Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment.

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.

Loss of TET reprograms Wnt signaling through impaired demethylation to promote lung cancer development.

Oncogenic imbalance of DNA methylation is well recognized in cancer development. The ten-eleven translocation (TET) family of dioxygenases, which facilitates DNA demethylation, is frequently dysregulated in cancers. How such dysregulation contributes to tumorigenesis remains poorly understood, especially in solid tumors which present infrequent mutational incidence of TET genes. Here, we identify loss-of-function mutations of TET in 7.4% of human lung adenocarcinoma (LUAD), which frequently co-occur with oncogenic KRAS mutations, and this co-occurrence is predictive of poor survival in LUAD patients. Using an autochthonous mouse model of KrasG12D -driven LUAD, we show that individual or combinational loss of Tet genes markedly promotes tumor development. In this Kras-mutant and Tet-deficient model, the premalignant lung epithelium undergoes neoplastic reprogramming of DNA methylation and transcription, with a particular impact on Wnt signaling. Among the Wnt-associated components that undergo reprogramming, multiple canonical Wnt antagonizing genes present impaired expression arising from elevated DNA methylation, triggering aberrant activation of Wnt signaling. These impairments can be largely reversed upon the restoration of TET activity. Correspondingly, genetic depletion of ß-catenin, the transcriptional effector of Wnt signaling, substantially reverts the malignant progression of Tet-deficient LUAD. These findings reveal TET enzymes as critical epigenetic barriers against lung tumorigenesis and highlight the therapeutic vulnerability of TET-mutant lung cancer through targeting Wnt signaling.

Involvement of expanded cytotoxic and proinflammatory CD28null T cells in primary Sjögren's syndrome.

OBJECTIVE: The absence of CD28 is a feature of antigen-experienced, highly differentiated and aged T cells. The pathogenicity of CD28null T cells remains elusive in primary Sjögren's syndrome (pSS). Therefore, this study was performed to explore the characteristics of CD28null T cells in both peripheral blood and minor salivary glands (MSGs) of pSS patients. METHODS: pSS patients and paired healthy controls (HCs) were enrolled. The phenotype of peripheral CD28null T cells was analyzed using flow cytometry. In vitro functional assays were performed to evaluate the cytotoxic and proinflammatory effects of peripheral CD28null T cells. In addition, polychromatic immunofluorescence staining was performed to investigate infiltrating CD28null T cells in MSGs. RESULTS: A significant expansion of peripheral CD28null T cells was observed in pSS patients compared with HCs (p < 0.001), which were primarily CD8+CD28null T cells. The proportion of peripheral CD8+CD28null T cells moderately correlated with the erythrocyte sedimentation rate (r = 0.57, p < 0.01) and IgG levels (r = 0.44, p < 0.01). Peripheral CD28null T cells had stronger capacities to secrete granzyme B and perforin, but comparable capacities to secrete IFN-γ and TNF-α than their CD28+ counterparts. An abundant amount of cytotoxic and pro-inflammatory CD28null T cells was also found in MSGs. Moreover, a high expression of the chemokine receptor CXCR3 was found on peripheral and tissue-resident CD28null T cells, with its ligands CXCL9/10 abundantly present in MSGs. CONCLUSION: Increasing CD28null T cells with strong cytotoxicity and proinflammatory effects were observed in both peripheral blood and MSGs from pSS patients. The precise mechanism of action and migration still needs further investigation.

Revealing the distinct clinical patterns and relapse risk factors in seronegative IgG4-RD patients: A retrospective cohort study over a decade.

