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Abstract Background Transcervical resection of adhesions (TCRA) is the standard treatment for intrauterine adhesion (IUA). Previous studies have shown that postoperative oral estrogen or an intrauterine physical barrier could reduce the recurrence of IUA by promoting the proliferation of the endometrium or inhibiting the reformation of adhesions. Our team designed an intrauterine stent that can release estrogen within the uterine cavity slowly. In this study, we aimed to investigate the efficacy and safety of the estrogen-releasing intrauterine system in preventing the recurrence of moderate to severe IUA. Methods This was a multicenter prospective randomized controlled 2-arm parallel trial that included patients who were diagnosed with moderate to severe IUA and who received TCRA. A total of 250 patients were randomly assigned, at a 1:1 ratio, to receive the intrauterine estrogen-releasing system or a Foley catheter balloon combined with oral estrogen therapy after surgery. The primary outcome was the rate of adhesion reduction in the two groups. The secondary outcomes included endometrial thickness at the ovulation period, menstrual improvement rates, and other reported adverse events during follow-up. Results The average daily drug release amount for all the tested stents was 0.21 mg/day. At 60 days postoperatively, the rate of adhesion reduction was significantly greater in the experimental group than in the control group (93.33% vs. 58.56%, p

Abstract Knockout of GAS2 (growth arrest-specific protein 2), causes disorganization and destabilization of microtubule bundles in supporting cells of the cochlear duct, leading to hearing loss in vivo. However, the molecular mechanism through which GAS2 variant results in hearing loss remains unknown. By Whole-exome sequencing, we identified a novel heterozygous splicing variant in GAS2 (c.616–2 A > G) as the only candidate mutation segregating with late-onset and progressive nonsyndromic hearing loss (NSHL) in a large dominant family. This splicing mutation causes an intron retention and produces a C-terminal truncated protein (named GAS2mu). Mechanistically, the degradation of GAS2mu via the ubiquitin-proteasome pathway is enhanced, and cells expressing GAS2mu exhibit disorganized microtubule bundles. Additionally, GAS2mu further promotes apoptosis by increasing the Bcl-xS/Bcl-xL ratio instead of through the p53-dependent pathway as wild-type GAS2 does, indicating that GAS2mu acts as a toxic molecule to exacerbate apoptosis. Our findings demonstrate that this novel variant of GAS2 promotes its own protein degradation, microtubule disorganization and cellular apoptosis, leading to hearing loss in carriers. This study expands the spectrum of GAS2 variants and elucidates the underlying pathogenic mechanisms, providing a foundation for future investigations of new therapeutic strategies to prevent GAS2-associated progressive hearing loss.

The Ag nanoparticles demonstrate potent bacteria eradication capabilities; however, their tendency to aggregate in aqueous solutions compromises the antibacterial efficacy. Furthermore, the Ag nanoparticles employed in sewage treatment are challenging to recycle, resulting in environmental pollution and resource wastage. Herein, the Ag-core Fe3O4-shell structured particles (Ag@Fe3O4) are synthesized by leveraging the reduction potential difference between Ag+/Ag0 and Fe3+/Fe2+ through a one-step polyol reduction process. The Fe3O4 shell in the Ag@Fe3O4 composite not only effectively inhibits the agglomeration of Ag, but also enhances the penetration capability of the composite into biofilms, thereby enabling Ag@Fe3O4 to possess remarkable antibacterial efficacy against Escherichia coli (E. coli). The Ag@Fe3O4 demonstrates nearly 100 % inhibition of E. coli at a concentration of 0.24 mg mL−1 (with an Ag content of 0.042 mg mL−1) while still maintaining antibacterial effectiveness of 74.6 % even after undergoing reutilization for 10 cycles. Meanwhile, due to the excellent electron conductivity of Ag and the effective adsorption capability of Fe3O4 shell towards organic dyes, Ag@Fe3O4 facilitates rapid electron transfer to organic dyes and further lead to their reduction and degradation in the presence of NaBH4. The Ag@Fe3O4 can catalytically degrade various organic dyes (including Rhodamine B, Rhodamine 6G, and Methylene blue) within only 15 min, while achieving an impressive degradation efficiency exceeding 90.9 % after 6 cycles of reutilization. The cost-effectiveness (approximately $0.17 per gram), facile magnetic recovery, along with the superior antibacterial and dye-degradation performance showcase the significant potential of Ag@Fe3O4 for medical applications and sewage treatment.

IntroductionWith the increasing demand for health products derived from Polygonati rhizoma (PR), people begin to artificially plant Polygonatum cyrtonema Hua (P. cyrtonema) in the middle and lower reaches of the Yangtze River. To promote P. cyrtonema cultivation and increase farmers’ income, efforts are needed to understand the ways to obtain high-quality PR under artificial cultivation conditions.MethodsRhizomes of artificial planting P. cyrtonema and rhizosphere soils were collected across five regions in Zhejiang Province, China. Subsequently, the contents of the main active ingredients of P. cyrtonema and soil properties were analyzed, and both rhizosphere and endophytic bacteria of P. cyrtonema were detected by 16S rDNA sequencing. The relationship between the active ingredients and soil properties, and the dominant bacteria were investigated by correlation analysis.ResultsThe content of active ingredients of P. cyrtonema from the five regions varied significantly, especially polysaccharides and saponins. High-throughput sequencing demonstrated that Proteobacteria was the dominant bacterial phylum in all samples, and Burkholderia-Caballeronia-Paraburkholderia was the main endophytic bacterial genus in rhizome. In addition, the bacterial diversity and richness of rhizosphere soil samples were higher than those of rhizome samples. Soil physicochemical properties and enzyme activities were significantly different across regions, leading to notable variations in the community structures of rhizosphere and endophytic bacteria. Redundancy analysis (RDA) displayed that pH and urease (UE) were the major factors altering shifting rhizosphere bacteria community structure. Moreover, the composition and diversity of rhizome endophytic bacteria were principally affected by both soil physicochemical properties and soil enzyme activities. Soil properties and bacteria from rhizosphere soil and rhizome had a considerable impact on certain active ingredients in P. cyrtonema under artificial cultivation conditions after Pearson correlation analysis. Polysaccharides were significantly correlated with nutrient-rich soil and endophytic bacteria, such as Burkholderia-Caballeronia-Paraburkholderia, Pseudomonas, Ralstonia, and Bacillus. However, flavonoids were associated with nutrient-poor soil. Saponins were positively correlated with OM and available phosphorous (AP) and were significantly negatively affected by rhizosphere bacterial communities.ConclusionThe study demonstrated that bacterial microorganisms were involved in the accumulation of active ingredients of P. cyrtonema together with soil physicochemical properties and enzyme activities, which provided a theoretical basis for the scientific and effective artificial cultivation of high-quality P. cyrtonema.

Abstract Background Serum uric acid (SUA), an end-product of purine catabolism diffused in the blood, is positively associated with the risk of type 2 diabetes mellitus (T2DM). However, in the T2DM population, the association of SUA fluctuation ( $$\Delta$$ Δ SUA) with the functional outcome of ischemic stroke (IS) is still unclear. Accordingly, this study aimed to assess the correlation between $$\Delta$$ Δ SUA and short-term IS functional outcomes in T2DM patients. Methods All T2DM patients diagnosed with IS in the China National Stroke Registry III were included. $$\Delta$$ Δ SUA, which was defined as the difference between the SUA levels at baseline and 3 months after symptom onset, was classified into two groups, i.e., elevated $$\Delta$$ Δ SUA ( $$\Delta$$ Δ SUA > 0) and reduced $$\Delta$$ Δ SUA ( $$\Delta$$ Δ SUA $$\le$$ ≤ 0). The outcomes measured using the Modified Rankin Scale (mRS) were scored from 0 to 6, and poor functional outcome was defined as an mRS score of 3–6 at 3 months after IS. Results Among the 1255 participants (mean age: 61.6 ± 9.8 years), 64.9% were men. Patients with elevated $$\Delta$$ Δ SUA had a lower incidence of poor functional outcomes at 3 months. Compared with reduced $$\Delta$$ Δ SUA, elevated $$\Delta$$ Δ SUA at 0–50 μmol/L (odds ratio [OR] = 0.46, 95% confidence interval [CI] = 0.28–0.78, p = 0.004) and 50–100 μmol/L (OR = 0.40, 95% CI = 0.21–0.77, p = 0.006) was significantly correlated with a reduced risk of poor functional outcomes at 3 months. Conclusion This study showed that a moderate increase in $$\Delta$$ Δ SUA in the range of 0–100 μmol/L at 3 months after IS might be beneficial in T2DM adults and more studies are warranted to confirm this.

