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Recurrent pregnancy loss (RPL) has become an important reproductive health issue worldwide. RPL affects about 2%–3% of reproductive-aged women, and makes serious threats to women’s physical and mental health. However, the etiology of approximately 50% of RPL cases remains unknown (unexplained RPL), which poses a big challenge for clinical management of these patients. RPL has been widely regarded as a complex disease where its etiology has been attributed to numerous factors. Heretofore, various risk factors for RPL have been identified, such as maternal ages, genetic factors, anatomical structural abnormalities, endocrine dysfunction, prethrombotic state, immunological factors, and infection. More importantly, development and applications of next generation sequencing technology have significantly expanded opportunities to discover chromosomal aberrations and single gene variants responsible for RPL, which provides new insight into its pathogenic mechanisms. Furthermore, based upon patients’ diagnostic evaluation and etiologic diagnosis, specific therapeutic recommendations have been established. This review will highlight current understanding and recent advances on RPL, with a special focus on the immunological and genetic etiologies, clinical diagnosis and therapeutic management.

Determination of calibration parameters is essential for the fusion performance of an inertial measurement unit (IMU) and odometer integrated navigation system. Traditional calibration methods are commonly based on the filter frame, which limits the improvement of the calibration accuracy. This paper proposes a graph-optimisation-based self-calibration method for the IMU/odometer using preintegration theory. Different from existing preintegrations, the complete IMU/odometer preintegration model is derived, which takes into consideration the effects of the scale factor of the odometer, and misalignments in the attitude and position between the IMU and odometer. Then the calibration is implemented by the graph-optimisation method. The KITTI dataset and field experimental tests are carried out to evaluate the effectiveness of the proposed method. The results illustrate that the proposed method outperforms the filter-based calibration method. Meanwhile, the performance of the proposed IMU/odometer preintegration model is optimal compared with the traditional preintegration models.

Invariant NK T (iNKT) cells are innate-like lymphocytes that can recognize the lipid Ag presented by MHC I like molecule CD1d. Distinct tissue distribution of iNKT cells subsets implies a contribution of these subsets to their related tissue regional immunity. iNKT cells are enriched in liver, an organ with unique immunological properties. Whether liver-specific iNKT cells exist and dedicate to the liver immunity remains elusive. Here, a liver-specific CD24+ iNKT subset is shown. Hepatic CD24+ iNKT cells show higher levels of proliferation, glucose metabolism, and mTOR activity comparing to CD24– iNKT cells. Although CD24+ iNKT cells and CD24– iNKT cells in the liver produce similar amounts of cytokines, the hepatic CD24+ iNKT cells exhibit lower granzyme B production. These liver-specific CD24+ iNKT cells are derived from thymus and differentiate into CD24+ iNKT in the liver microenvironment. Moreover, liver microenvironment induces the formation of CD24+ conventional T cells as well, and these cells exhibit higher proliferation ability but lower granzyme B production in comparison with CD24– T cells. The results propose that liver microenvironment might induce the generation of liver-specific iNKT subset that might play an important role in maintaining liver homeostasis.

GNSS/IMU/in-vehicle sensors navigation can provide accurate localization for land vehicles. Although the sensor fusion is often carried out by Kalman filter, graph optimization can obtain better state estimation. However, the graph optimization is still affected by the lack of rigorous IMU/in-vehicle sensors preintegration. In this paper, an improved preintegration method for GNSS/IMU/in-vehicle sensors navigation using graph optimization is proposed. Different from current methods, the preintegration that involves total error parameters of in-vehicle sensors is derived. The improved factors are subsequently fused with GNSS measurements and kinematic models using graph optimization, which can allow to yield a total parameters estimation. Thereby, more accurate relative constraints provided by the proposed method can improve the positioning accuracy compared with traditional preintegration methods. Meanwhile, the estimation accuracy of the proposed method for these error parameters can be superior to Kalman filter. The KITTI datasets and field tests are carried out to validate the competitive performance of the proposed method. Finally, the computational load of the proposed method is also discussed to verify its applicability for real-time operations.

