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Abstract Background Older adults are a growing segment of oncology population in China and beyong. However, older cancer patients were vastly underrepresented in clinical trial. To facilitate that all patients with cancer have equal access to the cutting edging treatment and receive evidence-based medication in mainland China, it’s of particular importance to fully grasp the proportion of upper age restriction in cancer clinical trials, as well as associated factors. Methods Based on clinical trials registered on the China Food and Drug Administration Registration and Information Disclosure Platform, we sought to characterize the overall proportion and trajectory of upper age-restriction among registered cancer drug trials in mainland China from 2009 to 2021, and potential influencing factors were determined by multivariate logistic regression. Results According to the 3485 trials, upper age restriction proportion of cancer drug trials for patients over 65 years and 75 years was 18.8% (95% CI = 17.5%-20.1%) and 56.5% (95% CI = 51.3%-54.6%), respectively. Phase IV trials, international multicenter trials, or trials initiated by global companies seldom excluded patients over 65 years compared with phase I trials, domestic trials and trials initiated by Chinese enterprise, similar for 75 years and above. Both of 65 and 75 years old age limit sponsored by domestic enterprises showed slowly downward trend, while no such trend was observed for that of foreign companies. Solution to upper age eligibility of cancer drug trials was also provided. Conclusions Although there is a certain downward trend, use of eligibility criteria that explicitly exclude older cancer patients in mainland China was remarkably high, especially for trials initiated by domestic enterprise, domestic trials and early-phase trials. Action is urgently needed to promote treatment equity in the older patients while obtaining adequate evidence in clinical trials.

Abstract Background Skeletal muscle development is a multistep process whose understanding is central in a broad range of fields and applications, from the potential medical value to human society, to its economic value associated with improvement of agricultural animals. Skeletal muscle initiates in the somites, with muscle precursor cells generated in the dermomyotome and dermomyotome-derived myotome before muscle differentiation ensues, a developmentally regulated process that is well characterized in model organisms. However, the regulation of skeletal muscle ontogeny during embryonic development remains poorly defined in farm animals, for instance in pig. Here, we profiled gene expression and chromatin accessibility in developing pig somites and myotomes at single-cell resolution. Results We identified myogenic cells and other cell types and constructed a differentiation trajectory of pig skeletal muscle ontogeny. Along this trajectory, the dynamic changes in gene expression and chromatin accessibility coincided with the activities of distinct cell type-specific transcription factors. Some novel genes upregulated along the differentiation trajectory showed higher expression levels in muscular dystrophy mice than that in healthy mice, suggesting their involvement in myogenesis. Integrative analysis of chromatin accessibility, gene expression data, and in vitro experiments identified EGR1 and RHOB as critical regulators of pig embryonic myogenesis. Conclusions Collectively, our results enhance our understanding of the molecular and cellular dynamics in pig embryonic myogenesis and offer a high-quality resource for the further study of pig skeletal muscle development and human muscle disease.

The tight formation of unmanned aerial vehicles (UAVs) provides numerous advantages in practical applications, increasing not only their range but also their efficiency during missions. However, the wingman aerodynamics are affected by the tail vortices generated by the leading aircraft in a tight formation, resulting in unpredictable interference. In this study, a mathematical model of wake vortex was developed, and the aerodynamic characteristics of a tight formation were simulated using Xflow software. A robust control method for tight formations was constructed, in which the disturbance is first estimated with an extended state observer, and then a sliding mode controller (SMC) was designed, enabling the wingman to accurately track the position under conditions of wake vortex from the leading aircraft. The stability of the designed controller was confirmed. Finally, the controller was simulated and verified in mathematical simulation and semi-physical simulation platforms, and the experimental results showed that the controller has high tight formation accuracy and is robust.

Maglev transportation is a highly promising form of transportation for the future, primarily due to its friction-free operation, exceptional comfort, and low risk of derailment. Unlike conventional transportation systems, maglev trains operate with no mechanical contact with the track. Maglev trains achieve levitation and guidance using electromagnetic forces controlled by a magnetic levitation control system. Therefore, the magnetic levitation control system is of utmost importance in maintaining the stable operation performance of a maglev train. However, due to the open-loop instability and strong nonlinearity of the control system, designing an active controller with self-adaptive ability poses a substantial challenge. Moreover, various uncertainties exist, including parameter variations and unknown external disturbances, under different operating conditions. Although several review papers on maglev levitation systems and control methods have been published over the last decade, there has been no comprehensive exploration of their modeling and related control technologies. Meanwhile, many review papers have become outdated and no longer reflect the current state-of-the-art research in the field. Therefore, this article aims to summarize the models and control technologies for maglev levitation systems following the preferred reporting items for systematic reviews and meta-analysis (PRISMA) criteria. The control technologies mainly include linear control methods, nonlinear control methods, and artificial intelligence methods. In addition, the article will discuss maglev control in other scenarios, such as vehicle–guideway vibration control and redundancy and fault-tolerant design. First, the widely used maglev levitation system modeling methods are reviewed, including the modeling assumptions. Second, the principle of the control methods and their control performance in maglev levitation systems are presented. Third, the maglev control methods in other scenarios are discussed. Finally, the key issues pertaining to the future direction of maglev levitation control are discussed.

Summary: Metastasis is the leading cause of high ovarian-cancer-related mortality worldwide. Three major processes constitute the whole metastatic cascade: invasion, intravasation, and extravasation. Tumor cells often reprogram their metabolism to gain advantages in proliferation and survival. However, whether and how those metabolic alterations contribute to the invasiveness of tumor cells has yet to be fully understood. Here we performed a genome-wide CRISPR-Cas9 screening to identify genes participating in tumor cell dissemination and revealed that PTGES3 acts as an invasion suppressor in ovarian cancer. Mechanistically, PTGES3 binds to phosphofructokinase, liver type (PFKL) and generates a local source of prostaglandin E2 (PGE2) to allosterically inhibit the enzymatic activity of PFKL. Repressed PFKL leads to downgraded glycolysis and the subsequent TCA cycle for glucose metabolism. However, ovarian cancer suppresses the expression of PTGES3 and disrupts the PTGES3-PGE2-PFKL inhibitory axis, leading to hyperactivation of glucose oxidation, eventually facilitating ovarian cancer cell motility and invasiveness.

Multi-modal brain networks characterize the complex connectivities among different brain regions from structure and function aspects, which have been widely used in the analysis of brain diseases. Although many multi-modal brain network fusion methods have been proposed, most of them are unable to effectively extract the spatio-temporal topological characteristics of brain network while fusing different modalities. In this paper, we develop an adaptive multi-channel graph convolution network (GCN) fusion framework with graph contrast learning, which not only can effectively mine both the complementary and discriminative features of multi-modal brain networks, but also capture the dynamic characteristics and the topological structure of brain networks. Specifically, we first divide ROI-based series signals into multiple overlapping time windows, and construct the dynamic brain network representation based on these windows. Second, we adopt adaptive multi-channel GCN to extract the spatial features of the multi-modal brain networks with contrastive constraints, including multi-modal fusion InfoMax and inter-channel InfoMin. These two constraints are designed to extract the complementary information among modalities and specific information within a single modality. Moreover, two stacked long short-term memory units are utilized to capture the temporal information transferring across time windows. Finally, the extracted spatio-temporal features are fused, and multilayer perceptron (MLP) is used to realize multi-modal brain network prediction. The experiment on the epilepsy dataset shows that the proposed method outperforms several state-of-the-art methods in the diagnosis of brain diseases.