This paper, starting from the effects of financial regulatory policies, considers the interaction between Chengxin_Moody and Lianhe_Fitch with the dual rating system and the multi-rating system, constructs a new ordered Logit model, and attempts to explore the impact of the Notice, the dual rating system and the multiple rating system on the probability of Chinese corporate bond defaults, rating upgrades, rating downgrades, and the magnitude of credit rating migrations. This study compares the effectiveness of different rating regulatory systems. Using nine thousand two hundred and sixty-two data of Chinese corporate bonds as the research samples. Empirical analysis and robustness test reveal the following findings: (1) The issuance of the Notice has a significant positive effect on the implementation of both the dual rating system and the multiple rating system, with a greater impact on the implementation of the multiple rating system; (2) The issuance of the Notice, along with the dual rating system and the multiple rating system, can all reduce the probability of corporate bond defaults, with the multiple rating system showing the best preventive effect against corporate bond defaults; (3) The dual rating system is more effective in promoting rating agencies to adjust rating behaviors, accurately correcting corporate bond ratings and effectively alleviating the issue of rating inflation. Competition among rating agencies intensifies rating shopping; (4) Under the dual rating system, rating agencies are more likely to expand the magnitude of credit rating upgrades and downgrades, enhancing the differentiation between high-quality corporate bonds and junk corporate bonds; (5) The selection of rating information from Chengxin_Moody and Lianhe_Fitch can appropriately adjust the degree of flexibility or tightening in response to rating regulatory systems. Chengxin_Moody demonstrates a more sensitive reaction compared to Lianhe_Fitch regarding the rating regulatory systems. This study provides valuable references for the formulation and evaluation of the effectiveness of Chinese corporate bond rating regulatory policies.

BackgroundHeadache is one of the most common symptoms of acute COVID-19 infection. However, its mechanisms remain poorly understood, and there is a lack of studies investigating changes in the periaqueductal gray (PAG) in COVID-19 patients exhibiting headaches.PurposeThe study aimed to explore the alterations in metabolites of the PAG pre- and post-COVID-19 infection in individuals who suffered from headaches during the acute phase of the disease using proton magnetic resonance spectroscopy (1H-MRS).MethodsFifteen participants who experienced headaches during the acute phase of COVID-19 were recruited. All subjects underwent two proton magnetic resonance spectroscopy (1H-MRS) examinations focusing on the PAG before and after they were infected. Metabolite changes were assessed between the pre- and post-infection groups.ResultsThe combined glutamine and glutamate/total creatine ratio (Glx/tCr) was increased in the PAG following COVID-19 infection. The total choline/total creatine ratio (tCho/tCr) in the pre-infection group was negatively correlated with the duration of headache during the COVID-19 acute phase.ConclusionThe present study indicates that PAG plays a pivotal role in COVID-19 headaches, thereby supporting the involvement of trigeminovascular system activation in the pathophysiology of COVID-19 headaches.

Objective To evaluate whether Zi Gui Nv Zhen capsules (ZGNZC) can increase the fertility rate of Chinese women with infertility due to thin endometrium.Methods Prospective, randomized, open-labeled 3-monthly study; 104 patients (aged 20–40 years) receiving either ZGNZC (experimental group, n = 55) or not (control group, n = 49). Main outcomes: thickness/type of the endometrium during ovulation and pregnancy rate. Between-group analysis (A) compares the experimental vs. control group, and within-group analysis (B) compares data at baseline and after study in the experimental group.Results (A) Between-group-analysis: Patients with ZGNZC had a higher endometrium thickness (0.8 ± 0.27 vs. 0.68 ± 0.10; p

Abstract Background The study was designed to explore the correlation of the asymmetric regulation between periaqueductal gray (PAG) and bilateral trigeminal nucleus caudalis (TNC) in migraine rats through studying the changes of metabolites in pain regulatory pathway of acute migraine attack. Methods Thirty male Sprague–Dawley (SD) rats were randomly divided into three groups: blank, control, model groups. Then, blank group was intraperitoneally injected with ultrapure water, while control group injected with saline and model group injected with Glyceryl Trinitrate (GTN). Two hours later, PAG and bilateral TNC were removed respectively, and metabolite concentrations of PAG, Left-TNC, Right-TNC were obtained. Lastly, the differences of metabolite among three brain tissues were compared. Results The relative concentrations of rNAA, rGlu, rGln, rTau, rMI in PAG or bilateral TNC had interaction effects between groups and sites. The concentration of rLac of three brain tissues increased in migraine rats, however, the rLac of LTNC and RTNC increased more than that of PAG. Besides, the concentrations of rNAA and rGln increased in RTNC, while rGABA decreased in RTNC. Conclusions There is correlation between PAG, LTNC and RTNC in regulation of pain during acute migraine attack, and the regulation of LTNC and RTNC on pain is asymmetric.

Flavonoids, a class of phenolic compounds, are one of the main functional components and have a wide range of molecular structures and biological activities in Polygonatum. A few of them, including homoisoflavonoids, chalcones, isoflavones, and flavones, were identified in Polygonatum and displayed a wide range of powerful biological activities, such as anti-cancer, anti-viral, and blood sugar regulation. However, few studies have systematically been published on the flavonoid biosynthesis pathway in Polygonatum cyrtonema Hua. Therefore, in the present study, a combined transcriptome and metabolome analysis was performed on the leaf, stem, rhizome, and root tissues of P. cyrtonema to uncover the synthesis pathway of flavonoids and to identify key regulatory genes. Flavonoid-targeted metabolomics detected a total of 65 active substances from four different tissues, among which 49 substances were first study to identify in Polygonatum, and 38 substances were flavonoids. A total of 19 differentially accumulated metabolites (DAMs) (five flavonols, three flavones, two dihydrochalcones, two flavanones, one flavanol, five phenylpropanoids, and one coumarin) were finally screened by KEGG enrichment analysis. Transcriptome analysis indicated that a total of 222 unigenes encoding 28 enzymes were annotated into three flavonoid biosynthesis pathways, which were “phenylpropanoid biosynthesis”, “flavonoid biosynthesis”, and “flavone and flavonol biosynthesis”. The combined analysis of the metabolome and transcriptome revealed that 37 differentially expressed genes (DEGs) encoding 11 enzymes (C4H, PAL, 4CL, CHS, CHI, F3H, DFR, LAR, ANR, FNS, FLS) and 19 DAMs were more likely to be regulated in the flavonoid biosynthesis pathway. The expression of 11 DEGs was validated by qRT-PCR, resulting in good agreement with the RNA-Seq. Our studies provide a theoretical basis for further elucidating the flavonoid biosynthesis pathway in Polygonatum.

