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Abstract Leafy spurge (Euphorbia esula) is an important herb and potential energy source with medicinal value. Codon usage bias (CUB) is a static feature of genes and genomes that results from adaptation and selection during long-term evolution and facilitates molecular breeding in transgenic plants. Here, we used TransDecoder to identify candidate coding regions from the downloaded leafy spurge transcriptome and generate coding region annotation files based on reference genomes. The whole genome showed A/T bias, especially at terminal positions, and seven high-frequency codons were identified. We compared codon usage frequencies to identify candidate exogenous expression receptor systems for leafy spurge. The identified factors affecting leafy spurge CUB included natural selection and other factors, mutation pressure and base composition, with natural selection and other factors being dominant. The observed CUB was significantly positively correlated with the gene expression levels. Systematic analysis of whole-genome leafy spurge revealed that highly expressed protein-coding genes presented greater CUB than did less expressed protein-coding genes. Furthermore, the highly expressed genes tended to have terminal G/C bases. In summary, we conducted a series of related studies based on the leafy spurge whole-genome sequence and laid a foundation for selecting suitable exogenous expression receptor systems and improving gene expression levels.

Abstract Bletilla striata has been used in traditional Chinese medicine for thousands of years to treat a variety of health diseases. Currently, metabolic causes of differences in medicinal values are unknown, due to the lack of a large-scale and comprehensive investigation of metabolites in Bletilla species. In order to gain a better understanding of the major chemical constituents responsible for the medicinal value, this study aimed to explore the metabolomic differences among three Bletilla species (Bletilla striata: Bs, Bletilla ochracea: Bo and Bletilla formosana: Bf). There were 258 different metabolites between ‘Bo’ and ‘Bf’, the contents of 109 metabolites had higher abundance, while 149 metabolites showed less accumulation. There were 165 different metabolites between the ‘Bs’ and ‘Bf’, content of 72 metabolites was increased and content of 93 metabolites was decreased. There were 239 different metabolites between the ‘Bs’ and ‘Bo’, content of 145 metabolites was increased and content of 94 metabolites was decreased. In the Bo_vs_Bf, Bs_vs_Bf and Bs_vs_Bo groups, the major differential categories were flavonoids, phenolic acids, organic acids and alkaloids. Moreover, the differential metabolites were clustered into clear and distinct profiles via K-means analysis. In addition, the major differential categories were flavonoids, phenolic acids, organic acids and alkaloids. The ‘Flavonoid biosynthesis’ (ko00941) and ‘Phenylalanine metabolism’ (ko00360) pathways were significantly enriched in Bo_vs_Bf, Bs_vs_Bf and Bs_vs_Bo comparisons. These results clarify the metabolomics in different Bletilla species, as well as providing basis for the phamaceutical value of novel species of Bletilla.

Abstract Background To investigate the association between surgical removal of tonsils and risk of COVID-19 with different severity. Methods Through a nested case–control study during January 31st to December 31st 2020, including 58,888 participants of the UK Biobank, we investigated the association of tonsillectomy with the future risk of mild and severe COVID-19, using binomial logistic regression. We further examined the associations of such surgery with blood inflammatory, lipid and metabolic biomarkers to understand potential mechanisms. Finally, we replicated the analysis of severe COVID-19 in the Swedish AMORIS Cohort (n = 451,960). Results Tonsillectomy was associated with a lower risk of mild (odds ratio [95% confidence interval]: 0.80 [0.75–0.86]) and severe (0.87 [0.77–0.98]) COVID-19 in the UK Biobank. The associations did not differ substantially by sex, age, Townsend deprivation index, or polygenic risk score for critically ill COVID-19. Levels of blood inflammatory, lipid and metabolic biomarkers did, however, not differ greatly by history of surgical removal of tonsils. An inverse association between tonsillectomy and severe COVID-19 was also observed in the AMORIS Cohort, primarily among older individuals (> 70 years) and those with ≤ 12 years of education. Conclusions Surgical removal of tonsils may be associated with a lower risk of COVID-19. This association is unlikely attributed to alterations in common blood inflammatory, lipid and metabolic biomarkers.

