seed abortion in triploid S. grosvenorii, identifying the abortion-related genes, and regulating their expression will be a new direction to obtain seedless S. grosvenorii. Herein, we examined the submicroscopic structure of triploid S. grosvenorii seeds during abortion. RESULTS: Upon measuring the endogenous hormone content, we found that abscisic acid (ABA) and trans-zeatin (ZR) levels were significantly downregulated after days 15 and 20 of flowering. RNA sequencing of triploid seeds at different developmental stages was performed to identify key genes regulating abortion in triploid S. grosvenorii seeds. Multiple genes with differential expression between adjacent stages were identified; seven genes were differentially expressed across all stages. Weight gene co-expression network analysis revealed that the enhancement of monoterpene and terpene metabolic processes might lead to seed abortion by reducing the substrate flow to ABA and ZR. CONCLUSIONS: These findings provide insights into the gene-regulatory network of seed abortion in triploid S. grosvenorii from different perspectives, thereby facilitating the innovation of the breeding technology of S. grosvenorii.

Farnesoid X receptor functions in cervical cancer via the p14ARF-mouse double minute 2-p53 pathway.

BACKGROUND: Cervical cancer is the second most common cancer among women living in developing countries. Farnesoid X receptor (FXR) is a member of the nuclear receptor family, which regulates the development and proliferation of cancer. However, the role of and molecular mechanism by which FXR acts in cervical cancer are still unknown. METHODS AND RESULTS: The relationship between FXR and the proliferation of cervical cancer cell lines was detected by MTT and colony formation assays. Immunohistochemistry was used to detect the expression of FXR in cervical cancer tissue slides. Western blotting was used to detect the expression of p14ARF, mouse double minute 2 (MDM2) and p53 when FXR was overexpressed or siRNA was applied. Western blotting was used to detect the expression of MDM2 and p53 when pifithrin-α (PFT-α) was applied. FXR activation inhibited the proliferation of cervical cancer cell lines. FXR was significantly decreased in cervical squamous cell carcinoma, which was correlated with TNM stage, but not with metastasis. Overexpression of FXR activated the p14ARF-MDM2-p53 pathway. As a p53 inhibitor, PFT-α increased MDM2 in Lenti-vector cells, but had no effect on MDM2 in Lenti-FXR cells. CONCLUSIONS: FXR inhibits cervical cancer by upregulating the p14ARF-MDM2-p53 pathway. Activation of FXR may be a potential strategy for the treatment of cervical cancer.

Arabinogalactan protein-rare earth element complexes activate plant endocytosis.

Endocytosis is essential to all eukaryotes, but how cargoes are selected for internalization remains poorly characterized. Extracellular cargoes are thought to be selected by transmembrane receptors that bind intracellular adaptors proteins to initiate endocytosis. Here, we report a mechanism for clathrin-mediated endocytosis (CME) of extracellular lanthanum [La(III)] cargoes, which requires extracellular arabinogalactan proteins (AGPs) that are anchored on the outer face of the plasma membrane. AGPs were colocalized with La(III) on the cell surface and in La(III)-induced endocytic vesicles in Arabidopsis leaf cells. Superresolution imaging showed that La(III) triggered AGP movement across the plasma membrane. AGPs were then colocalized and physically associated with the µ subunit of the intracellular adaptor protein 2 (AP2) complexes. The AGP-AP2 interaction was independent of CME, whereas AGP's internalization required CME and AP2. Moreover, we show that AGP-dependent endocytosis in the presence of La(III) also occurred in human cells. These findings indicate that extracellular AGPs act as conserved CME cargo receptors, thus challenging the current paradigm about endocytosis of extracellular cargoes.