Polygonatum cyrtonema Hua, an edible resource and medical material, is mainly consumed as a food in China. However, few published studies have comprehensively assessed its nutritional components. In this study, the proximate, carbohydrate, and dietary fiber contents as well as the mineral, vitamin, and amino acid compositions of five sources of P. cyrtomena grown in Yuhang district, Hangzhou city, Zhejiang province, were investigated. The nutritional profile of the five germplasms was investigated using analytical chemistry methods. All germplasms had a low starch content and contained greater amounts of carbohydrates (23.25–34.29%), protein (2.96–5.40%), Ca (195.08–282.08 mg/100 g), Fe (29.68–59.37 mg/100 g), and vitamin C (60.49–149.86 mg/100 g) in comparison to ginger, yam, and potatoes. The polysaccharide content ranged from 16.92% to 28.48%, representing the main source of carbohydrates. Fructose, a desirable sweetener, was the most abundant monosaccharide, representing 1.06% to 4.88% of the content. P. cyrtonema was found to be high in dietary fiber, with pectin and resistant starch being the major soluble components and hemicellulose being the dominant insoluble dietary fiber. A correlation analysis (CA) revealed significant correlations for the carbohydrate components and dietary fiber fractions with other nutrients. A principal component analysis (PCA) identified significant differences between the nutritional characteristics of the five germplasms, with Huanggang having the highest comprehensive quality scores. Moreover, ten nutrient components were selected as potential indicators that could be used to further evaluate the nutritional quality of P. cyrtomena. Our results demonstrate the rich nutrient composition and characteristics of P. cyrtonema and provide a valuable reference for the future development and utilization of Polygonatum.

Abstract This paper focuses on how to obtain globally optimal multisensor data association results under the condition that the number of targets is unknown. This problem is likely to occur in scenarios where the sensors’ fields of view (FoVs) are limited. The authors proved that, ideally, the cost of the association result is a convex function of the assumed target number and with the minimal value only if the target number is correctly assumed. Based on this, a multiple hypothesis S‐dimensional assignment (MHSDA) algorithm is proposed, which replaces the traditional irrevocable onetime assumption with a multiple hypothesis approach to counteract the effect of target number uncertainty. Furthermore, a hybrid implementation architecture based on Union Find plus MHSDA is proposed to ensure the real‐time performance. The proposed algorithm requires neither prior knowledge on the number of targets nor on the FoVs of sensors and is applicable to target dense scenarios. Simulation results under different FoV, target number and measurement noise configurations demonstrate the effectiveness of the proposed algorithm.

Gene therapy would benefit from the effective editing of targeted cells with CRISPR-Cas9 tools. However, it is difficult to precisely assess the editing performance in vivo because the tissues contain many non-targeted cells, which is one of the major barriers to clinical translation. Here, in the Atoh1-GFP;Kcnq4+/G229D mice, recapitulating a novel mutation we identified in a hereditary hearing loss pedigree, the high-efficiency editing of CRISPR-Cas9 in hair cells (34.10% on average) was precisely detected by sorting out labeled cells compared with only 1.45% efficiency in the whole cochlear tissue. After injection of the developed AAV_SaCas9-KKH_sgRNA agents, the Kcnq4+/G229D mice showed significantly lower auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) thresholds, shorter ABR wave I latencies, higher ABR wave I amplitudes, increased number of surviving outer hair cells (OHCs), and more hyperpolarized resting membrane potentials of OHCs. These findings provide an innovative approach to accurately assess the underestimated editing efficiency of CRISPR-Cas9 in vivo and offer a promising strategy for the treatment of KCNQ4-related deafness.

Abstract Background Spinal cord injury (SCI) causes devastating neurological damage, including secondary injuries dominated by neuroinflammation. The role of Apelin, an endogenous ligand that binds the G protein-coupled receptor angiotensin-like receptor 1, in SCI remains unclear. Thus, our aim was to investigate the effects of Apelin in inflammatory responses and activation of endogenous neural stem cells (NSCs) after SCI. Methods Apelin expression was detected in normal and injured rats, and roles of Apelin in primary NSCs were examined. In addition, we used induced pluripotent stem cells (iPSCs) as a carrier to prolong the effective duration of Apelin and evaluate its effects in a rat model of SCI. Results Co-immunofluorescence staining suggested that Apelin was expressed in both astrocytes, neurons and microglia. Following SCI, Apelin expression decreased from 1 to 14 d and re-upregulated at 28 d. In vitro, Apelin promoted NSCs proliferation and differentiation into neurons. In vivo, lentiviral-transfected iPSCs were used as a carrier to prolong the effective duration of Apelin. Transplantation of transfected iPSCs in situ immediately after SCI reduced polarization of M1 microglia and A1 astrocytes, facilitated recovery of motor function, and promoted the proliferation and differentiation of endogenous NSCs in rats. Conclusion Apelin alleviated neuroinflammation and promoted the proliferation and differentiation of endogenous NSCs after SCI, suggesting that it might be a promising target for treatment of SCI.

The location identification of dynamic load is an important part of load-identification technology. Traditional methods are mostly aimed at the identification of dynamic load’s amplitude and phase. A new method for dynamic load location identification is proposed in this paper. An amplitude ratio or a phase difference between structural dynamic response signals is only related to the frequency response function (FRF), which is a complex-valued function that implies the location information of the load to be identified. In this method, the amplitude and phase variables of the excitation can be eliminated with symbolic calculations, and the location variables can be extracted from the FRF in a complex-number field. An excitation location can be identified quickly with parameter optimization using a Genetic Algorithm (GA), avoiding the ill-posed problem caused by matrix inversion. Numerical simulations and experiments demonstrate that this method can realize the fast recognition of several excitation positions, and has a high recognition accuracy, a short calculation time and a strong anti-noise ability.

Summary: Testosterone is essential to human growth and development as well as immune regulation. Zika virus (ZIKV), an emerging arbovirus associated with neurological complications including neuroinflammation, can also cause testicular damage and decrease testosterone secretion. However, whether the dysregulation of testosterone plays a role in the process of neuroinflammation during ZIKV pathogenesis is still unclear. In this study, we found that ZIKV infection caused testicular damage and decreased testosterone secretion in male mice, and testosterone supplementation after ZIKV infection reduced their mortality and attenuated the pathological symptoms. Further investigation revealed that testosterone treatment after ZIKV infection alleviated inflammation and nerve injury in the mouse brain. Additionally, reduced CD8+ T cell infiltration and interferon-gamma production were observed in brains of testosterone-treated mice. Overall, our results demonstrated that testosterone plays a protective role in ZIKV-infected mice, and thus it can be developed as a potential therapeutic drug against ZIKV infection.

Objective: To explore the progress and prospect of evaluation methods for infertility patients. Methods: From September 2017 to December 2020, 199 cases of infertility patients who have accepted mini-hysteroscopy examination in the Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. The patients who had primary ovary insufficiency, tubal infertility were excluded; patients with hysteroscopy contradiction, such as acute or sub-acute vaginal tract inflammation, endometrium lesion or endometrium carcinoma, severe cardiovascular, liver or kidney insufficiency were excluded. 40 patients were excluded and 15 patients lost follow up, 144 patients were eventually included in the analysis. The patient's age, body mass index, infertility etiology, preoperative and postoperative stimulate ovulation cycle, pregnancy state and pregnancy time were recorded. The effect of mini-hysteroscopy on ovulation induction cycle was analyzed in pregnant patients. Results: The average age of 144 patients was 32.10±4.67 years old. 96 (66.67%) patients were found to have intrauterine abnormalities, while 48 (33.33%) patients were found to have normal intrauterine cavity. 48 cases of pregnancy, accounting for 33.33%; the median and interquartile ranges [M (Q1, Q3)] of ovulation induction cycles before and after surgery were respectively [3 (0, 5)], [2 (1,3)], the difference was statistically significant (P

Abstract Based on the random finite set (RFS) framework and the probability hypothesis density (PHD) filter, the extended target PHD (ET‐PHD) filter is proposed for multiple extended target tracking. However, the clutter process in the ET‐PHD filter is modelled as Poisson RFS, which is reasonable for only some scenarios in reality. An easily implemented ET‐PHD filter for arbitrary clutter process, has not yet been studied. In this work, another form of the general PHD filter, suitable for arbitrary clutter and target measurement is derived using a probability generating functional (PGFL)‐based RFS framework. The proposed filter is equivalent to the general PHD filter proposed by Clark and Mahler, but it is easily implemented in an arbitrary clutter process because its clutter process is denoted by the probability density function . Then, an arbitrary clutter ET‐PHD (AC‐ET‐PHD) filter is simplified from the general PHD filter derived by us. To reduce the computational complexity of the proposed filter, a variant of the distance partitioning algorithm is put forward. Simulation results show that the AC‐ET‐PHD filter can be applied to the scenarios with the non‐Poisson clutter process, which means that it will be useful for multiple extended targets tracking in a more complicated clutter process.