Relaxin family peptide receptor 4 (RXFP4) regulates pleiotropic biological processes. Here, authors report cryo-EM structures revealing the ligand-binding modes and key determinants of peptidomimetic agonism and subtype selectivity

Optically levitated oscillators in high vacuum have excellent environmental isolation and low mass compared with conventional solid-state sensors, which makes them suitable for ultrasensitive force detection. The force resolution usually scales with the measurement bandwidth, which represents the ultimate detection capability of the system under ideal conditions if sufficient time is provided for measurement. However, considering the stability of a real system, a method based on the Allan variance is more reliable to evaluate the actual force detection performance. In this study, a levitated optomechanical system with a force detection sensitivity of 6.33 ± 1.62 zN/Hz1/2 was demonstrated. And for the first time, the Allan variance was introduced to evaluate the system stability due to the force sensitivity fluctuations. The force detection resolution of 166.40 ± 55.48 yN was reached at the optimal measurement time of 2751 s. The system demonstrated in this work has the best force detection performance in both sensitivity and resolution that have been reported so far for optically levitated particles. The reported high-sensitivity force detection system is an excellent candidate for the exploration of new physics such as fifth force searching, high-frequency gravitational waves detection, dark matter research and so on.

Abstract Background Drug resistance is an important factor affecting the efficacy of chemotherapy in patients with colon cancer. However, clinical markers for diagnosing drug resistance of tumor cells are not only a few in number, but also low in specificity, and the mechanism of action of tumor cell drug resistance remains unclear. Methods Dipeptidase 1 (DPEP1) expression was analyzed using the cancer genome atlas (TCGA) and genotype‐Tissue Expression pan‐cancer data. Survival analysis was performed using the survival package in R software to assess the prognostic value of DPEP1 expression in colon cancer. Correlation and Venn analyses were adopted to identify key genes. Immunohistochemistry, western blot, qRT–PCR, Co‐immunoprecipitation, and dual‐luciferase reporter experiments were carried out to explore the underlying associations between DPEP1 and Achaete scute‐like 2 (ASCL2). MTT assays were used to evaluate the role of DPEP1 and ASCL2 in colon cancer drug resistance. Results DPEP1 was highly expressed in colon cancer tissues. DPEP1 expression correlated negatively with disease‐specific survival but not with overall survival. Bioinformatics analysis and experiments showed that the expressions of DPEP1 and ASCL2 in colon cancer tissues were markedly positively correlated. Mechanistic research indicated that DPEP1 enhanced the stability of protein ASCL2 by inhibiting its ubiquitination‐mediated degradation. In turn, ASCL2 functioned as a transcription factor to activate the transcriptional activity of the DPEP1 gene and boost its expression. Furthermore, DPEP1 also could enhance the expression of colon cancer stem cell markers (LGR5, CD133, and CD44), which strengthened the tolerance of colon cancer cells to chemotherapy drugs. Conclusions Our findings reveal that the DPEP1 enhances the stemness of tumor cells by forming a positive feedback loop with ASCL2 to improve resistance to chemotherapy drugs.

Abstract Symbiotic radio (SR) is a new spectrum sharing paradigm that allows backscatter device (BD) to transmit information over the ambient radio frequency signal, where the BD is parasitic in the primary transmission, and the secondary system (i.e. backscatter system) shares not only the same spectrum but also the same receiver with the primary system. Here, a multi‐BD SR system with a primary transmitter (PT), a cooperative receiver (CR) and two backscatter devices (BDs), that is, BD1 and BD2 is studied. The accurate expressions for the outage probability of both primary system and secondary system are derived. Simulation results verify the correctness of this theoretical analysis. Additionally, the effect of the distance parameters (i.e. the distance of the backscatter links) on the outage probability of BD1 and BD2 when the backscatter coefficients are fixed is investigated. Simulation results indicate that the desired outage performance can be obtained by adjusting the distance parameters. Finally, the performance of the multi‐BD SR system is compared with the SR system containing only one BD, and the results show that the multi‐BD SR system can enable the backscatter system to achieve better rate performance, which highlights the importance of applying multi‐BD to the SR system.

Abstract Background Increased frequency of circulating double negative T (DNT, CD4−CD8−CD3+) cells with protective immune function has been observed in human immunodeficiency virus (HIV) infection and tuberculosis (TB). Here the role of circulating TCRαβ+ DNT cells was further investigated in HIV/TB co-infection. Methods A cross-sectional study was conducted to investigate the frequency and functional profiles of peripheral TCRαβ+ DNT cells including apoptosis, chemokine and cytokine expression among healthy individuals and patients with TB, HIV infection and HIV/TB co-infection by cell surface staining and intracellular cytokine staining combined with flow cytometry. Results Significantly increased frequency of TCRαβ+ DNT cells was observed in HIV/TB co-infection than that in TB (p

The origin of the degradation of nanodevices under electrical pulses still remains unknown. Here, Li et al. reveal the mechanism of direct electron-dislocation interaction by decoupling the electron wind force using in situ electropulsing, providing atomistic insight into the electroplasticity.

In patients with locally advanced resectable oral squamous cell carcinoma (OSCC), the risk of recurrence and metastasis following treatment is high. Here, a phase I clinical trial reports safety and pathological response of neoadjuvant camrelizumab and apatinib in patients with locally advanced resectable OSCC.

Abstract Fumarylacetoacetate hydrolase (FAH) catalyzes the final step of Tyrosine (Tyr) degradation pathway essential to animals and the deficiency of FAH causes an inborn lethal disease. In plants, a role of this pathway was unknown until we found that mutation of Short-day Sensitive Cell Death1 (SSCD1), encoding Arabidopsis FAH, results in cell death under short day. Phenylalanine (Phe) could be converted to Tyr and then degraded in both animals and plants. Phe ingestion in animals worsens the disease caused by FAH defect. However, in this study we found that Phe represses cell death caused by FAH defect in plants. Phe treatment promoted chlorophyll biosynthesis and suppressed the up-regulation of reactive oxygen species marker genes in the sscd1 mutant. Furthermore, the repression of sscd1 cell death by Phe could be reduced by α-aminooxi-β-phenylpropionic acid but increased by methyl jasmonate, which inhibits or activates Phe ammonia-lyase catalyzing the first step of phenylpropanoid pathway, respectively. In addition, we found that jasmonate signaling up-regulates Phe ammonia-lyase 1 and mediates the methyl jasmonate enhanced repression of sscd1 cell death by Phe. These results uncovered the relation between chlorophyll biosynthesis, phenylpropanoid pathway and jasmonate signaling in regulating the cell death resulting from loss of FAH in plants.

Biliary adenofibroma is an extremely rare benign liver tumor, but it may be a precancerous lesion of cholangiocarcinoma. So far, only 29 cases have been reported in the literature. A 30-year-old woman was admitted to our department for upper abdomen mass. The computed tomography scan showed a huge cystic and partly substantial mass between the left lobe of the liver and the descending duodenum, which was considered to be an exophytic tumor derived from the left lobe of the liver. Laparoscopic liver segment IVb resection and cholecystectomy were performed. Microscopic examination showed that the tumor was composed of glandular cavities of varying sizes and fibrous interstitium. The glandular cavity was covered with cubic or columnar epithelium without atypia. Some of the mesenchymal cells are myofibroblast-like and spindle-shaped with red-stained cytoplasm. The mesenchymal cells in some areas proliferate densely with moderate atypia. It was considered to be an atypical biliary adenofibroma with focal necrosis and active cell proliferation which may have malignant transformation potential. There was no recurrence and metastasis at a 6-month follow-up. Biliary adenofibroma is a rare benign tumor derived from the bile duct, but it may progress to malignancy and develop distant metastasis. It is difficult to distinguish it from other liver tumors through imaging examination and the gold standard of diagnosis is histopathological examination. Close clinical follow-up is recommended.