OBJECTIVES: Our study aimed to investigate the distinct clinical patterns of seronegative IgG4-related disease (IgG4-RD) patients. METHODS: We retrospectively enrolled 698 treatment-naïve IgG4-RD patients in this study. Patients were divided into four different subgroups according to their baseline serum IgG4 levels. The distinct clinical patterns of seronegative IgG4-RD patients were revealed through the comparison of baseline clinical data and disease prognosis among the different subgroups. COX regression analyses were used to investigate the risk factors for disease relapse and to construct the nomogram model. RESULTS: Seronegative IgG4-RD patients account for a minority of IgG4-RD patients (49/698, 7.02%). The proportions of seronegative IgG-RD patients in our study and several Asian cohorts were significantly lower than those of the European and American cohorts. Seronegative IgG4-RD patients got lower serum IgG levels (p < 0.0001), lower eosinophil count (p < 0.0001), lower serum IgE levels (p < 0.0001)), lower IgG4-RD responder index (RI) scores (p < 0.0001), and fewer affected organ numbers (p < 0.0001) compared with other subgroups, whereas they were more likely to manifest fibrotic type with some special organ involvement. Younger age at onset, GCs monotherapy, elevated C-reactive protein level, and elevated erythrocyte sedimentation rate level are the risk factors for the disease relapse of seronegative IgG4-RD patients. An effective nomogram model predicting disease relapse of seronegative IgG4-RD patients was constructed. Seronegative IgG4-RD patients with scores >84.65 at baseline were susceptible to suffering from disease relapse. CONCLUSIONS: Distinct clinical features and multiple risk factors for disease relapse of seronegative IgG4-RD patients have been revealed in this study. A nomogram model was constructed to effectively predict disease relapse during the follow-up period.

Withdrawal of immunosuppressants and low-dose steroids in patients with stable IgG4-RD (WInS IgG4-RD): an investigator-initiated, multicentre, open-label, randomised controlled trial.

OBJECTIVES: IgG4-related disease (IgG4-RD) is an immune-mediated, fibroinflammatory disease. Induction treatment with glucocorticoid (GC) is usually effective, but its tendency of relapse makes the strategy for maintenance treatment a challenge. The WInS IgG4-RD (withdraw immunosuppressants (IMs) and steroid in stable IgG4-RD) trial tested whether discontinuation of GC and IM was feasible in stable IgG4-RD. METHODS: The WInS IgG4-RD trial was a multicentre, open-label, randomised controlled trial. Patients with IgG4-RD receiving GC+IM as maintenance treatment with clinically quiescent disease for at least 12 months were randomised (1:1:1) into three groups: group 1: withdraw GC+IM; group 2: withdraw GC but maintain IM; group 3: maintain GC+IM. The primary outcome was the relapse rate of disease within 18 months. The secondary outcomes included the changes of IgG4-RD Responder Index (RI), Physician's Global Assessment (PGA), serum IgG4 and IgG, as well as adverse events. RESULTS: One hundred and forty-six patients were randomised, with 48 patients in group 1, 49 patients in group 2 and group 3, respectively. Within the 18-month follow-up period, disease relapse occurred in 25 out of 48 (52.1%) patients in group 1 vs 7 out of 49 (14.2%) in group 2 and 6 out of 49 (12.2%) in group 3 (p<0.001). The changes in RI and PGA were significantly higher in group 1 than in group 2 (p<0.001) or group 3 (p<0.001). CONCLUSIONS: The maintenance of IMs, with or without low-dose GC, was found to be superior to withdraw GC+IM in preventing relapse for long-time stable IgG4-RD. TRIAL REGISTRATION NUMBER: NCT04124861.

Cellular Applications of DNP Solid-State NMR - State of the Art and a Look to the Future.

Sensitivity enhanced dynamic nuclear polarization solid-state NMR is emerging as a powerful technique for probing the structural properties of conformationally homogenous and heterogenous biomolecular species irrespective of size at atomic resolution within their native environments. Herein we detail advancements that have made acquiring such data, specifically within the confines of intact bacterial and eukaryotic cell a reality and further discuss the type of structural information that can presently be garnered by the technique's exploitation. Subsequently, we discuss bottlenecks that have thus far curbed cellular DNP-ssNMR's broader adoption namely due a lack of sensitivity and spectral resolution. We also explore possible solutions ranging from utilization of new pulse sequences, design of better performing polarizing agents, and application of additional biochemical/ cell biological methodologies.

Comparison of Neutralizing Antibody Response Kinetics in Patients with Hand, Foot, and Mouth Disease Caused by Coxsackievirus A16 or Enterovirus A71: A Longitudinal Cohort Study of Chinese Children, 2017-2019.