The Yangtze River is the mother river of China. To promote the aquatic ecosystem protection of the great river, the Project of Yangtze Fisheries Resources and Environment Investigation (2017–2021) supported by the Ministry of Agriculture and Rural Affairs, P. R. China carried out by 24 institutes and universities that located in the Yangtze River basin surveys the status of (1) fish species composition and spatial distribution, (2) current fish abundance, (3) endangered fishes, (4) Yangtze finless porpoise, (5) aquatic eco-environments, (6) water-level fluctuation areas, (7) capture fisheries and recreational fisheries of the Yangtze River mainstream and 10 of its main tributaries, including Yalong River, Heng River, Min River (including Dadu River), Chishui River, Tuo River, Jialing River, Wu River, Han River, Dongting Lake and Poyang Lake. The results showed that there were 443 fish species (belonging to 163 genus, 37 families, and 18 orders) before 2017, but only 323 fish species (including 15 new recorded exotic species) were recorded in the project of 2017–2021. Among them, Cyprinus carpio, Carassius auratus, Hypophthalmichthys molitrix, Pelteobagrus fulvidraco, Coilia brachygnathus, Silurus asotus, Saurogobio dabryi, Ctenopharyngodon idellus, Pelteobagrus nitidus, Hemiculter leucisculus, Siniperca chuatsi, Coreius heterodon, Culter alburnus, Parabramis pekinensis, and Aristichthys nobilis were the dominant species across the whole Yangtze River system. It is estimated that there were 886 million individuals weighing 124.8 million kg, merely equivalent to 27.3% of the resources in 1950s, 30.9% of the resources in 1960s, or 58.7% of the resources in 1980s. In the new list of protected fishes that recorded in the Yangtze River system, only 15 of 29 were collected in this project of 2017–2021. Psephurus gladius has been affirmed to be Extinct by International Union for Conservation of Nature (IUCN). The wild individuals of Tenualosa reevesii and Luciobrama macrocephalus have disappeared for many years and maybe have been extinct already. Acipenser dabryanus has been affirmed to be Extinct in the Wild by IUCN. The natural propagations of A. sinensis, Myxocyprinus asiaticus and Trachidermus fasciatus have been interrupted for many years. The populations of Yangtze finless porpoise in the Yangtze River mainstream, Dongting Lake and Poyang Lake have steadily rising sizes and expanding distributions in 2017–2021. Parts of them migrate from one region to another with the seasons, which would result in the fluctuation of Yangtze finless porpoise population within some regions. The conventional indicators of water quality in the Yangtze River system were good and conformed to the water quality criteria of fishery in 2017–2021. In the last 40 years, the maximum surface water area in the Yangtze River basin extended to approximately 63,360 km2, the minimum surface water area covered approximately 26,396 km2, and the seasonal water-level fluctuation areas occupied approximately 36,964 km2. Compared with 1984–2000 period, the 2001–2020 period witnessed an overall decreasing trend in the frequency of surface water occurrence within about 25,869 km2 of aquatic areas. From 1984 to 2000 period to 2001–2020 period, permanent surface water has decreased by nearly 8,750 km2. In 2017, the fishermen were mainly 40–60 years old and their educational levels were mainly lower than junior high school. In 2017, most anglers were older than 40 and used hand rod and/or sea rod. Their average catch of each time was mainly less than 1 kg. Results suggested that the fishing ban in key waters of the Yangtze River basin is not only an ecological project of aquatic ecosystem conservation, but also a livelihood project for the fisherman to embrace industrial transformation and improve their living conditions. After the implementation of the fishing ban, the fisheries resources would gradually recover, and the Yangtze finless porpoise population size would also see a steady increase. However, the endangered species would remain threatened for a long time. The degraded waterbodies and water-level fluctuation areas would be the key restrictive factors for future aquatic ecosystem recovery in the Yangtze River basin. Since this survey was carried out before the fishing ban, the current results could provide a baseline for future evaluation of the effect of the Yangtze River fishing ban.