Gradient colors are widely used in product design. The variation of gradient colors muting a color as a series of steps from bright to dull creates a soft and gradual impression while also affecting people's perceptions. This study manipulates the types of gradient colors to explore the relationship between color gradients and perception of stability to determine whether weight perception plays a role. In the case of controlling for aesthetic differences, the study manipulated two types of color gradients (dark colors fading upward from the bottom versus downward from the top) and measured the perceptions of product stability. In the same hue, an upward gradient gives a stronger perception of stability. In addition, gradient colors significantly influence women's perception of stability more than men's. The study also investigated the mediating effect of weight perception: participants evaluated color fading-upward products with less weight relative to fading-downward colors. Furthermore, dark colors fading upward from the bottom lead to a stronger perception of weight, increasing the stability perception of the object. Finally, to aid future research, we discuss the practical implications of the current findings for areas such as sensory marketing, as well as possible directions for future research.

Summary: The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas molecule, hydrogen sulfide (H2S), was found to bind at active-site copper of Cu/Zn-SOD using a series of methods including radiolabeled binding assay, X-ray absorption near-edge structure (XANES), and crystallography. Such an H2S binding enhanced the electrostatic forces to guide the negatively charged substrate superoxide radicals to the catalytic copper ion, changed the geometry and energy of the frontier molecular orbitals of the active site, and subsequently facilitated the transfer of an electron from the superoxide radical to the catalytic copper ion and the breakage of the copper-His61 bridge. The physiological relevance of such an H2S effect was also examined in both in vitro and in vivo models where the cardioprotective effects of H2S were dependent on Cu/Zn-SOD.

BackgroundCurrently the responses of peripheral cytokine-secreting cells in the natural course of human immunodeficiency virus (HIV) and tuberculosis (TB) co-infection haven’t been fully elucidated.MethodsThe function of peripheral proinflammatory, regulatory and cytotoxic cytokine-secreting cells were investigated by direct intracellular cytokine staining (ICS) and flow cytometry, additionally, the absolute numbers of different cytokine-secreting cells were measured among patients with HIV/TB co-infection (HT group), and compared them with the healthy controls (HC group), patients with TB (TB group) and patients with HIV infection (HIV group). After one week’s anti-TB treatment, the changes of the percentages of cytokine-secreting cells were further evaluated in TB and HT groups.ResultsTotally 26 individuals in the HC group, 51 in the TB group, 26 in the HIV group and 29 in the HT group were enrolled. The HT. HT group exhibited significantly lower absolute numbers of IFN-γ+CD4+, IFN-γ+CD8+, TNF-α+CD4+, IL17A+CD4+ T cells and TNF-α+CD14+ monocytes than the TB and HIV groups. Compared with the TB group, the percentages of CD8+ T cells secreting IFN-γ and perforin (p=0.010; p=0.043) were significantly lower among the HT group. Compared with the HIV group, the percentages of CD4+, CD8+ T cells and CD14+ monocytes secreting TNF-α (p=0.013; p=0.001; p

Summary: Intrauterine adhesion (IUA) is a common cause of uterine infertility and its histopathologic characteristic is endometrial fibrosis. A shortage of stem cells in the endometrial basalis has been recognized as a common cause of IUA development because approximately 90% of patients suffer from IUA after endometrial injury. In this study, we provide evidence that persistent inflammation is the main contributor to endometrial fibrosis in IUA patients. We further found that treating an IUA-like mouse model with ITI-hUC-MSCs (hUC-MSCs reprogrammed by IL-1β, TNF-α and IFN-γ) significantly decreased endometrial inflammation and fibrosis. Mechanistically, high levels of complement 1 inhibitor (C1INH) secreted by ITI-hUC-MSCs prevented inflammation from inducing profibrotic CD301+ macrophage polarization by downregulating the JAK-STAT signaling pathway. In conclusion, persistent inflammation in the endometria of IUA patients provides macrophage polarization with a profibrotic niche to promote endometrial fibrosis, and the powerful immunomodulatory effects of ITI-hUC-MSCs improve the immune microenvironment of endometrial regeneration.

ObjectiveTamoxifen is an effective anti-tumor medicine, but evidence has been provided on tamoxifen-related inflammation as well as its impact on gut microbiota. In this study, we aimed to investigate tamoxifen-induced gut microbiota and inflammation alteration.MethodsWe established a BC xenograft mouse model using the MCF-7 cell line. 16S rRNA gene sequencing was used to investigate gut microbiota. qRT–PCR, western blotting, and cytometric bead array were used to investigate inflammation-related biomarkers. Various bioinformatic approaches were used to analyze the data.ResultsSignificant differences in gut microbial composition, characteristic taxa, and microbiome phenotype prediction were observed between control, model, and tamoxifen-treated mice. Furthermore, protein expression of IL-6 and TLR5 was up-regulated in tamoxifen-treated mice, while the mRNA of Tlr5 and Il-6, as well as protein expression of IL-6 and TLR5 in the model group, were down-regulated in the colon. The concentration of IFN-γ, IL-6, and IL12P70 in serum was up-regulated in tamoxifen-treated mice. Moreover, correlation-based clustering analysis demonstrated that inflammation-negatively correlated taxa, including Lachnospiraceae-UCG-006 and Anaerotruncus, were enriched in the model group, while inflammation-positively correlated taxa, including Prevotellaceae_UCG_001 and Akkermansia, were enriched in the tamoxifen-treated group. Finally, colon histologic damage was observed in tamoxifen-treated mice.ConclusionTamoxifen treatment significantly altered gut microbiota and increased inflammation in the breast cancer xenograft mice model. This may be related to tamoxifen-induced intestinal epithelial barrier damage and TLR5 up-regulation.

BackgroundMetabolic syndrome (MetS) has been associated with digestive system diseases, and recent observational studies have suggested an association between MetS and cholelithiasis. However, the causal relationship between them remains unclear. This study aimed to assess the causal effect of MetS on cholelithiasis using Mendelian randomization (MR) analysis.MethodsSingle nucleotide polymorphisms (SNPs) of MetS and its components were extracted from the public genetic variation summary database. The inverse variance weighting method (IVW), weighted median method, and MR-Egger regression were used to evaluate the causal relationship. A sensitivity analysis was performed to ensure the stability of the results.ResultsIVW showed that MetS increased the risk of cholelithiasis (OR = 1.28, 95% CI = 1.13–1.46, P = 9.70E−05), and the weighted median method had the same result (OR = 1.49, 95% CI = 1.22–1.83, P = 5.68E−05). In exploring the causal relationship between MetS components and cholelithiasis, waist circumference (WC) was significantly associated with cholelithiasis. IVW analysis (OR = 1.48, 95% CI = 1.34–1.65, P = 1.15E−13), MR-Egger regression (OR = 1.62, 95% CI = 1.15–2.28, P = 0.007), and weighted median (OR = 1.73, 95% CI = 1.47–2.04, P = 1.62E−11) all found the same results.ConclusionOur study indicated that MetS increases the incidence of cholelithiasis, especially in MetS patients with abdominal obesity. Control and treatment of MetS can effectively reduce the risk of gallstone formation.

Achieving higher accuracy and robustness stands as the central objective in the navigation field. In complex urban environments, the integrity of GNSS faces huge challenges and the performance of integrated navigation systems can be significantly affected. As the proportion of faulty measurements rises, it can result in both missed alarms and false positives. In this paper, a robust method based on factor graph is proposed to improve the performance of integrated navigation systems. We propose a detection method based on multi-conditional analysis to determine whether GNSS is anomalous or not. Moreover, the optimal weight of GNSS measurement is estimated under anomalous conditions to mitigate the impact of GNSS outliers. The proposed method is evaluated through real-world road tests, and the results show the positioning accuracy of the proposed method is improved by more than 60% and the missed alarm rate is reduced by 80% compared with the traditional algorithms.

