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Accurate positioning and navigation play a vital role in vehicle-related applications, such as autonomous driving and precision agriculture. With the rapid development of Global Navigation Satellite Systems (GNSS), Precise Point Positioning (PPP) technique, as a global positioning solution, has been widely applied due to its convenient operation. Nevertheless, the performance of PPP is severely affected by signal interference, especially in GNSS-challenged environments. Inertial Navigation System (INS) aided GNSS can significantly improve the continuity and accuracy of navigation in harsh environments, but suffers from degradation during GNSS outages. LiDAR (Laser Imaging, Detection, and Ranging)-Inertial Odometry (LIO), which has performed well in local navigation, can restrain the divergence of Inertial Measurement Units (IMU). However, in long-range navigation, error accumulation is inevitable if no external aids are applied. To improve vehicle navigation performance, we proposed a tightly coupled GNSS PPP/INS/LiDAR (GIL) integration method, which tightly integrates the raw measurements from multi-GNSS PPP, Micro-Electro-Mechanical System (MEMS)-IMU, and LiDAR to achieve high-accuracy and reliable navigation in urban environments. Several experiments were conducted to evaluate this method. The results indicate that in comparison with the multi-GNSS PPP/INS tightly coupled solution the positioning Root-Mean-Square Errors (RMSEs) of the proposed GIL method have the improvements of 63.0%, 51.3%, and 62.2% in east, north, and vertical components, respectively. The GIL method can achieve decimeter-level positioning accuracy in GNSS partly-blocked environment (i.e., the environment with GNSS signals partly-blocked) and meter-level positioning accuracy in GNSS difficult environment (i.e., the environment with GNSS hardly used). Besides, the accuracy of velocity and attitude estimation can also be enhanced with the GIL method.

Abstract: Proteolysis-targeting chimeras (PROTACs) are an attractive means to target previously undruggable or drug-resistant mutant proteins. While small molecule-based PROTACs are stable and can cross cell membranes, there is limited availability of suitable small molecule warheads capable of recruiting proteins to an E3 ubiquitin ligase for degradation. With advances in structural biology and in silico protein structure prediction, it is now becoming easier to define highly selective peptides suitable for PROTAC design. As a result, peptide-based PROTACs are becoming a feasible proposition for targeting previously “undruggable” proteins not amenable to small molecule inhibition. In this review, we summarize recent progress in the design and application of peptide-based PROTACs as well as several practical approaches for obtaining candidate peptides for PROTACs. We also discuss the major hurdles preventing the translation of peptide-based PROTACs from bench to bedside, such as their delivery and bioavailability, with the aim of stimulating discussion about how best to accelerate the clinical development of peptide-based PROTACs in the near future.

Regenerative bio-scaffolds, widely used for clinical tissue reconstruction and tissue repairs, are functionally diversified and structurally complex decellularized tissue materials (e.g., extracellular matrix, ECM). ECM is naturally cross-linked and can be further selectively cross-linked upon processing. Identification, quantification and bioinformatics functional comparison of all ECM proteins are challenging for regenerative bio-scaffolds. In this study, we have applied proteomic profiling with a two-step sequential trypsinization method, and identified and quantified 300-400 constituent proteins in three commercially available regenerative bio-scaffolds (BioDesign Surgisis, ReGen tissue matrix, and ThormalGEN mesh). These proteins were classified into four categories and 14 subcategories based on their mainly biological function. The main components of regenerative bio-scaffolds were highly abundant ECM structural proteins, and the minor parts of bio-scaffolds were lowly abundant, less cross-linked, functionally more diversified proteins, especially extracellular fluid proteins that were easily solubilized by trypsin. The comparative analysis has revealed large differences in the number, type, abundance and function of identified proteins, as well as the extent of decellularization and cross-linking among regenerative bio-scaffolds. So, the proteomic profiling with a two-step sequential trypsinization method could not only provide the molecular basis to better understand the degradation process of regenerative bio-scaffolds in vivo and different clinical outcomes among various regenerative bio-scaffolds, facilitate the exploration of the response mechanisms in the host's early clinical stages of ECM-induced tissue regeneration that is still poorly understood, but also can be used for optimization of the decellularization and cross-linking process, product characterization and rational design of new ECM products.

Glutathione (GSH) is the most abundant biological thiol in cells. It can participate in metabolic processes, regulate the body's oxidation level and is essential for various cell functions. An abnormal concentration of glutathione in the cell is directly related to some diseases. Therefore, it is very important to develop fast, sensitive and reversible detection methods for GSH. Herein, we designed a reversible fluorescent probe (named GeP) for sensing GSH based on the nucleophilic addition and dissociation of intracellular GSH to GeP. The probe GeP showed a fast response time and a 20-fold fluorescence change toward GSH. It exhibited excellent mitochondrial-targeted performance and could be used to monitor GSH in mitochondria. Importantly, GeP could also enable superresolution fluorescence imaging of mitochondria through stochastic optical reconstruction microscopy.