In thin-slab continuous casting, due to the influence of the special shape of the funnel mold, cracks at the corner of the slab shell are more likely to occur than those in conventional slab shells, and a serious wear phenomenon also appears on the narrow face of the copper wall of the mold. Aimed at the corner cracks of thin slabs and the wear phenomenon of the copper wall, a new 3D stress analysis model in a funnel mold has been developed to simulate the stress-–train behavior of the slab shell under high-speed continuous casting. The results show that at the position 600 mm below the meniscus, the gap begins to appear at the corner of the slab; the maximum value of the first principal stress appears at the corner. The shell is squeezed by the copper wall during the downward movement in the funnel mold, and the slab shell in the funnel area moves towards the narrow face. The displacement causes the deformation of the slab shell to extend to the corners, the deformed shell is pressed against the corner of the copper wall. A new type of copper wall was designed for production, and it was found that the cracks at the corner of the slab shell were greatly reduced.

Context Physcion (Phy) exerts several pharmacological effects including anti-inflammatory, antioxidant, and antitumor properties. Objective This study investigates the cytotoxicity and its underlying mechanisms of Phy on breast cancer. Materials and methods Human breast cancer cell MCF-7 was treated with 5–400 µM Phy for 24 h, MCF-7-xenografted BALB/c nude mice and immunosuppressive mice model induced by cyclophosphamide were intraperitoneally injected with 0.1 mL/mouse normal saline (control group) and 30 mg/kg Phy every other day for 14 or 28 days, and pathological examination, ELISA and western blot were employed to investigate the Phy anti-breast cancer property in vitro and in vivo. Results In MCF-7 cells, Phy 24 h treatment significantly reduced the cell viability at dose of 50–400 µM and 24 h, with an IC50 of 203.1 µM, and 200 µM Phy induced 56.9, 46.9, 36.9, and 46.9% increment on LDH and caspase-3, −8 and −9. In MCF-7-xenograft tumour nude mice and immunosuppressive mice, 30 mg/kg Phy treatment inhibited tumour growth from the 8th day, and reduced Bcl-2 and Bcl-xL >50%, HO-1 and SOD-1 > 70% in tumour tissues of immunosuppressive mice. In addition, Phy reduced nuclear factor erythroid 2-related factor 2 > 30% and its downstream proteins, and enhanced the phosphorylation of nuclear factor-kappa B > 110% and inhibitor of NF-кB α > 80% in the tumour tissues of BALB/c mice. Discussion and conclusions This research demonstrated that Phy has an anti-breast cancer property via the modulation of oxidative stress-mediated mitochondrial apoptosis and immune response, which provides a scientific basis for further research on its clinical applications.

Abstract For the extremely small size and low signal‐to‐clutter ratio, target detection in infrared images is still a considerable challenge. Specifically, it is very difficult to detect the point targets because there is no texture and shape information can be used. A target‐oriented shallow‐deep feature‐based detection algorithm is proposed, opening up a promising direction for convolutional neural network‐based infrared dim small target detection algorithms. To ensure that small target instances can be used correctly for networks, the effective small anchor is designed according to the shallow layer of ResNet50. To determine whether a detection result belongs to the target, the authors depend on whether the detection centre is included in the ground truth area, rather than on the Intersection Over Union overlap rate, which avoids misjudging the detection result. In this way, small targets can be trained and detected correctly through ResNet50. More importantly, the authors demonstrate that spatially finer shallow features are crucial for small target detection and that semantically stronger deep features are helpful for improving detection probability. Experimental results on simulation data sets and real data sets show that the proposed algorithm can detect the point target when the local signal‐to‐clutter ratio is approximately 1.3, displaying infinite advantage and great potentiality.

Abstract The traditional way of passive sensor data association relies on the estimation of candidate target position, and hence suffers from severe performance degradation due to the estimation error and the so‐called ghosts. The proposed new cost function is based on epipolar geometry theory that uses fundamental matrix to measure the correlation between sensor measurements directly without estimation of candidate target position. This approach has two superiorities: (1) it declines the accuracy loss caused by a large number of trigonometric operations, and (2) it greatly immunes to the impact of ghosts. A comparison with three traditional cost functions via numerical experiments demonstrates that the proposed cost function significantly improves the accuracy of data association, especially when the number of targets is more and the sensor distribution is closer.

A scheme for improving entanglement is proposed by repeatedly performing number-conserving generalized superposition of products (GSP) operation, i.e., saa†+ta†amwith s2+t2=1,on each modes of even entangled coherent state (EECS). Both Einstein–Podolsky–Rosen (EPR) correlation and concurrence are used as the measures for describing entanglement. It is found that both single-mode and two-mode-symmetric GSP operations can be used for the entanglement improvement. In particular, for the optimal EPR correlation, the GSP-EECS with two-mode-symmetric first-order operations presents a better performance for the entanglement improvement than the cases of high-order GSP operations. Compared to several special non-Gaussian operations, including photon subtraction-then-addition (PSTA) (s=0)and photon-addition-then-subtraction (PATS) (s=1), it is shown that the entanglement of GSP-EECS is always superior to those of both PSTA-EECS and PATS-EECS at a small amplitude level. When the GSP-EECS is used as the entangled resource for teleportation, our optimal teleportation fidelity presents the best performance.

Background: The close relationship between colorectal cancer and inflammation has been widely reported. However, the relationship between colorectal cancer and inflammation at the genetic level is not fully understood.Method: From a genetic perspective, this study explored the relationship between inflammation-related genes and the immune microenvironment in colorectal cancer. We identified prognostic genes, namely CX3CL1, CCL22, SERPINE1, LTB4R, XCL1, GAL, TIMP1, ADIPOQ, and CRH, by using univariate and multivariate regression analyses. A risk scoring model for inflammatory response was established, and patients in The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were divided into two groups: high risk group and low risk group.Results: The analysis showed that the prognosis of the two groups was significantly different, and the low-risk group had a higher survival rate and longer survival time. Pathways related to apoptosis, inflammatory response, and hypoxia were significantly enriched as shown via Gene Set Enrichment Analysis (GSEA). Activated dendritic cell infiltration was found in both the TCGA and GEO databases, and the CCL21 gene played a significant role in the process of activated dendritic cell infiltration. CCL21 gene was also positively correlated with inflammatory response, and the gene expression and risk score were significantly different between the two groups.Conclusion: In summary, inflammatory response has a direct impact on patients with colorectal cancer in the prognosis and immune infiltration and further research studies on the inflammatory response can help in advancing the development of immunotherapy for colorectal cancer.