Obesity is one of the main risk factors for cardiovascular diseases, type II diabetes, hypertension, and certain cancers. Obesity in women at the reproductive stage adversely affects contraception, fertility, maternal well-being, and the health of their offspring. Being a major protein component in chylomicrons and high-density lipoproteins, apolipoprotein A-IV (apoA-IV) is involved in lipid metabolism, food intake, glucose homeostasis, prevention against atherosclerosis, and platelet aggregation. The goal of the present study is to determine the impact of apoA-IV deficiency on metabolic functions in 129X1/SvJ female mouse strain. After chronic high-fat diet feeding, apoA-IV−/− mice gained more weight with a higher fat percentage than wild-type (WT) mice, as determined by measuring their body composition. Increased adiposity and adipose cell size were also observed with a microscope, particularly in periovarian fat pads. Based on plasma lipid and adipokine assays, we found that obesity in apoA-IV−/− mice was not associated with hyperlipidemia but with higher leptin levels. Compared to WT mice, apoA-IV deficiency displayed glucose intolerance and elevated insulin levels, according to the data of the glucose tolerance test, and increased HOMA-IR values at fasting, suggesting possible insulin resistance. Lastly, we found obesity in apoA-IV−/− mice resulting from reduced energy expenditure but not food intake. Together, we established a novel and excellent female mouse model for future mechanistic study of obesity and its associated comorbidities.

Apolipoprotein A-IV (apoA-IV), synthesized by enterocytes, is potentially involved in regulating lipid absorption and metabolism, food intake, and glucose metabolism. In this study, we backcrossed apoA-IV knockout (apoA-IV−/−) mice onto the 129/SvJ background for eight generations. Compared to the wild-type (WT) mice, the 129/SvJ apoA-IV−/− mice gained more weight and exhibited delayed glucose clearance even on the chow diet. During a 16-week high-fat diet (20% by weight of fat) study, apoA-IV−/− mice were more obese than the WT mice, which was associated with their increased food intake as well as reduced energy expenditure and physical activity. In addition, apoA-IV−/− mice developed significant insulin resistance (indicated by HOMA-IR) with severe glucose intolerance even though their insulin levels were drastically higher than the WT mice. In conclusion, we have established a model of apoA-IV−/− mice onto the 129/SvJ background. Unlike in the C57BL/6J strain, apoA-IV−/− 129/SvJ mice become significantly more obese and insulin-resistant than WT mice. Our current investigations of apoA-IV in the 129/SvJ strain and our previous studies in the C57BL/6J strain underline the impact of genetic background on apoA-IV metabolic effects.

Abstract Background Long-term inhalation of cigarette smoke is considered to be one of the main causes of bronchial epithelioid cell damage, but its underlying mechanism has to be further clarified. Methods Gene expression at mRNA level and protein levels were detected by qRT-PCR and western blot analysis respectively. CCK-8, TUNEL assays, ELISA, western blot analysis and commercial kits were utilized to test cell viability, apoptosis inflammatory response and oxidative stress. The correlation between fatty acid binding protein 4 (FABP4) and the p38 mitogen-activated protein kinase (MAPK)/MAPK activated kinase 2 (MK2) signaling pathway was verified by western blot analysis and rescue assays. Results Cigarette smoke extract (CSE) exposure decreased viability, induced apoptosis and inflammatory response in 16HBE cells. Moreover, the expression of FABP4 in CSE-treated 16HBE cells was up-regulated in a time and dose-dependent manner. Ablation of FABP4 in 16HBE cells significantly protected against CSE-mediated cell viability decline and apoptosis. Further, FABP4 knockdown suppressed inflammatory response by down-regulating the elevated levels of cellular inflammatory factors including TNF-α, IL-1β, IL-6, Cyclooxygenase-2 (Cox-2) and inducible nitric oxide synthase (iNOS) in CSE-treated 16HBE cells. The oxidative stress induced by CSE in 16HBE cells was also inhibited by FABP4 silence as evidence by reduced ROS and MDA level but increased SOD activity caused by FABP4 silence. Finally, all the above effects of FABP4 silence on CSE-treated 16HBE cells were reversed by asiatic acid, an agonist of p38 mitogen-activated protein kinase (MAPK). Conclusions The up-regulation of FABP4 expression mediated by CSE exerted pro-inflammatory, pro-oxidative stress and pro-apoptotic effects on bronchial epithelial cells by activating the p38 MAPK/MK2 signaling pathway. Our findings help to further understand the underlying mechanism of cigarette smoke-induced bronchial inflammation.

Two different types of shear bands generate in ultrafine-grained (UFG) CoCrFeMnNi high-entropy alloys deformed at 77 K, i.e. commonly-observed low angle grain boundary (LAGB) type and unusual twin-coupled type. Twin-coupled shear bands exhibit a misorientation of 56–67° with the matrix, in contrast to the LAGB shear band with a misorientation of 6–12°. Both annealing twins and deformation twins can act as precursor for twin-coupled shear bands, where dislocation accumulation along twin boundaries can tune the orientation of twin lamella. These observations suggest that twin-coupled shear bands can act as an important plastic carrier in materials deformed under extreme conditions.

Pr3+ activated Gd2O2S and La2O2S are finding a wide range of luminescence applications but their solid-solution form has rarely been reported in the literature. A series of [(Gd1.0-xLax)0.99Pr0.01]2O2S (x = 0.0–1.0, GLOS:Pr3+) solid-solution phosphor nanopowders were directly produced in this work by calcining their sulfated hydroxide type precursors in flowing hydrogen at 900 °C, without using any of the harmful sulfidization reagents indispensable to other technical routes. The synthesis method also has the significant advantages of fine crystallites (∼20–35 nm), high specific surface area (∼16–21 m2/g) and unimodal particle size distribution (average particle size ∼120–140 nm) of the product. Photoluminescence study indicated that La3+ doping may remarkably enhance Pr3+ luminescence under 263 nm excitation, though tends to lower the thermal stability and elongate the lifetime of the emission. Aside from phosphor application, the thus-synthesized GLOS:Pr3+ powders would be well suited for the sintering of high-quality ceramic scintillators because of their fine particle/crystallite size and unimodal/narrow size distribution.

Abstract Background While recent works suggested that overweight/obesity may impair executive function (EF), the overweight/obesity-EF relationship has not been well studied in adolescents. Furthermore, no research has investigated adolescent EF impairments across the weight spectrum (e.g., underweight or thinness, normal, overweight/obesity), especially those with underweight condition, with the moderating effect of negative emotions in the weight-EF association being limitedly investigated. We aimed to determine whether overall and abdominal weight spectrum associated with EF impairments and to identity whether negative emotions moderate the weight-EF link in adolescents. Methods We applied a subsample of the SCHEDULE-A project. Adolescents (11–18 years) were recruited using a multi-stage cluster random sampling approach. We measured the overall and abdominal weight spectrum by body mass index z-score and waist-to-height ratio, respectively. We used the Behavior Rating Inventory of Executive Function (BRIEF) to evaluate adolescent EF in nature setting, and utilized the Depression Anxiety and Stress Scales (DASS-21) to assess three types of negative emotional status (i.e., depression, anxiety, and stress). Results Of the 1935 adolescents, 963 (49.8%) were male. We observed that abdominal, not overall, overweight was associated with the Global Executive Composite (GEC) impairment (OR = 1.59, 95% CI 1.07–2.35), particularly for inhibit, emotion control, shift, working memory, and monitor domains. Furthermore, depression moderated the abdominal overweight-GEC association (P = 0.032 for interaction term), especially for emotional control, working memory, and initiate dimensions. Moreover, we also found abdominal thinness was associated with the Metacognition Index problem (OR = 1.33, 95% CI 1.04–1.72), particularly for plan and monitor areas. Conclusions Both abdominal overweight and thinness were associated with adolescent EF, and depression would be a modifiable target to improve EF in adolescents with abdominal overweight. Future longitudinal studies are needed to investigate the causal relationship between abdominal weight spectrum and EF, as well as the underlying mechanisms among adolescents suffering from depression.