In recent years, with the rapid development of automated driving technology, the task for achieving continuous, dependable, and high-precision vehicle navigation becomes crucial. The integration of the global navigation satellite system (GNSS) and inertial navigation system (INS), as a proven technology, is confined by the grade of inertial measurement unit and time-increasing INS errors during GNSS outages. Meanwhile, the ability of simultaneous localization and environment perception makes the vision-based navigation technology yield excellent results. Nevertheless, such methods still have to rely on global navigation results to eliminate the accumulation of errors because of the limitation of loop closing. In this case, we proposed a GNSS/INS/Vision integrated solution to provide robust and continuous navigation output in complex driving conditions, especially for the GNSS-degraded environment. Raw observations of multi-GNSS are used to construct double-differenced equations for global navigation estimation, and a tightly coupled extended Kalman filter-based visual-inertial method is applied to achieve high-accuracy local pose. The integrated system was evaluated in experimental validation by both the GNSS outage simulation and vehicular field experiments in different GNSS availability situations. The results indicate that the GNSS navigation performance is significantly improved comparing to the GNSS/INS loosely coupled solution in the GNSS-challenged environment.

Background: Poor ovarian response (POR), a manifestation of low ovarian reserve and ovarian aging, leads to a significant reduction in the pregnancy rate after in vitro fertilization-embryo transfer. Acupuncture has increasingly been used to improve the ovarian reserve. The purpose of this study will be to evaluate the effect of acupuncture on increasing the number of retrieved oocytes after controlled ovarian hyperstimulation in women with POR.Methods: This will be a multicenter randomized controlled trial. A total of 140 women with POR will be randomly assigned to receive acupuncture or nontreatment for 12 weeks before controlled ovarian hyperstimulation. The primary outcome will be the number of retrieved oocytes. The secondary outcomes will be antral follicle counts, serum levels of anti-Müllerian hormone, basal serum levels of follicle stimulating hormone, luteinizing hormone and estradiol levels, scores from the self-rating anxiety scale, fertilization rates, cleavage rates, available embryo rates and high-quality embryo rates. The safety of acupuncture will also be assessed.Discussion: The results of this trial will help to determine the effectiveness of acupuncture in the treatment of POR. This may provide a new treatment option for patients with POR and their physicians.Trial registration: AMCTR-IPR-18000198. Registered on 10 August 2018, http://www.acmctr.org/showproj.aspx?proj=289

MicroRNAs (miRNAs) have been improved to regulate oocyte development in a cell- or stage-specific manner. In this study, we aimed to clarify microRNA-224's (miR-224) role in cumulus cells (CCs), to find out whether a change level of miR-224 in CCs could influence the maturation of oocyte. We found that overexpression of miR-224 of CCs led to the impairment of cell expansion, along with a decrease in the gene expression associated with cell expansion and maturation of oocyte. The increased expression of miR-224 in CC interrupted oocyte cell cycle at the GV stage. The GDF9, BMP15 and ZP3 of the oocytes were also down-regulated. The following in vitro fertilization had yielded a lower number of oocytes from cumulus-oocyte complexes (COCs) overexpressing miR-224 when reaching the blastocyst stage. The suppressive effect of miR-224 in the maturation of COC is validated by the miR-224 knockdown model, where the expansion of cumulus cell was increased and oocyte was developed to MII stage. In addition, the expression of aromatase in CCs was down-regulated by miR-224, resulting in a decreased level of estradiol (E2). A further investigation found that miR-224 down-regulated the expression of protein and mRNA of Ptx3 by targeting its 3'UTR. Our study revealed that miR-224 regulates the gene expression and function of CCs, which influences the maturation of oocyte, at least in part, via targeting Ptx3.

Zeyu Wang,1 Chong Luo,1 Huidan Wang,2 Xia Yan,2 Wei Liu,1 Zengdong Meng1 1Department of Orthopaedics, The First People’s Hospital of Yunnan Province, Dali 650000, Yunnan, People’s Republic of China; 2Medical Faculty, Kunming University of Science and Technology, Dali 650000, Yunnan, People’s Republic of China Background: Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is a member of CEACAM family and has been reported to be upregulated in various types of human cancer and involved in tumor progression and metastasis. However, the biological roles and clinical significances of CEACAM6 in osteosarcoma still remain to be elucidated.Materials and methods: Real-time PCR, immunohistochemistry and Western blot analysis were used to determine CEACAM6 expression in osteosarcoma cell lines and clinical specimens. Then the clinical relevance of CEACAM6 was analyzed in osteosarcoma. The function of CEACAM6 in osteosarcoma was examined by wound-healing and cell invasion assays, and expression levels of epithelial–mesenchymal transition markers.Results: In the present study, we found that CEACAM6 was markedly upregulated in metastatic osteosarcoma tissues when compared with the nonmetastatic osteosarcoma tissues. Upregulation of CEACAM6 was significantly associated with lung metastasis status (P=0.006) in patients with osteosarcoma. Survival analyses suggested that osteosarcoma patients with high CEACAM6 expression had a significantly shorter overall survival time and lung metastasis-free survival time than those with low CEACAM6 expression. Knockdown of CEACAM6 inhibits osteosarcoma cell migration and invasion. Moreover, silencing CEACAM6 suppressed osteosarcoma cells epithelial–mesenchymal transition.Conclusion: Taken together, this study suggests that CEACAM6 might be a promising biomarker and a potential therapeutic target for the treatment of metastatic osteosarcoma. Keywords: CEACAM6, osteosarcoma, metastasis, epithelial–mesenchymal transition, prognosis