Hand, foot, and mouth disease (HFMD), which is mainly caused by coxsackievirus A16 (CVA16) or enterovirus A71 (EV-A71), poses a serious threat to children's health. However, the long-term dynamics of the neutralizing Ab (NAb) response and ideal paired-serum sampling time for serological diagnosis of CVA16-infected HFMD patients were unclear. In this study, 336 CVA16 and 253 EV-A71 PCR-positive HFMD inpatients were enrolled and provided 452 and 495 sera, respectively, for NAb detection. Random-intercept modeling with B-spline was conducted to characterize NAb response kinetics. The NAb titer of CVA16 infection patients was estimated to increase from negative (2.1, 95% confidence interval [CI]: 1.4-3.3) on the day of onset to a peak of 304.8 (95% CI: 233.4-398.3) on day 21 and then remained >64 until 26 mo after onset. However, the NAb response level of EV-A71-infected HFMD patients was much higher than that of CVA16-infected HFMD patients throughout. The geometric mean titer was significantly higher in severe EV-A71-infected patients than in mild patients, with a 2.0-fold (95% CI: 1.4-3.2) increase. When a 4-fold rise in titer was used as the criterion for serological diagnosis of CVA16 and EV-A71 infection, acute-phase serum needs to be collected at 0-5 d, and the corresponding convalescent serum should be respectively collected at 17.4 (95% CI: 9.6-27.4) and 24.4 d (95% CI: 15.3-38.3) after onset, respectively. In conclusion, both CVA16 and EV-A71 infection induce a persistent humoral immune response but have different NAb response levels and paired-serum sampling times for serological diagnosis. Clinical severity can affect the anti-EV-A71 NAb response.

Placental inflammatory injury induced by chlorinated polyfluorinated ether sulfonate (F-53B) through NLRP3 inflammasome activation.

Chlorinated polyfluorinated ether sulfonate, commercially known as F-53B, has been associated with adverse birth outcomes. However, the reproductive toxicology of F-53B on the placenta remains poorly understood. To address this gap, we examined the impact of F-53B on placental injury and its underlying molecular mechanisms in vivo. Pregnant C57BL/6 J female mice were randomly allocated to three groups: the control group, F-53B 0.8 µg/kg/day group, and F-53B 8 µg/kg/day group. After F-53B exposure through free drinking water from gestational day (GD) 0.5-14.5, the F-53B 8 µg/kg/day group exhibited significant increases in placental weights and distinctive histopathological alterations, including inflammatory cell infiltration, heightened syncytiotrophoblast knots, and a loosened trophoblastic basement membrane. Within the F-53B 8 µg/kg/day group, placental tissue exhibited increased apoptosis, as indicated by increased caspase3 activation. Furthermore, F-53B potentially induced the NF-κB signaling pathway activation through IκB-α phosphorylation. Subsequently, this activation upregulated the expression of inflammatory cytokines and components of the NLRP3 inflammasome, including activated caspase1, IL-1ß, IL-18, and cleaved gasdermin D (GSDMD), ultimately leading to pyroptosis in the mouse placenta. Our findings reveal a pronounced inflammatory injury in the placenta due to F-53B exposure, suggesting potential reproductive toxicity at concentrations relevant to the human population. Further toxicological and epidemiological investigations are warranted to conclusively assess the reproductive health risks posed by F-53B.

Combined effects of pre-pregnancy BMI and gestational weight gain on preterm birth: comparison between spontaneous and ART conception.

BACKGROUND: Inappropriate pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) are both linked to preterm birth (PTB); however, which one plays a dominant role in PTB risk is not yet sure. We aimed to evaluate the combined effect of pre-pregnancy BMI and GWG on the risk of PTB in singleton pregnancies conceived both spontaneously and through assisted reproductive technology (ART). METHODS: The data included all mothers (n = 17,540,977) who had a live singleton birth from the US National Vital Statistics System (NVSS) 2015-2019. Logistic regression models, quantile-g-computation, and generalized additive model were used to analyze the combined association of pre-pregnancy BMI and GWG with PTB. RESULTS: The singleton PTB rate was significantly higher in ART pregnancies (11.5%) than in non-ART pregnancies (7.9%). When compared to those women with pre-pregnancy normal weight and GWG within Institute of Medicine (IOM) guidelines, the highest PTB risk was observed in non-ART women with pre-pregnancy underweight and GWG below IOM guidelines (aOR 2.56; 95% CI 2.53-2.60) and in ART women with pre-pregnancy obese and GWG below IOM guidelines (aOR 2.56; 95%CI 2.36-2.78). GWG dominated the combined effect with its joint effect coefficient of - 0.281 (P < 0.05) in non-ART women and - 0.108 (P < 0.05) in ART women. CONCLUSIONS: Inappropriate GWG played a dominant role in increasing the risk of PTB in both non-ART and ART populations. Counseling regarding pre-pregnancy BMI and especially GWG appears to be even more crucial for pregnancies conceived via ART, given their impact on PTB.