ABSTRACT Climate change in the future could potentially expand, shrink, or alter the habitats of numerous species, leading to changes in their spatial distributions. Predicting suitable areas for cultivating medicinal plants through modeling has become an effective tool for assessing site suitability and conserving medicinal plant resources. Utilizing GIS and MaxEnt model, we predicted the spatial distribution of Terminalia chebula Retz. in China for the current and for the future (2050s and 2070s) under the RCP4.5 and RCP8.5 representative concentration pathways. In this study, we utilized 73 occurrence records and incorporated eight environmental factors from WorldClim for the modeling process. The findings revealed that the evaluation of the model's performance was based on the area under the curve (AUC) of the receiver operating characteristic (ROC). All AUC values exceeded 0.9, classifying these models as “Excellent.” Additionally, the jackknife test analysis revealed that the main influential variables were bio11 and bio4. Under the present climate conditions, the estimated total suitable habitat for T. chebula is approximately 29.14 × 104 km2, representing around 2.78% of China's total land area. Within these suitable regions, high suitability, medium suitability, and low suitability areas make up 0.39%, 0.54%, and 1.85% of the total area, respectively. According to future climate, the potential growth range of T. chebula is expected to expand due to climate variability, showing a significant pattern of expansion towards the north and east within China. In the 2050s and 2070s, the total area of regions with high suitability, medium suitability, and low suitability under RCP4.5 and RCP8.5 will increase compared to the current distribution. This study will provide theoretical suggestions for preservation, management, and sustainable utilization of T. chebula resources.

Background Carboxylesterase 4A (CES4A) belongs to the member of the carboxylesterase family, yet there has been limited research into its malignant biological behavior in malignant tumors. Here, we aim to investigate the expression, cellular biological functions, and the potential underlying mechanism of CES4A in nasopharyngeal carcinoma (NPC). Method A standardized mean difference (SMD) analysis was used to analyze the dysregulation of CES4A based on the gene expression omnibus (GEO) database. qRT-PCR and immunohistochemical staining (IHC) were used to identify the mRNA and protein levels of CES4A in NPC cell lines and tissues, respectively. CCK-8, colony formation, wound healing and transwell assays were utilized to estimate cellular growth and metastasis, respectively. Western blot was conducted to evaluate the activity of PI3K/AKT signaling pathway. Result Both mRNA and protein expression of CES4A was significantly diminished both in NPC cell lines and primary tumor tissues. Ectopic expression of CES4A restrains the proliferation, colony formation, migration and invasion of NPC. Additionally, KEGG analysis based on GEO data and high-throughput transcriptome sequencing of cell lines all strongly suggested that CES4A was involved in regulating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. It was observed that AKT and phosphorylated AKT were remarkably reduced in CES4A overexpressing NPC cells, indicating that PI3K/AKT signaling pathway is hindered by CES4A. Conclusion CES4A expression is silenced in NPC, functioning as a tumor suppressor by negatively modulating the PI3K/AKT signaling pathway.

BackgroundTo study the relationship between the monocyte/high-density lipoprotein cholesterol ratio (MHR) and neutrophil-to-lymphocyte ratio (NLR) and coronary artery stenosis in Non-st-elevation acute coronary syndromes (NSTE-ACS) patients of different genders.MethodsA total of 253 control and 800 NSTE-ACS patients were included, and clinic data (29 items) were also collected. NSTE-ACS patients were divided into low-risk (0–23) and high-risk (≥ 23) groups based on the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) score. Then, Spearman correlation and multivariate logistic regression analyses were performed to study the associated factors of high-risk SYNTAX score in male and female NSTE-ACS patients, respectively. Finally, the receiver operating characteristic (ROC) curve was used to calculate the diagnostic value of MHR and NLR for predicting high-risk SYNTAX scores in male NSTE-ACS patients.ResultsSixteen distinct factors differed between the high- and low-risk groups in male NSTE-ACS patients, a significantly higher number than female NSTE-ACS patients. Gout/hyperuricemia, smoking, NLR, and MHR are independent risk factors for arterial stenosis. At the same time, high-density lipoprotein and left ventricular ejection fraction (LVEF) are found to be protective factors in male NSTE-ACS patients. Fibrinogen, apolipoprotein B/A, and neutrophils are identified as independent risk factors for arterial stenosis in female NSTE-ACS patients, while LVEF and high-density lipoprotein are protective factors. Finally, combined NLR and MHR [p = 0.000, 95% confidence interval (CI) = 0.726–0.810] had better predictive efficacy on the degree of arterial vessel stenosis than NLR or MHR alone. The sensitivity and specificity of the ROC curve were 0.672 and 0.769, respectively.ConclusionThe combination of MHR and NLR shows potential for predicting and assessing the severity of coronary artery stenosis in male patients with NSTE-ACS.