Currently, for ovarian cancer, which has the highest mortality rate among all gynecological cancers, the standard treatment protocol is initial tumor cytoreductive surgery followed by platinum-based combination chemotherapy. Although the survival rate after standard treatment has improved, the therapeutic effect of traditional chemotherapy is very limited due to problems such as resistance to platinum-based drugs and recurrence. With the advent of the precision medicine era, molecular targeted therapy has gradually entered clinicians’ view, and individualized precision therapy has been realized, surpassing the limitations of traditional therapy. The detection of genetic mutations affecting treatment, especially breast cancer susceptibility gene (BRCA) mutations and mutations of other homologous recombination repair defect (HRD) genes, can guide the targeted drug treatment of patients, effectively improve the treatment effect and achieve a better patient prognosis. This article reviews different sites and pathways of targeted therapy, including angiogenesis, cell cycle and DNA repair, and immune and metabolic pathways, and the latest research progress from preclinical and clinical trials related to ovarian cancer therapy.

Abstract A first‐order finite‐state Markov chain (FSMC) typically models the Rayleigh fading channel in the open literature because the first‐order FSMC is analytically tractable and can derive closed‐form results. Non‐orthogonal multiple access (NOMA) has been recognised as a novel wireless technology that addresses challenges in the next generation of mobile communications. According to the power‐domain NOMA protocol, channels in the NOMA wireless network are sorted by the channel gain. Then considering NOMA, there is insufficient information on how to further form a suitable model for ordered Rayleigh fading channels based on the first‐order FSMC. Given the mathematical statement on how to model the order statistics of multidimensional Markov chains for ordered Rayleigh fading channels, the authors consider these order statistics as a Markov chain, and propose specific processes of representing the state space and constructing the transition probability matrix accordingly. Numerical and simulation results validate the mathematical correctness and accuracy of these novel processes. In addition, for ordered Rayleigh fading channels, the performances of various methods of partitioning the entire signal‐to‐noise ratio range are compared. The performance comparison results are the same as those obtained for the individual unordered Rayleigh fading channel.

IntroductionResting-state brain network with physiological and pathological basis has always been the ideal data for intelligent diagnosis of major depression disease (MDD). Brain networks are divided into low-order networks and high-order networks. Most of the studies only use a single-level network to classify while ignoring that the brain works cooperatively with different levels of networks. This study hopes to find out whether varying levels of networks will provide complementary information in the process of intelligent diagnosis and what impact will be made on the final classification results by combining the characteristics of different networks.MethodsOur data are from the REST-meta-MDD project. After the screening, 1,160 subjects from ten sites were included in this study (597 MDD and 563 normal controls). For each subject, we constructed three different levels of networks according to the brain atlas: the traditional low-order network based on Pearson’s correlation (low-order functional connectivity, LOFC), the high-order network based on topographical profile similarity (topographical information-based high-order functional connectivity, tHOFC) and the associated network between them (aHOFC). Two sample t-test is used for feature selection, and then features from different sources are fused. Finally, the classifier is trained by a multi-layer perceptron or support vector machine. The performance of the classifier was evaluated using the leave-one-site cross-validation method.ResultsThe classification ability of LOFC is the highest among the three networks. The classification accuracy of the three networks combined is similar to the LOFC network. These are seven features chosen in all networks. In the aHOFC classification, six features were selected in each round but not seen in other classifications. In the tHOFC classification, five features were selected in each round but were unique. These new features have crucial pathological significance and are essential supplements to LOFC.ConclusionA high-order network can provide auxiliary information for low-order networks but cannot improve classification accuracy.

BackgroundDizziness in children, which could not be diagnosed at an early stage in the past, is becoming increasingly clear to a large extent. However, the recognition of the diagnosis and management remains discrepant and controversial due to their complicated and varied etiology. Central and peripheral vestibular disorders, psychogenic and systemic diseases, and genetic pathogeny constitute childhood etiological entities. Further understanding of the etiology and the prevalence of vertigo disorders is of crucial importance and benefit in the diagnosis and management of pediatric patients.MethodsThis systematic review and meta-analysis were conducted by systematically searching Embase, PubMed, the Cochrane Library, CNIK, the Chinese Wan-Fang database, CBM, the Chinese VIP database, and the Web of Science for literature on childhood vertigo disorders published up to May 2022. The literature was evaluated under strict screening and diagnostic criteria. Their quality was assessed using the Agency for Healthcare and Research Quality (AHRQ) standards. The test for homogeneity was conducted to determine the fixed effects model or random-effect model employed.ResultsTwenty-three retrospective cross-sectional studies involving 7,647 children with vertigo disorders were finally included, with an AHRQ score >4 (high or moderate quality). Our results demonstrated that peripheral vertigo (52.20%, 95% CI: 42.9–61.4%) was more common in children than central vertigo (28.7%, 95% CI: 20.8–37.4%), psychogenic vertigo (7.0%, 95% CI: 4.8–10.0%), and other systemic vertigo (4.7%, 95% CI: 2.6–8.2%). The five most common etiological diagnoses associated with peripheral vertigo included benign paroxysmal vertigo of childhood (BPVC) (19.50%, 95% CI: 13.5–28.3%), sinusitis-related diseases (10.7%, 95% CI: −11.2–32.6%), vestibular or semicircular canal dysfunction (9.20%, 95% CI: 5.7–15.0%), benign paroxysmal positional vertigo (BPPV)(7.20%, 95% CI: 3.9–11.5%), and orthostatic dysregulation (6.8%, 95% CI: 3.4–13.0%). Vestibular migraine (20.3%, 95% CI: 15.4–25.2%) was the most seen etiological diagnosis associated with central vertigo in children. In addition, we found the sex-based difference influenced the outcome of psychogenic vertigo and vestibular migraine, while there was no significant difference in other categories of the etiology. For the management of vertigo, symptomatical management is the first choice for most types of vertigo disorder in pediatrics.ConclusionComplex etiology and non-specific clinical manifestations of vertigo in pediatrics are challenging for their diagnoses. Reliable diagnosis and effective management depend on the close cooperation of multiple disciplines, combined with comprehensive consideration of the alternative characteristics of vertigo in children with growth and development.

Introduction: Although the molecular mechanisms of Krüpple-like factor 4 (KLF4) as a tumor suppressor in HCC tumorigenesis have been thoroughly examined, its clinical application in terms of precise prognostication and its influence on tumor immune microenvironment in patients with HCC require further investigation.Methods: Bioinformatics and immunohistochemistry (IHC) were used to validate KLF4 expressions in a tissue microarray (TMA) containing HCC samples. Using Cox regression models, independent prognostic factors were identified and employed in the development of nomograms. Decision curve analysis (DCA) demonstrated the superiority of the nomograms. GO and KEGG pathway analyses were applied to the functional study of KLF4. The GSVA program explored the link between KLF4 expression and tumor-infiltrating immune cells, and CAMOIP was used to construct KLF4 expression immune scores. Changes in immune-related gene markers were also investigated in relation to KLF4 expression. The association between immune cell infiltration and KLF4 expression was validated by IHC in TMA.Results: HCC was reported to have a notable depletion of KLF4. The absence of KLF4 was associated with advanced clinicopathological characteristics of HCC and predicted a bad prognosis for patients. Nomograms constructed using KLF4 expression, tumor differentiation, and TNM stage provided a more accurate prognostic assessment of HCC patients than TNM stage alone. KLF4 expression was associated with immunological-related functions, infiltration of macrophages, CD8+ T cells, and other immune cells, and elevation of immune checkpoints. Higher levels of CD8+ T cells and macrophage infiltration are associated with increased KLF4 expression in HCC TMA.Conclusion: KLF4 loss in HCC is a prognostic biomarker that influences the tumor immune microenvironment (TIME).