Mathematical modeling of viral infection and the immune response controlled by the circadian clock.

Time of day affects how well the immune system responds to viral or bacterial infections. While it is well known that the immune system is regulated by the circadian clock, the dynamic origin of time-of-day-dependent immunity remains unclear. In this paper, we studied the circadian control of immune response upon infection of influenza A virus through mathematical modeling. Dynamic simulation analyses revealed that the time-of-day-dependent immunity was rooted in the relative phase between the circadian clock and the pulse of viral infection. The relative phase, which depends on the time the infection occurs, plays a crucial role in the immune response. It can drive the immune system to one of two distinct bistable states, a high inflammatory state with a higher mortality rate or a safe state characterized by low inflammation. The mechanism we found here also explained why the same species infected by different viruses has different time-of-day-dependent immunities. Further, the time-of-day-dependent immunity was found to be abolished when the immune system was regulated by an impaired circadian clock with decreased oscillation amplitude or without oscillations.

mTORC1-GLUT1-mediated glucose metabolism drives hyperactivation of B cells in primary Sjogren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by B cell hyperactivation and hypergrammaglobulinemia. Currently, the role of metabolic pathways in the B cells of pSS patients is poorly defined. Here, we showed that upon cytosine phosphate-guanine (CpG)/sCD40L/IL-4 stimulation, B cells proportionally increased glycolysis and oxygen consumption, and compared with B cells from healthy controls (HCs), B cells from pSS patients exhibited higher glycolysis capacity and maximal oxidative respiration (OXPHOS). We also found that glucose transporter 1 (GLUT1) expression in B cells from pSS patients was significantly higher than that in B cells from HCs. Treatment with 2-deoxy-d-glucose (2-DG) inhibited the activation of B cells in pSS patients. Both 2-DG and Metformin inhibited the proliferation, formation of plasma/plasmablasts and decreased the IgG and IgM levels in the supernatants of B cells from pSS patients. Furthermore, inhibition of mTORC1 by rapamycin had an effect similar to that of 2-DG, suppressing B cell activation, proliferation and antibody production. Taken together, we demonstrated that B cells from pSS patients are more metabolically active than those from HCs and suggested that the mTORC1-GLUT1 glycolysis pathways were the major drivers of B cell hyperactivation and autoantibody production in pSS patients.

Memory CD4+T cell profile is associated with unfavorable prognosis in IgG4-related disease: Risk stratification by machine-learning.

IgG4-related disease (IgG4-RD) is a chronic immune-mediated disease with heterogeneity. In this study, we used machine-learning approaches to characterize the immune cell profiles and to identify the heterogeneity of IgG4-RD. The XGBoost model discriminated IgG4-RD from HCs with an area under the receiver operating characteristic curve of 0.963 in the testing set. There were two clusters of IgG4-RD by k-means clustering of immunological profiles. Cluster 1 featured higher proportions of memory CD4+T cell and were at higher risk of unfavorable prognosis in the follow-up, while cluster 2 featured higher proportions of naïve CD4+T cell. In the multivariate logistic regression, cluster 2 was shown to be a protective factor (OR 0.30, 95% CI 0.10-0.91, P = 0.011). Therefore, peripheral immunophenotyping might potentially stratify patients with IgG4-RD and predict those patients with a higher risk of relapse at early time.

Complement factor H attenuates TNF-α-induced inflammation by upregulating EIF3C in rheumatoid arthritis.