ObjectiveMild cognitive impairment (MCI) is a common, chronic, and complex disease in the elderly, which is often influenced by a variety of factors that include nutrition and inflammation. This study was undertaken to evaluate the mediation effects of inflammation on the association between vitamin D levels and MCI.MethodsWe explored the associations of inflammation and cognitive impairment related to 25(OH)D3 deficiency among 360 older people from the communities in China. Demographic characteristics, lifestyle, and health status were investigated by questionnaire, cognitive function was detected by MoCA, and plasma 25(OH)D3, interleukin-1β (IL-1β), and interleukin-18 (IL-18) were measured by ELISA. Spearman’s correlation analysis and logistic regression analysis were used to analyze the relationship among 25(OH)D3, IL-1β, and IL-18 in the MCI group and the control group and further to analyze the relationship between 25(OH)D3 and inflammatory factors in the MCI group. Finally, mediation analysis was performed to evaluate whether inflammation mediated the effect of 25(OH)D3 deficiency on cognitive impairment.ResultsThere were lower plasma 25(OH)D3 concentration and higher IL-1β and IL-18 levels in the MCI group compared with the controls. The levels of 25(OH)D3 were positively correlated with the MoCA scores and scores of different domains; the levels of IL-1β and IL-18 were negatively correlated with them (p < 0.05). In multivariate logistic analysis, there were significant associations among 25(OH)D3, IL-1β, IL-18, and MCI after adjusted. Further analysis revealed the significant association between the subjects with VD deficiency and the highest quartile of IL-18 in MCI (OR = 4.066), not with IL-1β after adjusting the confounding variables in MCI group. Ultimately, mediation analysis suggested that IL-1β and IL-18 could explain 25.4 and 17.5% of effect of the risk of cognitive impairment related to 25(OH)D3 deficiency.ConclusionOur findings suggested that 25(OH)D3 deficiency could increase the risk of cognitive impairment by a mechanism partly involving inflammation. Therefore, vitamin D supplementation may improve or delay the decline in cognitive function caused by inflammation in the elderly.

Context Alcoholic liver disease, caused by abuse and consumption of alcohol, exhibits high morbidity and mortality. Boletus aereus Bull. (Boletaceae) (BA) shows antioxidant, anti-inflammatory and antimicrobial effects. Objectives To investigate the hepatoprotective effects of BA using an acute alcohol-induced hepatotoxicity mice model. Materials and methods The composition of BA fruit body was first systematically analyzed. Subsequently, a C57BL/6 mice model of acute alcohol-induced liver injury was established by intragastrically administration of alcohol, which was intragastrically received with BA powder at 200 mg/kg and 800 mg/kg for 2 weeks, 60 mg/kg silybin treatment was used as positive control group. By employing the pathological examination, ELISA, RT-PCR and western blot, the regulation of BA on oxidative stress signals was investigated. Results The LD50 of BA was much higher than 4 g/kg/p.o. In acute alcohol-damaged mice, BA reduced the levels of alanine aminotransferase (>18.3%) and aspartate aminotransferase (>27.6%) in liver, increased the activity of liver alcohol dehydrogenase (>35.0%) and serum acetaldehyde dehydrogenase (>18.9%). BA increased the activity of superoxide dismutase (>13.4%), glutathione peroxidase (>11.0%) and 800 mg/kg BA strongly reduced chemokine (C-X-C motif) ligand 13 (14.9%) and chitinase-3 like-1 protein (13.4%) in serum. BA reversed mRNA over-expression (>70%) and phosphor-stimulated expression (>45.0%) of an inhibitor of nuclear factor κ-B kinase (NF-κB, an inhibitor of nuclear factor κ-B α and nuclear factor κ-B in the liver. Conclusions BA is effective in ameliorating alcohol-induced liver injury through regulating oxidative stress-mediated NF-κB signalling, which provides a scientific basis for further research on its clinical applications.

Background. Resting-state functional MRI is widely used in migraine research. However, the pathophysiology and imaging markers specific for migraine pathologies are not well understood. In this study, we combined both structural and functional images to explore the concurrence and process of migraines. Methods. Thirty-four patients with a history of migraine without aura presenting during the interictal period (MwoA-DI), 10 patients with migraine without aura presenting during the acute attack (MwoA-DA), and 32 healthy controls (HCs) were recruited in this study. All participants underwent scanning via MRI. Voxel-based morphometry (VBM) and seed-based resting-state functional connectivity (rs-FC) analysis were used to detect the brain structural and associated brain functional connectivity. Results. In VBM analysis, a decrease of gray matter volume (GMV) in the middle frontal cortex was found in MwoA patients compared with HCs. The GMV of the middle frontal cortex had a negative correction with the duration of disease. In rs-FC analysis, the left middle frontal cortex (lower, VBM result) in both the MwoA-DA and the HC groups showed significantly increased functional connectivity with the left middle frontal cortex (upper) and left superior frontal cortex compared with MwoA-DI. The left middle frontal cortex (lower) in the MwoA-DI group also showed decreased functional connectivity in the left posterior cingulate cortex (PCC) compared with the HC group. The left middle frontal cortex (lower) in the MwoA-DA group demonstrated significantly increased functional connectivity in the left cerebellum lobule VI compared with the HC group. Conclusions. Our results demonstrated that the middle frontal cortex may serve as an important target in the frequency and severity of migraines due to its role in pain regulation through the default mode network, especially in the PCC. In addition, the cerebellum may modulate the pathophysiology of migraines by serving as a communication point between the cortex and the brainstem.

Cervical carcinoma (CC) is the second most prevalent gynecologic cancer in females across the world. To obtain a better understanding of the mechanisms underlying the development of CC, high-resolution label-free mass spectrometry was performed on CC and adjacent normal tissues from eight patients. A total of 2631 proteins were identified, and 46 significant differently expressed proteins (DEPs) were found between CC and normal tissues (p < 0.01, fold change >10 or

Tea polyphenols (TP) are the main active components of tea. In our study, the effect of TP on the menopause and aging related memory decline and the mechanisms focused on the brain glucose metabolism were clarified. In vivo, ovariectomy (OVX) combined with D-galactose (D-gal) injection were used to establish the memory decline model. TP administration improved the spatial memory by increasing the expressions of GLUT1, 3 and Tau protein O-GlcNAc glycosylation, decreasing Tau hyper-phosphorylation and the Aβ1-42 level, and improving the morphology of mitochondria in hippocampus. Furthermore, in vitro, PC12 cells were treated with Aβ1-42 and EGCG treatment regulated the mitochondrial respiratory function and glycolytic functions, improved the activities of the key enzymes in glycolysis and tricarboxylic acid cycle, increased the SOD activity and decreased the MDA levels in cells. Our study suggests that TP improve the memory in aging ovariectomized rats by regulating brain glucose metabolism.

ABSTRACT Type I interferon (IFN-I) is a key component of the host innate immune system. To establish efficient replication, viruses have developed several strategies to escape from the host IFN response. Japanese encephalitis virus (JEV) NS1′, a larger NS1-related protein, is known to inhibit the mitochondrial antiviral signaling (MAVS)-mediated IFN-β induction by increasing the binding of transcription factors (CREB and c-Rel) to the microRNA 22 (miRNA-22) promoter. However, the mechanism by which NS1′ induces the recruitment of CREB and c-Rel onto the miRNA-22 promoter is unknown. Here, we found that JEV NS1′ protein interacts with the host cyclin-dependent kinase 1 (CDK1) protein. Mechanistically, NS1′ interrupts the CDC25C phosphatase-mediated dephosphorylation of CDK1, which prolongs the phosphorylation status of CDK1 and leads to the inhibition of MAVS-mediated IFN-β induction. Furthermore, the CREB phosphorylation and c-Rel activation through the IκBα phosphorylation were observed to be enhanced upon the augmentation of CDK1 phosphorylation by NS1′. The abrogation of CDK1 activity by a small-molecule inhibitor significantly suppressed the JEV replication in vitro and in vivo. Moreover, the administration of CDK1 inhibitor protected the wild-type mice from JEV-induced lethality but showed no effect on the MAVS–/– mice challenged with JEV. In conclusion, our study provides new insight into the mechanism of JEV immune evasion, which may lead to the development of novel therapeutic options to treat JEV infection. IMPORTANCE Japanese encephalitis virus (JEV) is the main cause of acute human encephalitis in Asia. The unavailability of specific treatment for Japanese encephalitis demands a better understanding of the basic cellular mechanisms that contribute to the onset of disease. The present study identifies a novel interaction between the JEV NS1′ protein and the cellular CDK1 protein, which facilitates the JEV replication by dampening the cellular antiviral response. This study sheds light on a novel mechanism of JEV replication, and thus our findings could be employed for developing new therapies against JEV infection.