Activation of mTORC1 is essential for anti-tumor function of iNKT cells. The mechanisms underlying impaired mTORC1 activation in intratumoral iNKT cells remain unclear. Here, we showed that lactic acid from tumor cells increased Vam6 expression in iNKT cells which led to impaired mTORC1 activation and IFN-γ production. Mechanistically, Vam6 in iNKT cells was essential for Rab7a-Vam6-AMPK complex formation and thus for recruitment of AMPK to lysosome to activate AMPK, a negative regulator of mTORC1. Additionally, Vam6 relieved inhibitory effect of VDAC1 on Rab7a-Vam6-AMPK complex formation at mitochondria-lysosome contact site. Given the key roles of lactic acid-increased Vam6 in promoting AMPK activation in intratumoral iNKT cells, reducing Vam6 expression significantly enhanced the mTORC1 activation in intratumoral iNKT cells as well as their anti-tumor efficacy. Together, we propose Vam6 as a target for iNKT cell-based immunotherapy.

The high-precision positioning of the shearer is the key technology to realize the automation of longwall mining. Since mine is a Global Position System (GPS)-denied environment, highly autonomous Inertial Navigation System (INS)/odometer integrated navigation has been widely used. At present, the shearer positioning method based on INS/odometer has been challenging to meet the requirements of long-time and high-precision mining. Aiming at the high-precision navigation in the complex mining environment, this paper constructs a comprehensive rail kinematics model of the shearer that does not rely on external sensors. By analyzing the kinematic characteristics of the shearer and the scraper conveyor during the longwall mining process, a method of information fusion and navigation system fault diagnosis based on the assistance of the shearer rail kinematics model was proposed. According to the working principle of the shearer rails and hydraulic supports, the characteristics of the trajectory deviation caused by the sensor fault of the hydraulic support are analyzed. Combined with the engineering requirements of shearer mining, the model fault identification was carried out by the fading probability ratio detection algorithm. The simulation results show that the proposed algorithm effectively improves the positioning of shearer accuracy in multiple cutting cycles. At the same time, it avoids the influence of the rail deviation caused by the rail kinematics model fault on the positioning of the shearer.

Enterobacter hormaechei is an opportunistic pathogen and is found in a large variety of food including animal-derived food. In recent years, bacteria present a severe clinical challenge due to their increasing resistance to antibiotics. Bacteriophages have gained attention as a new antibacterial strategy. In this study, we isolated a novel E. hormaechei bacteriophage IME278 from hospital sewage in Beijing, China. Bacteriophage IME278 had a double-stranded linear DNA genome with 40,164 bp and 51.99% GC content. Whole-genome alignments showed IME278 shared 87% homology with other phages in the National Center for Biotechnology Information (NCBI) database. And phylogenetic analysis demonstrated that IME278 was highly similar to bacteriophages belonging to the genus Kayfunavirus, family Autographiviridae, indicating IME278 can be classified as a new member of the Autographiviridae family. Transmission electron microscopy revealed that IME278 had an icosahedral head 51.72 nm in diameter and a tail 151.28 nm in length. Bacteriophage IME278 was able to survive under high temperature (50 °C-70 °C) and its activity decreased significantly above 70 °C and almost completely inactivated at 80 °C. Bacteriophage IME278 could survive in a wide pH range (4.0-11.0) and it was stable in chloroform (up to 5%). The phage was sensitive to UV irradiation. Bacteriophage IME278 had a latent period of 40 min and reached a plateau stage at 150 min and its cleavage was approximately 8.21 × 10

Invariant NK T (iNKT) cells are innate-like lymphocytes that can recognize the lipid Ag presented by MHC I like molecule CD1d. Distinct tissue distribution of iNKT cells subsets implies a contribution of these subsets to their related tissue regional immunity. iNKT cells are enriched in liver, an organ with unique immunological properties. Whether liver-specific iNKT cells exist and dedicate to the liver immunity remains elusive. Here, a liver-specific CD24

Invariant natural killer T (iNKT) cells play important roles in regulating immune responses. Based on cytokine profiling and key transcriptional factors, iNKT cells are classified into iNKT1, iNKT2, and iNKT17 subsets. However, whether the development and functions of these subsets are controlled by distinct mechanisms remains unclear. Here, we show that forkhead box protein O1 (Foxo1) promotes differentiation of iNKT1 and iNKT2 cells but not iNKT17 cells because of its distinct contributions to IL7R expression in these subsets. Nuclear Foxo1 is essential for Il7r expression in iNKT1 and iNKT2 cells at early stages of differentiation but is dispensable in iNKT17 cells. RORγt, instead of Foxo1, promotes IL7R expression in iNKT17 cells. Additionally, Foxo1 is required for the effector function of iNKT1 and iNKT2 cells but not iNKT17 cells. Cytoplasmic Foxo1 promotes activation of mTORC1 in iNKT1 and iNKT2 cells through inhibiting TSC1-TSC2 interaction, whereas it is dispensable for mTORC1 activation in iNKT17 cells. iNKT17 cells display distinct metabolic gene expression patterns from iNKT1 and iNKT2 cells that match their different functional requirements on Foxo1. Together, our results demonstrate that iNKT cell subsets differ in their developmental and functional requirements on Foxo1.