In this retrospective study, the relationship between demographic characteristics, past medical history, general lifestyle habits and susceptibility of premature ovarian failure (POF) in Han Chinese population was investigated. Five hundred and fifty-three patients with POF and 400 women with normal ovarian function were recruited. A questionnaire was designed to gather information from responders. Logistic regression was carried out to calculate odds ratios (OR), 95% confidence intervals (95% CI) and P-values. History of pelvic surgery, mumps, having relatives with menstrual abnormalities and exposure to chemical agents were significantly associated with increased risk of POF (OR 5.53 [2.15 to 14.23]; 3.26 [2.38 to 4.47]; 28.12 [8.84 to 89.46]; 4.47 [2.09 to 9.58]). Vegetarian diet, tea and mineral water consumption reduced the risk of POF (OR 0.27 [0.19 to 0.37]; 0.04 [0.03 to 0.07]; 0.63 [0.47 to 0.85], respectively). Heredity, pelvic surgery, mumps and exposure to chemical agents were identified as risk factors for POF, whereas vegetarian diet, tea consumption and mineral water drinking were protective. Therefore, genetic consultation could help those women whose relatives manifested an early or premature menopause to avoid the consequences of possible premature ovarian function cessation. Avoidance of exposure to endocrine disrupters and flavonoids intake should be considered.

The ZLC method is a simple and rapid approach to measure adsorption equilibrium isotherms. When extending this technique to the measurement of large concentration steps, the primary problem is how to estimate the outlet flowrate from the measured concentration signal. In this paper, two different corrections to calculate the outlet flowrate are introduced. Based on simulations of the ZLC system that are in good agreement with reported experimental results, a series of desorption cases were simulated. Isotherms were calculated using the two approximations of the outlet flowrate. The comparisons are used to identify the range in which the approximations are applicable. Darken’s thermodynamic correction factors were also calculated to verify the validity of the flow corrections.

Premature ovarian failure (POF) is a heterogeneous disease. Though dozens of candidate genes have been identified for the genetic etiology of POF, it is largely unexplained in majority of patients. Recently, Wt1+/R394W mice was found to present POF-like phenotype, which indicates that WT1 might be a plausible candidate gene for non-syndromic POF. The coding region of WT1 gene was screened in 384 patients with POF and 6 novel variations were identified, including two missense mutations (p. Pro126Ser in exon1 and p. Arg370His in exon7) and four intronic variants (c.647-27C > T, c.647-13G > C, c.647-13G > A in intron1 and c.950 + 14T > C in intron 4). In vitro experiments showed that both mutant p. Pro126Ser and p. Arg370His repressed the expression of Amh and Cdh1 and induced the expression of Fshr and Cyp19 in mRNA level (P AMH, FSHR, CYP19 and CDH1) are required for granular cells (GCs) proliferation, differentiation and oocyte-GCs interaction. The novel mutant p. P126S and p. R370H in the WT1 gene potentially impaired GCs differentiation and oocyte-GCs interaction, which might result in loss of follicles prematurely. Therefore, WT1 is a plausible causal gene for POF.

The coding region of the disrupted meiotic cDNA gene ( DMC1 ) was examined in 192 Chinese women with premature ovarian failure. Two known single-nucleotide polymorphisms, c.8632C>T in intron 4 and c.32377G>C in intron 10, were identified. The results suggest that mutations in the coding sequence of DMC1 are not associated with premature ovarian failure in Chinese women. The coding region of the disrupted meiotic cDNA gene ( DMC1 ) was examined in 192 Chinese women with premature ovarian failure. Premature ovarian failure is defined as secondary amenorrhoea, infertility, oestrogen deficiency, and elevated gonadotrophin concentration in women younger than 40 years. DMC1 is a meiosis-specific gene, encoding a protein essential for meiotic homologous recombination. It participates in the formation of synaptonemal complexes and repair of double-strand breaks at recombination hotspots. Two known single-nucleotide polymorphisms, c.8632C>T in intron 4 and c.32377G>C in intron 10, were identified. No additional single-nucleotide polymorphisms or mutations were found. The results suggested mutations in the coding sequence of DMC1 are not associated with premature ovarian failure in Chinese women.