Flaviviruses are the major emerging arthropod-borne pathogens globally. However, there is still no practical anti-flavivirus approach. Therefore, existing and emerging flaviviruses desperately need active broad-spectrum drugs. In the present study, the antiviral effect of steroidal dehydroepiandrosterone (DHEA) and 23 synthetic derivatives against flaviviruses such as Japanese encephalitis virus (JEV), Zika virus (ZIKV), and Dengue virus (DENV) were appraised by examining the characteristics of virus infection both in vitro and in vivo. Our results revealed that AV1003, AV1004 and AV1017 were the most potent inhibitors of flavivirus propagation in cells. They mainly suppress the viral infection in the post-invasion stage in a dose-dependent manner. Furthermore, orally administered compound AV1004 protected mice from lethal JEV infection by increasing the survival rate and reducing the viral load in the brain of infected mice. These results indicate that the compound AV1004 might be a potential therapeutic drug against JEV infection. These DHEA derivatives may provide lead scaffolds for further design and synthesis of potential anti-flavivirus potential drugs.

The detection and tracking of small targets under low signal-to-clutter ratio (SCR) has been a challenging task for infrared search and track (IRST) systems. Track-before-detect (TBD) is a widely-known algorithm which can solve this problem. However, huge computation costs and storage requirements limit its application. To address these issues, a dynamic programming (DP) and multiple hypothesis testing (MHT)-based infrared dim point target detection algorithm (DP–MHT–TBD) is proposed. It consists of three parts. (1) For each pixel in current frame, the second power optimal merit function-based DP is designed and performed in eight search areas to find the target search area that contains the real target trajectory. (2) In the target search area, the parallel MHT model is designed to save the tree-structured trajectory space, and a two-stage strategy is designed to mitigate the contradiction between the redundant trajectories and the requirements of more trajectories under low SCR. After constant false alarm segmentation of the energy accumulation map, the preliminary candidate points can be obtained. (3) The target tracking method is designed to eliminate false alarms. In this work, an efficient second power optimal merit function-based DP is designed to find the target search area for each pixel, which greatly reduces the trajectory search space. A two-stage MHT model, in which pruning for the tree-structured trajectory space is avoided and all trajectories can be processed in parallel, is designed to further reduce the hypothesis space exponentially. This model greatly reduces computational complexity and saves storage space, improving the engineering application of the TBD method. The DP–MHT–TBD not only takes advantage of the small computation amount of DP and high accuracy of an exhaustive search but also utilizes a novel structure. It can detect a single infrared point target when the SCR is 1.5 with detection probability above 90% and a false alarm rate below 0.01%.

BackgroundHelicobacter pylori (H. pylori) is a type I biological carcinogen, which may cause about 75% of the total incidence of gastric cancer worldwide. H. pylori infection can induce and activate the cancer-promoting signaling pathway and affect the occurrence and outcome of gastric cancer through controlling the regulatory functions of long non-coding RNAs (lncRNAs). However, we have no understanding of the prognostic worth of lncRNAs for gastric cancer patients infected with H. pylori.MethodWe screened differentially expressed lncRNAs using DESeq2 method among TCGA database. And we built the H. pylori infection-related lncRNAs regulatory patterns. Then, we constructed H. pylori infection-based lncRNAs prognostic signatures for gastric cancer patients together with H. pylori infection, via uni-variable and multi-variable COX regression analyses. Based on receiver operator characteristic curve (ROC) analysis, we evaluated the prediction effectiveness for this model.ResultsWe identified 115 H. pylori infection–related genes were differentially expressed among H. pylori–infected gastric cancer tissues versus gastric cancer tissues. Functional enrichment analysis implies that H. pylori infection might interfere with the immune-related pathways among gastric cancer tissues. Then, we built H. pylori infection–related dys-regulated lncRNA regulatory networks. We also identified 13 differentially expressed lncRNAs were associated with prognosis for gastric cancer patients together with H. pylori infection. Kaplan-Meier analysis demonstrated that the lncRNA signatures were correlated with the poor prognosis. What is more, the AUC of the lncRNA signatures was 0.712. Also, this prognostic prediction model was superior to the traditional clinical characters.ConclusionWe successfully constructed a H. pylori–related lncRNA risk signature and nomogram associated with H. pylori–infected gastric cancer patients prognosis, and the signature and nomogram can predict the prognosis of these patients.

Abstract Background Gastric cancer, as a multifactorial disorders, shows cytological and architectural heterogeneity compared to other gastrointestinal cancers, making it therapeutically challenging. Cisplatin is generally used in clinic for gastric cancer treatment but with toxic side effects and develops resistance. Anti-tumor properties of copper and its coordinated compounds have been explored intensively in recent years. Methods In this study, we synthesized a novel Schiff base copper coordinated compound (SBCCC) and examined its antitumor effects in two gastric cancer cell lines SGC-7901 and BGC-823 as well as a mouse model of gastric cancer. Results The results show that SBCCC can significantly inhibit the proliferation of gastric cancer cells in a dose- and time-dependent manner. The IC50 of SBCCC in SGC-7901 and BGC-823 cells is 1 μM, which is much less than cisplatin’s IC50. SBCCC induces apoptosis and causes cell cycle arrest at the G1 phase. SBCCC induces apoptosis via multiple pathways including inhibition of NF-κB, ROS production and autophagy. Conclusions The synthesized SBCCC induced cancer cell death via inhibition of NF-κB, ROS production and autophagy. The multiple cell-killing mechanisms were important to overcome therapeutic failure because of multidrug-resistance of cancer cells. SBCCC, with a lower IC50 compared to cisplatin, could render it the potential to overcome the side-effect for clinical application.

This paper analyzes the development processes of the text on the narration of case facts until it finally be ascertained in trial. It is a subtle evolution process from evidence to the list of events and eventually to the factual text. It is a complex task to distinguish the content that would be inexorable once being proved and to reach consensus from the content that could only be presented through rhetoric. Meanwhile, this paper compares some existing documents of chronicles, annals, and narrative history with the events list and the factual text in Cui Yingjie Case so as to illustrate how the vertical evolution takes place in the description of the case as well as the differences of all evolution stages in judicial practice.

Background: Although there have been many magnetic resonance spectroscopy (MRS) studies of migraine, few have focused on migraines during an attack. Here, we aimed to assess metabolite changes in the brain of patients with migraine, both during an attack and in the interictal phase.Methods: Six patients (one man and five women, mean age: 39 ± 10 years) with migraine without aura during the attack (MWoA-DA), 13 patients (three men and 10 women, mean age: 31 ± 9 years) with migraine without aura during the interictal period (MWoA-DI), and 13 healthy controls (HC) (four men and nine women, mean age: 31 ± 9 years) were studied. All subjects underwent an MRS examination focusing on the occipital lobe. Metabolite changes were investigated among three groups.Results: The MWoA-DA patients had lower glutathione/total creatine ratio (GSH/tCr) than the MWoA-DI patients and HC. Furthermore, MWoA-DI patients showed lower total choline/total creatine ratio (tCho/tCr) than those in the other two groups. The GSH/tCr ratio was positively correlated with attack frequency in the MWoA-DI group. The tCho/tCr ratio was positively correlated with attack frequency and Migraine Disability Assessment Scale (MIDAS) scores in the MWoA-DA group.Conclusion: The present study suggests the existence of distinct pathophysiological states between the MWoA-DA and MWoA-DI groups. Neuronal dysfunction is a possible predisposing factor for migraine attack onset, along with oxidative stress and inflammation.