OBJECTIVE: To explore the role and underlying mechanism of Complement Factor H (CFH) in the peripheral and joint inflammation of RA patients. METHODS: The levels of CFH in the serum and synovial fluid were determined by ELISA. The pyroptosis of monocytes was determined by western blotting and flow cytometry. The inflammation cytokine release was tested by ELISA. The cell migration and invasion ability of fibroblast-like synoviocytes (FLS) were tested by Wound healing Assay and transwell assay, respectively. The potential target of CFH was identified by RNA sequencing. RESULTS: CFH levels were significantly elevated in the serum and synovial fluid from RA and associated with high sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and disease activity score 28 (DAS28). TNF-α could inhibit CFH expression, and CFH combined with TNF-α significantly decreased cell death, cleaved-caspase 3, gasdermin E N-terminal (GSDME-N), and inflammatory cytokines release (IL-1ß and IL-6) of RA-derived monocytes. Stimulated with TNF-α increased CFH levels in RA FLS and CFH inhibits the migration, invasion, and TNF-α-induced production of inflammatory mediators, including proinflammatory cytokines (IL-6, IL-8) as well as matrix metalloproteinases (MMPs, MMP1 and MMP3) of RA FLSs. The RNA-seq results showed that CFH treatment induced upregulation of eukaryotic translation initiation factor 3 (EIF3C) in both RA monocytes and FLS. The migration of RA FLSs was promoted and the expressions of IL-6, IL-8, and MMP-3 were enhanced upon EIF3C knockdown under the stimulation of CFH combined with TNF-α. CONCLUSION: In conclusion, we have unfolded the anti-inflammatory roles of CFH in the peripheral and joints of RA, which might provide a potential therapeutic target for RA patients.

Early recognition of catastrophic antiphospholipid syndrome in patients with antiphospholipid syndrome based on a Chinese cohort study.

OBJECTIVES: Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening form of antiphospholipid syndrome (APS) with high mortality. We try to develop a predictive model to achieve early recognition of CAPS. METHODS: Data of APS patients referred into Peking Union Medical College Hospital from May 2013 to October 2021 was collected. A binary logistic regression method was used to identify predictors of CAPS, coefficient B was assigned with score value in the development of prediction model, and risk-stratification was based on the calculated scores using the model. RESULTS: Twenty-seven CAPS (11.9%) occurred in 226 APS patients. CAPS was more likely to occur in male secondary APS patients with a history of hypertension, hyperlipidaemia, and arterial thrombosis, presented with haematological, nephrological and immunological abnormalities simultaneously. Hypertension history (OR 5.091, 95% CI 1.119-23.147), anaemia (OR 116.231, 95% CI 10.512-1285.142), elevated LDH (OR 59.743, 95% CI 7.439-479.815) and proteinuria (OR 11.265, 95% CI 2.118-59.930) were independent predictors for CAPS, and the scores were 1, 3, 3 and 2 points, respectively. The risk scores were divided into high-risk (6-9) and low risk (0-5), the risk for CAPS were 54.1% and 0.6%, with sensitivity of 0.963 and specificity of 0.886. The Nagelkerke's R2 (0.739) and the Omnibus test (χ2 =109.231, df=4, p=0.000) indicated the model has a good fit. The AUC of 0.971 indicated good discrimination. The calibration curve in internal validation showed good calibration of this predictive model. CONCLUSIONS: A predictive model of CAPS was developed with hypertension, anaemia, elevated LDH and proteinuria. This model could help identify CAPS in high-risk patients, achieve early recognition and intervention to improve prognosis.

Hypermethylation of the ADIRF promoter regulates its expression level and is involved in NNK-induced malignant transformation of lung bronchial epithelial cells.

The carcinogenic mechanism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a well-known tobacco carcinogen, has not been fully elucidated in epigenetic studies. 5-Methylcytosine (5mC) modification plays a major role in epigenetic regulation. In this study, the 5mC level increased in both BEAS-2B human bronchial epithelium cells treated with 100 mg/L NNK for 24 h and NNK-induced malignant-transformed BEAS-2B cells (2B-NNK cells), suggesting that 5mC modification is associated with the malignant transformation mechanism of NNK. Using a combination of Methylated DNA Immunoprecipitation Sequencing (MeDIP-seq), RNA sequencing (RNA-seq), and bioinformatics analysis of data from the Genomic Data Commons database, we found that the Adipogenesis regulatory factor (ADIRF) promoter region was abnormally hypermethylated, yielding low ADIRF mRNA expression, and that ADIRF overexpression could inhibit the proliferation, migration, and invasion of 2B-NNK cells. This finding suggests that ADIRF plays a tumor suppressor role in the NNK-induced malignant transformation of cells. Subsequently, using 5-Aza-2'-deoxycytidine (5-Aza-2'-dC) and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Catalytically Dead Cas9 (dCas9 system), we verified that the demethylation of the ADIRF promoter region in 2B-NNK cells inhibited the proliferation, migration, and invasion ability of the cells and increased their apoptosis ability. These results suggest that abnormal 5mC modification of the ADIRF promoter plays a positive regulatory role in the pathogenesis of NNK-induced lung cancer. This study offers a new experimental basis for the epigenetic mechanism of NNK-induced lung cancer.