The diagnosis and clinical management of aneurysmal subarachnoid hemorrhage (aSAH) is currently limited by the lack of accessible molecular biomarkers that reflect the pathophysiology of disease. We used microRNAs (miRNAs) as diagnostics to characterize plasma extracellular vesicles in aSAH. It is unclear whether they can diagnose and manage aSAH. Next-generation sequencing (NGS) was used to detect the miRNA profile of plasma extracellular vesicles (exosomes) in three patients with SAH and three healthy controls (HCs). We identified four differentially expressed miRNAs and validated the results using quantitative real-time polymerase chain reaction (RT-qPCR) with 113 aSAH patients, 40 HCs, 20 SAH model mice, and 20 sham mice. Exosomal miRNA NGS revealed that six circulating exosomal miRNAs were differentially expressed in patients with aSAH versus HCs and that the levels of four miRNAs (miR-369-3p, miR-410-3p, miR-193b-3p, and miR-486-3p) were differentially significant. After multivariate logistic regression analysis, only miR-369-3p, miR-486-3p, and miR-193b-3p enabled prediction of neurological outcomes. In a mouse model of SAH, greater expression of miR-193b-3p and miR-486-3p remained statistically significant relative to controls, whereas expression levels of miR-369-3p and miR-410-3p were lower. miRNA gene target prediction showed six genes associated with all four of these differentially expressed miRNAs. The circulating exosomes miR-369-3p, miR-410-3p, miR-193b-3p, and miR-486-3p may influence intercellular communication and have potential clinical utility as prognostic biomarkers for aSAH patients.

An 8-week growth trial was designed to evaluate the effects of low-protein diets and subsequent recovery on grass carp (Ctenopharyngodon idellus) and black carp (Mylopharngodon piceus) in order to compare the compensatory growth of the two species with different feeding habits. During the restricted period (weeks 1–4), grass carp were fed three kinds of isoenergetic and isolipid diets containing 32% (C, Control), 27% (LEP), and 22% (LP) protein individually, and black carp were fed diets containing 37% (C, Control), 32% (LEP) and 27% (LP) protein individually. In the recovery period (weeks 5–8), all fish were fed the control diets individually. The results showed that the protein restriction led to significantly lower feed conversion efficiency (FCE) and specific growth rate (SGR) for two species. In the recovery period, test group grass carp had similar protein retention efficiency (PRE) and FCE to the control group and had significantly lower final body weights (FBW), succinate dehydrogenase (SDH), significantly higher lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) than the control group. The test group black carp had significantly higher PRE and FCE than the control group, and the LEP group had similar FBW, LDH, AST, and alanine aminotransferase (ALT) to the control group and had significantly lower pyruvate kinase (PK) and SDH. The study reveals that grass carp increase gluconeogenesis and fail to increase feed utilization efficiency significantly, thus failing to obtain compensatory growth. Black carp decrease the carbohydrate catabolism and tricarboxylic acid (TCA) cycle, increase feed utilization efficiency significantly and get compensatory growth in the LEP group. Black carp have better compensatory growth capacity than grass carp, and the different capacities may be related to the different nutrient utilization strategies of the two species.

Summary: Overall survival (OS) is considered the standard clinical endpoint to support effectiveness claims in new drug applications globally, particularly for lethal conditions such as cancer. However, the source and reliability of OS in the setting of clinical trials have seldom been doubted and discussed. This study first raised the common issue that data integrity and reliability are doubtful when we collect OS information or other time-to-event endpoints based solely on simple follow-up records by investigators without supporting material, especially since the 2019 COVID-19 pandemic. Then, two rounds of discussions with 30 Chinese experts were held and 12 potential source scenarios of three methods for obtaining the time of death of participants, including death certificate, death record and follow-up record, were sorted out and analysed. With a comprehensive assessment of the 12 scenarios by legitimacy, data reliability, data acquisition efficiency, difficulty of data acquisition, and coverage of participants, both short-term and long-term recommended sources, overall strategies and detailed measures for improving the integrity and reliability of death date are presented. In the short term, we suggest integrated sources such as public security systems made available to drug inspection centres appropriately as soon as possible to strengthen supervision. Death certificates provided by participants’ family members and detailed standard follow-up records are recommended to investigators as the two channels of mutual compensation, and the acquisition of supporting materials is encouraged as long as it is not prohibited legally. Moreover, we expect that the sharing of electronic medical records and the legal disclosure of death records in established health registries can be realized with the joint efforts of the whole industry in the long-term. The above proposed solutions are mainly based on the context of China and can also provide reference for other countries in the world.

Abstract Chemotherapy resistance poses an obstacle for effective treatment of uveal melanoma. In this study, we aim to investigate the effects of jumonji domain containing 2C (JMJD2C)-mediated mouse double minute-2 homolog (MDM2)/p53/interleukin 5 receptor subunit alpha (IL5RA) axis on cisplatin (CDDP) resistance in uveal melanoma. RT-qPCR and Western blot assay were performed to determine their expression patterns in uveal melanoma cell line (MUM-2B) and CDDP-resistant cell line (MUM-2B/CDDP). The enrichment of H3K9me3 in MDM2 promoter region was examined by ChIP, and the binding between p53 and ubiquitin in MUM-2B cells testified by co-IP assay. Following overexpression or silencing of JMJD2C/MDM2/p53/IL5RA, the 50% concentration of inhibition (IC50) and the biological characteristics of MUM-2B and MUM-2B/CDDP cells were examined using CCK-8 assay, SA-β-gal staining, fluorescence-activated cell sorting analysis, and Transwell assay. Finally, the tumorigenicity of transplanted MUM-2B and MUM-2B/CDDP cells in nude mice was assessed. JMJD2C was documented to be highly expressed in uveal melanoma cells, promoting the CDDP resistance. Histone demethylase JMJD2C removed the H3K9me3 modification of MDM2 promoter, which promoted the expression of MDM2. MDM2 enhanced the IL5RA expression through stimulating the ubiquitination and degradation of p53, thus inducing CDDP resistance of uveal melanoma cells. Furthermore, the results of in vivo experiments revealed that JMJD2C mediated the MDM2/p53/IL5RA axis to expedite the growth of uveal melanoma and augment the CDDP resistance. Taken together, JMJD2C can induce histone demethylation to upregulate MDM2, thereby ubiquitinating p53 and upregulating IL5RA. As a consequence, CDDP resistance in uveal melanoma is ultimately accelerated.

Abstract Preparation, analysis and lithium storage performance of a series of nitrogen‐doped carbon nanotube sponges (CNX) is presented in this work. The synthesis was performed using an aerosol‐assisted chemical vapor deposition (AACVD) in a bi‐sprayer system by using various carbon and nitrogen precursors made of mixtures of benzylamine with toluene, urea, pyridine and 1,2‐dichlorbenzene, with ferrocene as catalyst. A series of physico‐chemical analysis techniques are used to characterize the composition and the morphology of the obtained materials, and a correlation of these with the lithium storage performances is attempted. The samples reveal an interconnected core‐shell CNX fiber morphology with a CNT‐core surrounded by an amorphous carbon shell. Appealing lithium storage performances are attained, while also considering aspects of safety, low potential, and long‐term cycling stability. The best performing sponges display a high specific capacity (223 mAh g−1) when cycled in a practically relevant voltage window (0.01–1V vs. Li), high first cycle (90%) and long‐term cycling (99.3%) coulombic efficiencies and excellent capacity retention after 1500 cycles. This study further analyses the interplay between the morphology and the physico‐chemistry of nitrogen‐doped carbon nanotube materials for Lithium storage and provides guidelines for future developments.