BackgroundImmune checkpoint inhibitors (ICIs) have become a high-profile regimen for malignancy recently. However, only a small subpopulation obtains long-term clinical benefit. How to select optimal patients by reasonable biomarkers remains a hot topic.MethodsPaired tissue samples and blood samples from 51 patients with advanced malignancies were collected for correlation analysis. Dynamic changes in blood PD-L1 (bPD-L1) expression, including PD-L1 mRNA, exosomal PD-L1 (exoPD-L1) protein and soluble PD-L1 (sPD-L1), were detected after 2 months of ICIs treatment in advanced non-small-cell lung cancer (NSCLC) patients. The best cutoff values for progression-free survival (PFS) and overall survival (OS) of all three biomarkers were calculated with R software.ResultsIn 51 cases of various malignancies, those with positive tissue PD-L1 (tPD-L1) had significantly higher PD-L1 mRNA than those with negative tPD-L1. In 40 advanced NSCLC patients, those with a fold change of PD-L1 mRNA ≥ 2.04 had better PFS, OS and best objective response (bOR) rate. In addition, a fold change of exoPD-L1 ≥ 1.86 was also found to be associated with better efficacy and OS in a cohort of 21 advanced NSCLC cases. The dynamic change of sPD-L1 was not associated with efficacy and OS. Furthermore, the combination of PD-L1 mRNA and exoPD-L1 could screen better patients for potential benefit from ICIs treatment.ConclusionThere was a positive correlation between bPD-L1 and tPD-L1 expression. Increased expression of PD-L1 mRNA, exoPD-L1, or both in early stage of ICIs treatment could serve as positive biomarkers of efficacy and OS in advanced NSCLC patients.

BackgroundImbalanced nutritional supply and demand in the tumor microenvironment often leads to hypoxia. The subtle interaction between hypoxia and immune cell behavior plays an important role in tumor occurrence and development. However, the functional relationship between hypoxia and the tumor microenvironment remains unclear. Therefore, we aimed to investigate the effect of hypoxia on the intestinal tumor microenvironment.MethodWe extracted the names of hypoxia-related genes from the Gene Set Enrichment Analysis (GSEA) database and screened them for those associated with colorectal cancer prognosis, with the final list including ALDOB, GPC1, ALDOC, and SLC2A3. Using the sum of the expression levels of these four genes, provided by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the expression coefficients, we developed a hypoxia risk score model. Using the median risk score value, we divided the patients in the two databases into high- and low-risk groups. GSEA was used to compare the enrichment differences between the two groups. We used the CIBERSORT computational method to analyze immune cell infiltration. Finally, the correlation between these five genes and hypoxia was analyzed.ResultThe prognosis of the two groups differed significantly, with a higher survival rate in the low-risk group than in the high-risk group. We found that the different risk groups were enriched by immune-related and inflammatory pathways. We identified activated M0 macrophages in TCGA and GEO databases and found that CCL2/4/5, and CSF1 contributed toward the increased infiltration rate of this immune cell type. Finally, we observed a positive correlation between the five candidate genes’ expression and the risk of hypoxia, with significant differences in the level of expression of each of these genes between patient risk groups.ConclusionOverall, our data suggest that hypoxia is associated with the prognosis and rate of immune cell infiltration in patients with colorectal cancer. This finding may improve immunotherapy for colorectal cancer.

Immune-checkpoint inhibitors (ICIs) are revolutionizing the field of immuno-oncology. Side effects and tumor microenvironment currently represent the most significant obstacles to using ICIs. In this study, we conducted an extensive cross-sectional survey to investigate the concept and practices regarding the use of ICIs in cancer patients in China. The results provide real-world data on the adverse events (AEs) of ICIs and the factors influencing the use of ICIs. This survey was developed by the Expert Committee on Immuno-Oncology of the Chinese Society of Clinical Oncology (CSCO-IO) and the Expert Committee on Patient Education of the Chinese Society of Clinical Oncology (CSCO-PE). The surveys were distributed using a web-based platform between November 29, 2019 and December 21, 2019. A total of 1,575 patients were included. High costs (43.9%), uncertainty about drug efficacy (41.2%), and no reimbursement from medical insurance (32.4%) were the factors that prevented the patients from using ICIs. The patients were most concerned about the onset time or effective duration of ICIs (40.3%), followed by the indications of ICIs and pre-use evaluation (33.4%). Moreover, 9.0, 57.1, 21.0, and 12.9% of the patients reported tumor disappearance, tumor volume reduction, no change in tumor volume, and increased tumor volume. Among the patients who received ICIs, 65.7% reported immune-related AEs (irAEs); 96.1% reported mild-to-moderate irAEs. Cancer patients in China had a preliminary understanding of ICIs. Yet, the number of patients treated with ICIs was small.

Inflammatory bowel disease (IBD), which main clinical manifestations include abdominal pain and diarrhea occurring repeatedly, is a kind of autoimmune disease. It has been reported in preceding studies that mesenchymal stem cells (MSCs) can reduce inflammation by regulating the function of immune cells. But studies about the interaction between MSCs and adaptive immune cells, especially in IBD models, are insufficient. Therefore, the objective of this research was to estimate the therapeutic effects of MSCs from human umbilical cord blood (hUCB-MSCs) in an IBD model of rodent and to clarify the therapeutic mechanisms of hUCB-MSCs. Dextran sulfate sodium (DSS) was used to induce colitis in rodent. Mice with colitis were treated with intraperitoneal infusions of hUCB-MSCs and evaluated for mortality and diverse disease symptoms containing weight reduction, diarrhea, and bloody stools. The levels of histopathologic severity and generation of regulatory T cells (Treg) were also determined. Treatment with hUCB-MSCs ameliorated the clinical and histopathologic severity of acute and chronic colitis in mice. Furthermore, T cell infiltration into the inflamed colon was significantly decreased (p = 0.0175), and Foxp3+ cells were substantially higher in the hUCB-MSC group than that of the DSS group. Our results suggest that hUCB-MSCs are able to alleviate inflammation via adding Foxp3+ Tregs in an IBD model of mouse. As a result, these findings suggest the opportunity of hUCB-MSC being applied to patients with IBD.

Apoptosis of cochlear hair cells is a key step towards age-related hearing loss. Although numerous genes have been implicated in the genetic causes of late-onset, progressive hearing loss, few show direct links to the proapoptotic process. By genome-wide linkage analysis and whole exome sequencing, we identified a heterozygous p.L183V variant in THOC1 as the probable cause of the late-onset, progressive, non-syndromic hearing loss in a large family with autosomal dominant inheritance. Thoc1, a member of the conserved multisubunit THO/TREX ribonucleoprotein complex, is highly expressed in mouse and zebrafish hair cells. The thoc1 knockout (thoc1 mutant) zebrafish generated by gRNA-Cas9 system lacks the C-startle response, indicative of the hearing dysfunction. Both Thoc1 mutant and knockdown zebrafish have greatly reduced hair cell numbers, while the latter can be rescued by embryonic microinjection of human wild-type THOC1 mRNA but to significantly lesser degree by the c.547C>G mutant mRNA. The Thoc1 deficiency resulted in marked apoptosis in zebrafish hair cells. Consistently, transcriptome sequencing of the mutants showed significantly increased gene expression in the p53-associated signaling pathway. Depletion of p53 or applying the p53 inhibitor Pifithrin-α significantly rescued the hair cell loss in the Thoc1 knockdown zebrafish. Our results suggested that THOC1 deficiency lead to late-onset, progressive hearing loss through p53-mediated hair cell apoptosis. This is to our knowledge the first human disease associated with THOC1 mutations and may shed light on the molecular mechanism underlying the age-related hearing loss.

Abstract Background Nonsyndromic hearing loss is clinically and genetically heterogeneous. In this study, we characterized the clinical features of 12 Chinese Han deaf families in which mutations in common deafness genes GJB2, SLC26A4, and MT‐RNR1 were excluded. Methods Targeted next‐generation sequencing of 147 known deafness genes was performed in probands of 10 families, while whole‐exome sequencing was applied in those of the rest two. Results Pathogenic mutations in a total of 11 rare deafness genes, OTOF, CDH23, PCDH15, PDZD7, ADGRV1, KARS, OTOG, GRXCR2, MYO6, GRHL2, and POU3F4, were identified in all 12 probands, with 16 mutations being novel. Intrafamilial cosegregation of the mutations and the deafness phenotype were confirmed by Sanger sequencing. Conclusion Our results expanded the mutation spectrum and genotype‒phenotype correlation of nonsyndromic hearing loss in Chinese Hans and also emphasized the importance of combining both next‐generation sequencing and detailed auditory evaluation to achieve a more accurate diagnosis for nonsyndromic hearing loss.