Dysfunction of invariant natural killer T (iNKT) cells in tumor microenvironment hinders their anti-tumor efficacy, and the underlying mechanisms remain unclear. Here we report that iNKT cells increase lipid biosynthesis after activation, and that is promoted by PPARγ and PLZF synergically through enhancing transcription of Srebf1. Among those lipids, cholesterol is required for the optimal IFN-γ production from iNKT cells. Lactic acid in tumor microenvironment reduces expression of PPARγ in intratumoral iNKT cells and consequently diminishes their cholesterol synthesis and IFN-γ production. Importantly, PPARγ agonist pioglitazone, a thiazolidinedione drug for type 2 diabetes, successfully restores IFN-γ production in tumor-infiltrating iNKT cells from both human patients and mouse models. Combination of pioglitazone and alpha-galactosylceramide treatments significantly enhances iNKT cell-mediated anti-tumor immune responses and prolongs survival of tumor-bearing mice. Our studies provide a strategy to augment the anti-tumor efficacy of iNKT cell-based immunotherapies via promoting their lipid biosynthesis., Lipid metabolism has been linked to iNKT function largely as it impacts processing and presentation of lipids they recognize. Here the authors show that iNKT-intrinsic lipid biosynthesis is important for their function but is impaired in tumors, and its restoration with PPARγ agonist drugs promotes anti-tumor iNKT response.

Activation of NLRP3 inflammasome is precisely controlled to avoid excessive activation. Although multiple molecules regulating NLRP3 inflammasome activation have been revealed, the checkpoints governing NLRP3 inflammasome activation remain elusive. Here, we show that activation of NLRP3 inflammasome is governed by GSTO1-promoted ASC deglutathionylation in macrophages. Glutathionylation of ASC inhibits ASC oligomerization and thus represses activation of NLRP3 inflammasome in macrophages, unless GSTO1 binds ASC and deglutathionylates ASC at ER, under control of mitochondrial ROS and triacylglyceride synthesis. In macrophages expressing ASCC171A, a mutant ASC without glutathionylation site, activation of NLRP3 inflammasome is GSTO1 independent, ROS independent, and signal 2 less dependent. Moreover, AscC171A mice exhibit NLRP3-dependent hyperinflammation in vivo. Our results demonstrate that glutathionylation of ASC represses NLRP3 inflammasome activation, and GSTO1-promoted ASC deglutathionylation at ER, under metabolic control, is a checkpoint for activating NLRP3 inflammasome.

Background: The majority of unexplained recurrent spontaneous abortion (URSA) was related to immune abnormalities. Inappropriate changes of microbiota could cause immune disorders. However, the role of uterine cavity microbiota in URSA has not be elucidated and few related studies are available for reference. Methods: Using the double-lumen embryo transfer tubes to collect uterine cavity fluid samples from pregnant women in their first trimester. 16S rRNA sequencing was conducted to analysis the composition and abundance of the microbiota in samples. Findings: We enrolled 10 URSA cases and 28 induced miscarriage cases in their early pregnancy. Microbial communities were detected in all samples of URSA group (100%, n = 10) vs. none of control group (0%, n=28). Two most dominant microbes are Lactobacillus and Curvibacter. Interpretation: This study showed Lactobacillus and Curvibacter dominated colonizing in uterine cavity of URSA patients during early pregnancy and associated with URSA. Changes of dominant microbiota will lead to bad pregnancy outcome. Funding Statement: This study was supported by grants from the National Natural Science Foundation of China (grant nos. 81771660 and 81741017), the Science and Technology Planning Project of Guangdong Province (2017A020214018 and 2017A020214003), the Guangdong Natural Science Foundation (2018A030313023 and 2018A030310162), the Science and Technology Planning Project of Guangzhou City Central Universities (201704020034); the 5010 projects of Sun Yat-Sen University (2012006), and the Fundamental Research Funds for the Central Universities (Youth Program12ykpy29). Declaration of Interests: No conflicts of interest in this study. Ethics Approval Statement: Approval for our study was obtained from the Ethics Committee of Sun Yat-sen Memorial Hospital of Sun Yat-sen University (SYSEC-KY-KS-2020-146) and written informed consent was obtained from all participants.