Ultra-flat multicarrier light source based on recirculating frequency shift loop driven by a parity-time symmetric optoelectronic oscillator.

A multicarrier light source based on a recirculating frequency shift loop (RFSL) driven by a parity-time (PT)-symmetric optoelectronic oscillator (OEO) is proposed and experimentally demonstrated. The impact of the side-mode suppression ratio (SMSR) of the radio frequency (RF) signal on the multicarrier is studied for the first time, to our knowledge. The RFSL driven by PT-symmetric OEO significantly optimizes the phase noise and flatness of the multicarrier, facilitating the system miniaturization. In the experiment, a 10.019 GHz RF signal with a SMSR of 42 dB is generated with -98.63d B c/H z measured phase noise at 10 kHz offset frequency (actual phase noise should be lower than -122.87d B c/H z). Up to 120 subcarriers with 2.32 dB flatness are obtained successfully, covering the overall bandwidth of approximately 1.2 THz.

Applicability of the London Atlas method in the East China population.

BACKGROUND: Dental age estimation is important for developmental assessment and individual identification. The London Atlas, a recently proposed method for dental age estimation, has been reported to perform satisfactorily in various populations. OBJECTIVE: In this study, we assessed the reproducibility, repeatability and applicability of the London Atlas method in the East China population and compared it with the Demirjian method. MATERIALS AND METHODS: We assessed panoramic radiographs of 835 pediatric patients ages 6.0-19.9 years using the London Atlas and the Demirjian method. We employed the intraclass correlation coefficient and Bland-Altman analysis to evaluate reproducibility and repeatability, respectively. We assessed the agreement between dental age and chronological age and calculated 95% and 80% prediction intervals for each dental age stage. Sensitivity, specificity and predictive values were calculated to assess the performance of both methods for identifying threshold ages. RESULTS: The London Atlas has better reproducibility and repeatability (intraclass correlation coefficients: 0.98 and 0.99; 95% limits of agreement: - 1.34 to 1.56 and - 1.22 to 0.88, respectively). Dental age estimated using the London Atlas was closer to chronological age in both genders (median absolute error = 0.58). The 95% prediction intervals for chronological age were wide (0.99 to 9.89 years). CONCLUSION: The London Atlas has excellent reproducibility and repeatability. Thus, it might offer an alternative method for developmental assessment. We observed considerable variation in dental development in the East China population, which needs further research.

Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression.

Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.

The Five-DOF Explosion-Removal Manipulator Based on Position and Velocity Feedforward Compensation Control.

The main problem with a robotic system arm is its sensitivity to time delays in the control process. Due to this problem, it is necessary to further optimize the control process of the system. One solution is to deal with the control accuracy and response speed issues of robotic arm joints, to improve the system's response performance and enhance the system's anti-interference ability. This paper proposes a speed feedforward and position control scheme for robotic arm joint control. The conclusion section shows that compared to traditional five-degree-of-freedom robotic arm systems, the addressed robotic arm control system has a lower tracking delay and better dynamic response performance. It can improve the system's response performance while also enhancing its anti-interference ability.

Research on Two-Round Self-Balancing Robot SLAM Based on the Gmapping Algorithm.

Aiming at the inconvenience of inspection and monitoring of coal mine pump room equipment in a narrow and complex environment, this paper proposes and designs a two-wheel self-balancing inspection robot based on laser SLAM. Using SolidWorks, the three-dimensional mechanical structure of the robot is designed, and the overall structure of the robot is analyzed by finite element statics. The kinematics model of the two-wheel self-balancing robot was established, and the multi-closed-loop PID controller was used to design the two-wheel self-balancing control algorithm of the robot. The 2D LiDAR-based Gmapping algorithm was used to locate the robot and construct the map. Through the self-balancing test and anti-jamming test, it is verified that the self-balancing algorithm designed in this paper has a certain anti-jamming ability and good robustness. By using Gazebo to build a simulation comparison experiment, it is verified that the selection of the particle number is of great significance for improving the map accuracy. The actual test results show that the constructed map has high accuracy.