Tumor-associated macrophages (TAMs) exert integrated effects in all aspects of tumor progression, including tumor cell proliferation, angiogenesis, invasion, and metastasis. Recently, considerable preclinical and clinical trials have demonstrated that TAM-targeted therapy is an effective antitumor therapeutic approach, especially as a complementary strategy in combination with conventional chemotherapy, radiotherapy, or emerging immunotherapy. Here, we review all of the current clinical trials targeting TAMs worldwide up to May 2021 and highlight instances of the synergetic therapeutic efficacy of TAM-targeted combined therapeutic strategies. In total, 606 clinical trials were conducted, including 143 tested products. There has been explosive growth in macrophage-targeted therapy around the world during the past decade. Most trials were at early phase, and two-thirds used macrophage-targeting therapy as part of a combination approach. The most common combination is that of traditional chemotherapy with TAM-targeted therapy, followed by immune checkpoint inhibitors and targeted drugs. TAM-targeted therapeutic approaches are a newly emerging but rapidly developing area of anticancer therapy, especially as a combinatorial therapeutic approach. Further investigation of promising combination strategies will pave the way to more effective anticancer therapies.

Calcining an amorphous precursor in flowing hydrogen at 900 °C directly produced nanocrystalline La2O2S:Pr3+ powder (LOS:Pr3+; average size ∼35 nm) of a unimodal distribution of particle size (mean diameter ∼90 nm). The precursor, precipitated by titrating an aqueous solution of rare-earth nitrate and ammonium sulfate with ammonia water, was deduced to have an approximate composition of (La,Pr)2(OH)2.6(CO3)0.7SO4·2H2O. Aside from simplicity, the synthesis method reported herein has the obvious advantage of environmental friendliness, as it did not involve any harmful sulfidizing agent. The products were characterized in detail by XRD, FTIR, TG/DTA, and SEM/TEM to reveal the process of phase/morphology development and fine microstructure. Photoluminescence study found that the LOS:Pr3+ nanopowder exhibited strong luminescence at ∼508 nm (3P0,1 → 3H4 transition), with a fluorescence lifetime of ∼4.22 ± 0.03 μs, either through exciting the LOS host (∼263 nm, more efficient) or directly exciting the Pr3+ activator (∼304 nm), and retained ∼45% of its room-temperature intensity at 150 °C. Aside from phosphor application, the thus-synthesized powder would be useful for the fabrication of ceramic scintillators because of its nanosized crystallites and narrow distribution of particle size.

The mammalian target of rapamycin (mTOR) pathway is abnormally activated in lung cancer. However, the anti-lung cancer effect of mTOR inhibitors as monotherapy is modest. Here, we identified that ginsenoside Rh2, an active component of Panax ginseng C. A. Mey., enhanced the anti-cancer effect of the mTOR inhibitor everolimus both in vitro and in vivo. Moreover, ginsenoside Rh2 alleviated the hepatic fat accumulation caused by everolimus in xenograft nude mice models. The combination of everolimus and ginsenoside Rh2 (labeled Eve-Rh2) induced caspase-independent cell death and cytoplasmic vacuolation in lung cancer cells, indicating that Eve-Rh2 prevented tumor progression by triggering paraptosis. Eve-Rh2 up-regulated the expression of c-MYC in cancer cells as well as tumor tissues. The increased c-MYC mediated the accumulation of tribbles homolog 3 (TRIB3)/P62+ aggresomes and consequently triggered paraptosis, bypassing the classical c-MYC/MAX pathway. Our study offers a potential effective and safe strategy for the treatment of lung cancer. Moreover, we have identified a new mechanism of TRIB3/P62+ aggresomes-triggered paraptosis and revealed a unique function of c-MYC.

Abstract Background Thin endometrium (TE) is a challenging clinical issue in the reproductive medicine characterized by inadequate endometrial thickness, poor response to estrogen and no effective treatments currently. At present, the precise pathogenesis of thin endometria remains to be elucidated. We aimed to explore the related molecular mechanism of TE by comparing the transcriptome profiles of late-proliferative phase endometria between TE and matched controls. Methods We performed a bulk RNA-Seq (RNA-sequencing) of endometrial tissues in the late-proliferative phase in 7 TE and 7 matched controls for the first time. Differential gene expression analysis, gene ontology enrichment analysis and protein-protein interactions (PPIs) network analysis were performed. Immunohistochemistry was used for molecular expression and localization in endometria. Human endometrial stromal cells (HESCs) were isolated and cultured for verifying the functions of hub gene. Results Integrative data mining of our RNA-seq data in endometria revealed that most genes related to cell division and cell cycle were significantly inhibited, while inflammation activation, immune response and reactive oxygen species associated genes were upregulated in TE. PBK was identified as a hub of PPIs network, and its expression level was decreased by 2.43-fold in endometria of TE patients, particularly reduced in the stromal cells, which was paralleled by the decreased expression of Ki67. In vitro experiments showed that the depletion of PBK reduced the proliferation of HESCs by 50% and increased the apoptosis of HESCs by 1 time, meanwhile PBK expression was inhibited by oxidative stress (reduced by 76.2%), hypoxia (reduced by 51.9%) and inflammatory factors (reduced by approximately 50%). These results suggested that the insufficient expression of PBK was involved in the poor endometrial thickness in TE. Conclusions The endometrial transcriptome in late-proliferative phase showed suppressed cell proliferation in women with thin endometria and decreased expression of PBK in human endometrial stromal cells (HESCs), to which inflammation and reactive oxygen species contributed.

Constructing ultraviolet lasing is of great significance for basic research and medical use. Here the authors present a strategy for generating ultraviolet lasing through a tandem upconversion process with ultralarge anti-Stokes shift (1260 nm).

Background: Brain network describing interconnections between brain regions contains abundant topological information. It is a challenge for the existing statistical methods (e.g., t test) to investigate the topological differences of brain networks. Methods: We proposed a kernel based statistic framework for identifying topological differences in brain networks. In our framework, the topological similarities between paired brain networks were measured by graph kernels. Then, graph kernels are embedded into maximum mean discrepancy for calculating kernel based test statistic. Based on this test statistic, we adopted conditional Monte Carlo simulation to compute the statistical significance (i.e., P value) and statistical power. We recruited 33 patients with Alzheimer's disease (AD), 33 patients with early mild cognitive impairment (EMCI), 33 patients with late mild cognitive impairment (LMCI) and 33 normal controls (NC) in our experiment. There are no statistical differences in demographic information between patients and NC. The compared state-of-the-art statistical methods include t test, t squared test, two-sample permutation test and non-normal test. Results: We applied the proposed shortest path matched kernel to our framework for investigating the statistical differences of shortest path topological structures in brain networks of AD and NC. We compared our method with the existing state-of-the-art statistical methods in brain network characteristic including clustering coefficient and functional connection among EMCI, LMCI, AD, and NC. The results indicate that our framework can capture the statistically discriminative shortest path topological structures, such as shortest path from right rolandic operculum to right supplementary motor area (P = 0.00314, statistical power = 0.803). In clustering coefficient and functional connection, our framework outperforms the state-of-the-art statistical methods, such as P = 0.0013 and statistical power = 0.83 in the analysis of AD and NC. Conclusion: Our proposed kernel based statistic framework not only can be used to investigate the topological differences of brain network, but also can be used to investigate the static characteristics (e.g., clustering coefficient and functional connection) of brain network.