Epidemiological studies have revealed that sulfur dioxides (SOTo study the effect of SOSwan.71 trophoblast cells were treated with various concentrations of SOExposure to SOSO

Background: Mounting evidence has revealed that impaired spiral artery remodeling, placental dysfunction, and inadequate trophoblast invasion are closely correlated with the etiology and pathogenesis of pre-eclampsia (PE). However, the detailed molecular pathology of PE remains unclear. Although circRNAs, as a new type of stable and abundant endogenous noncoding RNA, have been proven to be essential to the pathogenesis of various diseases, their role in PE requires further verification. In this context, it is necessary to unveil the roles of circRNAs in regulating the migration and invasion of extravillous trophoblasts. Methods: To exploit the roles of circRNAs together with PAPPA2 in the pathogenesis of PE, circPAPPA2 (hsa_circ_0111277) was applied in this study to determine the molecular mechanisms controlling trophoblastic invasion and migration in PE. Findings: In this study, using quantitative real-time PCR, we confirmed that circPAPPA2 was upregulated in PE placentas relative to the level in normal pregnancy placentas. In addition, positive correlations between hsa_circ_0111277 expression and PE-related factors (proteinuria level at 24 h and placental weight) were identified by Pearson’s analysis based on the clinical data of 25 PE patients. Moreover, fluorescence in situ hybridization analysis illustrated that circ_0111277 was preferentially localized within the cytoplasm. Mechanistically, circ_0111277 sponged hsa-miR-494-3p in trophoblast cells to attenuate the latter’s repression by regulating HTRA1/Notch-1 expression. Interpretation: In conclusion, trophoblast cell migration and invasion were shown to be promoted and modulated by the circPAPPA2/miR-494-3p/HTRA1/Notch-1 axis, which provides useful insight for exploring a new therapeutic approach for PE. Funding Statement: This study was supported by the National Nature Science Foundation of China (No. 81771660, 81741017), Guangdong Natural Science Foundation (2018A030310162, 18zxxt56), and 5010 projects at Sun Yat-Sen University (2012006). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital and the enrolled subjects provided informed consent to participate in this research.

In a dual-axis rotational inertial navigation system (RINS), there are two kinds of installation errors, nonorthogonal installation errors of inertial sensors, and installation errors between the inertial measurement unit (IMU) and rotation axes. Traditionally, these two errors are not considered simultaneously. Thus, they are calibrated separately by different estimation algorithms and rotation schemes. In this paper, a system-level self-calibration method for installation errors of a dual-axis RINS is proposed. Based on the Kalman filter, the measurement model is reestablished to ensure that all installation errors can be estimated together. First, the relationship between the initial attitude and subsequent attitude of IMU during rotation is used as a constraint to estimate nonorthogonal installation errors of accelerometers, and installation errors between the IMU and rotation axes. Then, the angular rate of the rotation mechanism is used as a reference to estimate nonorthogonal installation errors of the gyros. The rotation scheme of the IMU is designed to make all installation errors observable, and the observability of the system is analyzed based on the piecewise constant system method. Simulation and laboratory experiment results suggest that installation errors can be effectively estimated by the proposed method, thereby avoiding the complex separating process.

Two-dimensional (2D) porous carbon nanosheets (PCNs) have drawn tremendous concern due to they possess large specific surface area, reduced ion transportation resistance and shorten ion diffusion distance. However, the traditional template method is complex and time-consuming. Here, we reported a convenient strategy to synthesize 2D PCNs derived from cationic starch using graphene oxide (GO) as template through an electrostatic self-assembly strategy with KOH activation. Due to the unique 2D highly interconnected nanosheet-like porous framework with suitable specific surface area, the as-prepared PCNs-1 electrode delivers high specific capacitance (232.1 F g−1 at 2 mV s−1) and impressive electrochemical stabilization (100.3% retention after 10,000 cycles) in 6 M KOH aqueous electrolyte. Meanwhile, the constructed PCNs-1//PCNs-1 symmetrical supercapacitor shows an energy density of 19.2 Wh kg−1 and remarkable electrochemical stabilization (93.7% retention after 10,000 cycles) in 1 M Na2SO4 aqueous electrolyte. The strategy provides a novel and convenient approach to construct porous carbon nanosheets for supercapacitors.