Aim. To identify the most effective laxative for bowel preparation in unsedated colonoscopy. Methods. Between April 2019 and April 2020, a total of 586 outpatients scheduled for unsedated colonoscopy at the First Hospital of Jilin University (Changchun, China) were randomized into one of two groups, namely, the polyethylene glycol (PEG) group or the oral sodium phosphate solution (OSP) group. The cleaning efficiency and other relevant clinical parameters were compared between the two groups. Results. Each group consisted of 293 patients. There were no significant differences in gender, body mass index, and history of abdominal surgery between the two groups. There were more cases of laxative intolerance in the PEG group than in the OSP group (7.5% vs. 0.7%, P0.05). The colonoscopic insertion time of the PEG group was significantly shorter than that of the OSP group (10.0 vs. 12.0 min, P=0.002), and colonoscopic insertion was more difficult in the OSP group than in the PEG group (P=0.036). The VAS score of the PEG group patients was significantly lower than that of OSP group patients (4.0±1.3 vs. 5.2±1.7, P≤0.001). There were no significant differences in the cecal intubation rate and the detection rate of polyps and ulcers/erosion between the two groups. Conclusion. The cleaning efficiency and tolerability of OSP were preferable to those of PEG, but there was no significant difference in bowel cleanliness after washing the colon and suctioning the fluid. Compared with patients of the OSP group, those of the PEG group required a shorter colonoscopic insertion time and reported a more comfortable experience. Therefore, for cases that are tolerant of PEG, PEG is a better choice for unsedated colonoscopy.

The present study, based on Labov′s narrative theory, focuses on how witnesses′ involvement affects their narrative reconstruction of the criminal case. Witnesses′ involvement is first subcategorized, and there are two circumstances concerning their involvements, one being single suspect versus victim(s) crime and the other multiple suspects versus victim(s) crime. The present study takes four witness statements from a single suspect malicious injury case as data to further analyze the effects exerted by different witness involvements on witness statements and their corresponding representations. Results of the analysis indicate that how witnesses are involved in the criminal event exert different effects on witness statements in three aspects as follows: narrative structure, participant distribution, and language strategies. The results of this study further revealed that the more legal responsibility a witness is likely to take for the criminal event, the more transformations he would make in his narrative reconstruction of the crime.

This paper endeavors to explore how to analyze the lateral difference between factual narrative texts to the same case, as well as the narrative mechanism that caused such lateral difference. It applies its four perspectives of the story model, namely, (1) coverage, (2) coherence, (3) uniqueness, and (4) goodness of fit to the study of evidence in Cui Yingjie case. The author explores why different interpretations the prosecution and defense adopted in the trial of the case could not provide a reliable logic to illustrate the necessity of their statements. In light of the story model, this paper explains the mechanism behind the techniques of evidence presentation both prosecution and defense adopted in the trial of Cui Yingjie case.

There is a pressing need to further our understanding of the mechanisms underlying the depression symptoms in patients with post-stroke depression (PSD) in order to inform targeted therapeutic approaches. While previous research has demonstrated a reorganization in the functional brain network of PSD, it remains uncertain whether, or not it also occurs in the structural brain network. We therefore aim to investigate the structural brain network of patients with PSD as compared to post-stroke non-depression (PSND) patients. In addition, our research considers the relationship between network metrics and functional measurements. Thirty-one PSD patients and twenty-three PSND patients were recruited. All patients underwent MRI and functional assessments, including the Barthel index, mini-mental state examination (MMSE), and Hamilton depression rating scale (HAMD). Diffusion tensor imaging was used to construct the structural brain network and to conduct the subsequent graph theoretical analysis. Network measures were computed and compared between PSD and PSND patients. Associations between functional assessments and network measures were studied as well. We successfully detected increased global and local efficiency in patients with PSD. Regions with disrupted local connections were located primarily in the cognitive and limbic systems. More importantly, PSD patients’ global and regional network measures were associated with depression severity, as measured by HAMD. These findings suggest that disrupted global and local network topologies might contribute to PSD patients’ depression symptoms. Therefore, connectome-based network measures could be potential bio-markers for evaluating stroke patients’ depression levels.

Nonsyndromic hearing loss has been shown to have high genetic heterogeneity. In this report, we aimed to disclose the genetic causes of the subjects from the ten Chinese deaf families who did not have pathogenic common genes/mutation. Next-generation sequencing (NGS) of 142 known deafness genes was performed in the probands of ten families followed by cosegregation analysis of all family members. We identified novel pathogenic variants in six families including p.D1806E/p.R1588W, p.R964W/p.R1588W, and p.G17C/p.G1449D in CDH23; p.T584M/p.D1939N in LOXHD1; p.P1225L in MYO7A; and p.K612X in EYA4. Sanger sequencing confirmed that these mutations segregated with the hearing loss of each family. In four families, no pathogenic variants were identified. Our study provided better understanding of the mutation spectrum of hearing loss in the Chinese population.

Small and major accidents and near misses are still occurring in nuclear power plants (NPPs). Risk level has increased with the degradation of NPP equipment and instrumentation. In order to achieve NPP safety, it is important to continuously evaluate risk for all potential hazard and fault propagation scenarios and map protection layers to fault / failure / hazard propagation scenarios to be able to evaluate and verify safety level during NPP operation. There are major limitations in current real time safety verification tools, as it is mainly offline and with no integration to NPP simulation tools. The main goal of this research is to develop real time safety verification with co-simulation tool to be integrated with plant operation support systems. This includes the development of static and dynamic fault semantic network (FSN) to model possible fault propagation scenarios and the interrelationships among associated process variables. The detailed methodology involves the integration of process models, construction of static FSN with fault propagation scenarios, and evaluation and tuning of dynamic FSN with probabilistic and process variable interaction values. The focus however of the present study is to highlight the need to incorporate error reduction in performing safety verification of NPPs. Two selected case studies were used to demonstrate the proposed methodology; one on a turbine trip and the other on steam generator tube rupture. In the former case, the error reduction concept was shown while the safety verification method was demonstrated in the latter case. The results confirmed the importance of error reduction as well as the need to constantly undertake safety verification of safety critical systems such as a NPP.

Several single nucleotide polymorphisms (SNPs) of the Glutamate metabotrophic receptor 7 gene (GRM7) have recently been identified by the genome-wide association study (GWAS) as potentially playing a role in susceptibility to age-related hearing impairment (ARHI), however this has not been validated in the Han Chinese population. The aim of this study was to determine if these SNPs are also associated with ARHI in an elderly male Han Chinese population. In this case-control candidate genes association study, a total of 982 men with ARHI and 324 normal-hearing controls subjects were studied. Using K-means cluster analysis, four audiogram shape subtypes of ARHI were identified in the case group: ''flat shape (FL)'', ''sloping shape (SL)'', ''2-4 kHz abrupt loss (AL) shape'' and ''8 kHz dip (8D) shape''. Results suggested that the SNP rs11928865 (A>T) of GRM7 was significantly associated with ARHI after adjusting for non-genetic factors (p = 0.000472, OR = 1.599, 95%CI = 1.229~2.081). Furthermore, frequency of TT genotype (rs11928865) were significant higher in the SL subgroup and AL subgroup with compared to controls group (p = 9.41E-05, OR = 1.945, 95%CI = 1.393~2.715; p = 0.000109, OR = 1.915, 95%CI = 1.378~2.661 adjusted, respectively) after Bonferroni correction. However, there wasn't significant difference in the frequency of the TT genotype between cases in the FL subgroup or the 8D subgroup with when compared with controls. Results of the current study suggest that, in an elderly male Han Chinese population, GRM7 SNP rs11928865 (TT) occurs more frequently in ARHI patients with SL and AL phenotype patterns.