Coal gangue is a solid waste formed during coal production, and the acid mine drainage it generates during open-pit storage severely pollutes the ecological environment of mining areas. Microorganisms play a crucial catalytic role in acidification, and their species and gene functions change during the oxidation process of coal gangue. In this study, the changes in microbial community structure were investigated during the initial acidification process for newly produced gangue exposed to moisture by monitoring the changes in pH, EC, sulfate ion concentration, and the iron oxidation rate of gangue leaching solutions. Moreover, the composition and functional abundance of microbial communities on the surface of the gangue were analyzed with rainfall simulation experiments and 16S rRNA sequencing. The study yielded the following findings: (1) The critical period for newly produced gangue oxidation spanned from 0~15 d after its exposure to water; the pH of leaching solutions decreased from 4.65 to 4.09 during this time, and the concentration and oxidation rate of iron in the leaching solutions remained at low levels, indicating that iron oxidation was not the main driver for acidification during this stage. (2) When the gangue was kept dry, Burkholderia spp. dominated the gangue microbial community. When the gangue was exposed to moisture, the rate of acidification accelerated, and Pseudomonas replaced Burkholderia as the dominant genus in the community. (3) In terms of gene function, the microbial community of the acidified gangue had stronger nitrogen cycling functions, and an increase in the abundance of microorganisms related to the sulfur cycle occurred after day 15 of the experiment. The microbial community in the acidified gangue had more stress resistance than the community of the newly formed gangue, but its potential to decompose environmental pollutants decreased.

Sauce-flavor Daqu is a saccharifying and fermenting agent for sauce-flavor baijiu. Three kinds of Daqu (White Daqu (WQ), Yellow Daqu (YQ), and Black Daqu (BQ)) with different qualities are formed owing to the stacking fermentation. Maillard reaction is an important factor that causes significant differences among the three kinds of high-temperature Daqu, which is also an important source of flavor substances. However, there is a lack of research on the composition differences of Maillard reaction products in the three types of Daqu. In our study, HS-SPME-GC/MS, Py-GC/MS, and high-throughput sequencing were used to investigate the small molecule volatile Maillard substances, melanoidin (macromolecular Maillard substance) composition, and microbial community of three kinds of Daqu. The results showed that there were significant differences in the composition of Maillard products (furans, pyrazines, and melanoidin structure) between the three kinds of Daqu. The melanoidin was mainly composed of furans, pyrrolopyrazines, phenols, and indoles, the proportions of which were different in the three types of Daqu. BQ contained more Maillard products, making the melanoidin more complex. Kroppenstedtia, Monascus, and Thermoascus were the biomarkers of BQ, which contribute to the Maillard reaction. This study is of great significance to further deepen the understanding of the formation mechanism of BQ.

The development of mammalian skeletal muscle is a highly complex process involving multiple molecular interactions. As a prevalent RNA modification, N6-methyladenosine (m6A) regulates the expression of target genes to affect mammalian development. Nevertheless, it remains unclear how m6A participates in the development of goat muscle. In this study, methyltransferase 3 (METTL3) was significantly enriched in goat longissimus dorsi (LD) tissue. In addition, the global m6A modification level and differentiation of skeletal muscle satellite cells (MuSCs) were regulated by METTL3. By performing mRNA-seq analysis, 8050 candidate genes exhibited significant changes in expression level after the knockdown of METTL3 in MuSCs. Additionally, methylated RNA immunoprecipitation sequencing (MeRIP-seq) illustrated that myocyte enhancer factor 2c (MEF2C) mRNA contained m6A modification. Further experiments demonstrated that METTL3 enhanced the differentiation of MuSCs by upregulating m6A levels and expression of MEF2C. Moreover, the m6A reader YTH N6-methyladenosine RNA binding protein C1 (YTHDC1) was bound and stabilized to MEF2C mRNA. The present study reveals that METTL3 enhances myogenic differentiation in MuSCs by regulating MEF2C and provides evidence of a post-transcriptional mechanism in the development of goat skeletal muscle.

Coal gangue is a solid waste emitted during coal production. Coal gangue is deployed adjacent to mining land and has characteristics similar to those of the soils of these areas. Coal gangue–soil ecosystems provide habitats for a rich and active bacterial community. However, co-existence networks and the functionality of soil and coal gangue bacterial communities have not been studied. Here, we performed Illumina MiSeq high-throughput sequencing, symbiotic network and statistical analyses, and microbial phenotype prediction to study the microbial community in coal gangue and soil samples from Shanxi Province, China. In general, the structural difference between the bacterial communities in coal gangue and soil was large, indicating that interactions between soil and coal gangue are limited but not absent. The bacterial community exhibited a significant symbiosis network in soil and coal gangue. The co-occurrence network was primarily formed by Proteobacteria, Firmicutes, and Actinobacteria. In addition, BugBase microbiome phenotype predictions and PICRUSt bacterial functional potential predictions showed that transcription regulators represented the highest functional category of symbiotic bacteria in soil and coal gangue. Proteobacteria played an important role in various processes such as mobile element pathogenicity, oxidative stress tolerance, and biofilm formation. In general, this work provides a theoretical basis and data support for the in situ remediation of acidified coal gangue hills based on microbiological methods.

Both the nanoscale helium (He) bubble and grain boundaries (GBs) play important roles in the dynamic mechanical behavior of irradiated nanocrystalline materials. Using molecular dynamics simulations, we study the shock-induced deformation and spallation failure of bicrystal copper with a nanoscale He bubble. Two extreme loading directions (perpendicular or parallel to the GB plane) and various impact velocities (0.5–2.5 km/s) are considered. Our results reveal that the He bubble shows hindrance to the propagation of shock waves at lower impact velocities but will accelerate shock wave propagation at higher impact velocities due to the local compression wave generated by the collapse of the He bubble. The parallel loading direction is found to have a greater effect on He bubble deformation during shock compression. The He bubble will slightly reduce the spall strength of the material at lower impact velocities but has a limited effect on the spallation process, which is dominated by the evolution of the GB. At lower impact velocities, the mechanism of spall damage is dominated by the cleavage fracture along the GB plane for the perpendicular loading condition but dominated by the He bubble expansion and void growth for the parallel loading condition. At higher impact velocities, micro-spallation occurs for both loading conditions, and the effects of GBs and He bubbles can be ignored.

A UAV-assisted caching strategy considering content cache pricing in vehicular networks is proposed to address the problem of high communication load and high backhaul link overhead in vehicular networks. Consider a traffic scenario consisting of a content provider (CP), a network operator (NO), and multiple mobile users, where the NO has a set of cache-enabled roadside units (RSUs) and an unmanned aerial vehicle (UAV). The CP leases some popular contents to the NO for its benefit and the NO places this leased content in its RSU’s local cache to save expensive backhaul transmission overhead and latency. However, both NO and CP are selfish and their interests conflict with each other because they have opposing expectations for content pricing. In order to take into account the interests of both, this paper defines the utilities of CP and MNO and uses the Stackelberg game framework to model the competition between the two entities, where CP acts as a leader and sets the rental price of the content and NO acts as a follower responding to CP’s actions. An iteration-based dynamic programming algorithm is also designed to find the Stackelberg equilibrium. Meanwhile, a caching-capable UAV is introduced into the vehicular network and, based on this, a Dijkstra-based path planning algorithm is designed to further increase the total utility of NO by optimizing the trajectory of the UAV. The simulation results show that the strategy in this paper can reasonably allocate the benefits of CP and NO, reduce the average request delay, and increase the utility of NO; for example, we reduced the request latency for vehicle users by 27% and increased the total utility of NO by 13%.