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes that express an invariant T cell receptor (TCR), which recognizes glycolipid antigens presented on CD1d molecules. These cells are phenotypically and functionally distinct from conventional T cells. When we characterized the metabolic activity of iNKT cells, consistent with their activated phenotype, we found that they had much less mitochondrial respiratory capacity but increased glycolytic activity in comparison to naive conventional CD4+ T cells. After TCR engagement, iNKT cells further increased aerobic glycolysis, which was important for the expression of interferon-γ (IFN-γ). Glycolytic metabolism promoted the translocation of hexokinase-II to mitochondria and the activation of mammalian target of rapamycin complex 2 (mTORC2). Inhibiting glycolysis reduced the activity of Akt and PKCθ, which inhibited TCR recycling and accumulation within the immune synapse. Diminished TCR accumulation in the immune synapse reduced the activation of proximal and distal TCR signaling pathways and IFN-γ production in activated iNKT cells. Our studies demonstrate that glycolytic metabolism augments TCR signaling duration and IFN-γ production in iNKT cells by increasing TCR recycling.

SummaryAntibodies developed during HIV-1 infection lose efficacy as the viral spike mutates. We postulated that anti-HIV-1 antibodies primarily bind monovalently because HIV’s low spike density impedes bivalent binding through inter-spike crosslinking, and the spike structure prohibits bivalent binding through intra-spike crosslinking. Monovalent binding reduces avidity and potency, thus expanding the range of mutations permitting antibody evasion. To test this idea, we engineered antibody-based molecules capable of bivalent binding through intra-spike crosslinking. We used DNA as a “molecular ruler” to measure intra-epitope distances on virion-bound spikes and construct intra-spike crosslinking molecules. Optimal bivalent reagents exhibited up to 2.5 orders of magnitude increased potency (>100-fold average increases across virus panels) and identified conformational states of virion-bound spikes. The demonstration that intra-spike crosslinking lowers the concentration of antibodies required for neutralization supports the hypothesis that low spike densities facilitate antibody evasion and the use of molecules capable of intra-spike crosslinking for therapy or passive protection.

This study aimed to evaluate whether the use of preoperative ultrasound (US)-guided wire localization of metastatic axillary lymph nodes (LN) assessed previously by core needle biopsy (CNB) and clip placement in breast cancer patients improves successful surgical removal.A retrospective review examined breast cancer patients who underwent US-guided CNB of an axillary LN and biopsy clip placement as well as axillary lymph node dissection (ALND) or sentinel node lymph node biopsy (SLNB) from 1 January 2010 to 30 September 2013. Preoperative needle localization status, neoadjuvant chemotherapy, and type of axillary LN surgery were reviewed. Confirmation that the metastatic LN had been surgically removed was determined on the specimen image, by pathologic report confirmation, or by pre-radiation therapy computed tomography (CT) scan.Preoperative US-guided needle localization was performed for 68.2 % (73/107) of the patients, with 97.3 % (n = 71) demonstrating confirmation of biopsy clip and LN removal versus 79.4 % (n = 27) of the 34 patients showing no performance of needle localization (p = 0.0043). Subgroup analysis showed a significant difference in removal of metastatic LN between the patients who received neoadjuvant chemotherapy [97 % of LNs removed with wire localization (n = 65/67) vs. 83.3 % of LNs removed without wire localization (n = 20/24; p = 0.04)] and the patients who had ALND, [96.3 % of LNs removed with wire localization (n = 52/54) vs. 77.8 % of LNs removed without wire localization (n = 21/27; p = 0.015)].US-guided wire localization of metastatic axillary LNs that have had biopsy with clip placement significantly improves the success rate of surgical removal, allowing more accurate staging and decreasing the false-negative rates of SLNB after neoadjuvant therapy.

Background Factors influencing recurrence of ileocecal Crohn's disease (CD) after surgical resection may differ between adolescents and adults. Methods CD patients who underwent ileocecectomy were retrospectively divided into pediatric onset (age at diagnosis ≤ 16 years, n = 34) and adult onset (>16, n = 108) patients to evaluate differences in risks of endoscopic and clinical recurrence. Results In 142 patients, rates of any recurrence, endoscopic recurrence, and clinical recurrence at 5 years were 78%, 88%, and 65%, respectively. Risks of recurrence were similar between groups. Younger patients were more likely to be on immunologics preoperatively and more likely to be started on immunoprophylaxis postoperatively. Immediate postoperative prophylaxis was predictive of delayed clinical recurrence only in the older group. Conclusions Despite increased preoperative and postoperative immunoprophylaxis in younger patients, recurrence rates of CD after ileocecectomy do not differ between these groups. Immediate postoperative prophylaxis was predictive of delayed clinical recurrence only in patients with adult onset CD.