Osteosarcoma is the most common bone malignancy in children and adolescents with a less than 30% overall survival rate for those with metastatic disease, particularly pulmonary metastases. Drug resistance hinders the effectiveness of current chemotherapies, making osteosarcoma a leading cause of mortality and an urgent requirement of new therapeutics in this population. Here, we developed a triptolide (TP)-loaded, pH-responsive and near-infrared light-activated nanoplatform (TP-TPBC-PEG) with photodynamic therapy (PDT) to target osteosarcoma cells both in vitro and in vivo. Our results demonstrated that PDT and chemotherapy of TP-TPBC-PEG synergistically reduced cell viability, colony proliferation, migration, and invasion in vitro, and inhibited osteosarcoma growth and pulmonary metastasis in vivo which the nano-micelles were intravenously injected to intratibia injection induced osteosarcoma mouse models, showing enhanced osteosarcoma cell killing by nanoparticle inflating in response to acidic endosomal pH and sensitized osteosarcoma cells to TP chemotherapy. Importantly, the nano-micelles did not exhibit organ toxicity in vivo. Dual-luciferase reporter gene and nuclear/ cytoplasm protein expression assays identified the involvement of HIPPO signaling pathway in mediating these effects. Overall, our study provides a promising therapeutic approach for treating primary osteosarcoma and preventing pulmonary metastases by activating the HIPPO signaling pathway.

Abstract Background Hemorrhagic stroke is a devastating cerebrovascular event with a high rate of early mortality and long-term disability. The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) for neurological conditions, such as intracerebral hemorrhage (ICH), has garnered considerable interest, has garnered considerable interest, though their mechanisms of action remain poorly understood. Methods EVs were isolated from human umbilical cord MSCs, and SPECT/CT was used to track the 99mTc-labeled EVs in a mouse model of ICH. A series of comprehensive evaluations, including magnetic resonance imaging (MRI), histological study, RNA sequencing (RNA-Seq), or miRNA microarray, were performed to investigate the therapeutic action and mechanisms of MSC-EVs in both cellular and animal models of ICH. Results Our findings show that intravenous injection of MSC-EVs exhibits a marked affinity for the ICH-affected brain regions and cortical neurons. EV infusion alleviates the pathological changes observed in MRI due to ICH and reduces damage to ipsilateral cortical neurons. RNA-Seq analysis reveals that EV treatment modulates key pathways involved in the neuronal system and metal ion transport in mice subjected to ICH. These data were supported by the attenuation of neuronal ferroptosis in neurons treated with Hemin and in ICH mice following EV therapy. Additionally, miRNA microarray analysis depicted the EV-miRNAs targeting genes associated with ferroptosis, and miR-214-3p was identified as a regulator of neuronal ferroptosis in the ICH cellular model. Conclusions MSC-EVs offer neuroprotective effects against ICH-induced neuronal damage by modulating ferroptosis highlighting their therapeutic potential for combating neuronal ferroptosis in brain disorders.

Abstract Developing light yet strong aluminum (Al)-based alloys has been attracting unremitting efforts due to the soaring demand for energy-efficient structural materials. However, this endeavor is impeded by the limited solubility of other lighter components in Al. Here, we propose to surmount this challenge by converting multiple brittle phases into a ductile solid solution in Al-based complex concentrated alloys (CCA) by applying high pressure and temperature. We successfully develop a face-centered cubic single-phase Al-based CCA, Al55Mg35Li5Zn5, with a low density of 2.40 g/cm3 and a high specific yield strength of 344×103 N·m/kg (typically ~ 200×103 N·m/kg in conventional Al-based alloys). Our analysis reveals that formation of the single-phase CCA can be attributed to the decreased difference in atomic size and electronegativity between the solute elements and Al under high pressure, as well as the synergistic high entropy effect caused by high temperature and high pressure. The increase in strength originates mainly from high solid solution and nanoscale chemical fluctuations. Our findings could offer a viable route to explore lightweight single-phase CCAs in a vast composition-temperature-pressure space with enhanced mechanical properties.

During chronic infection or tumorigenesis, persistent antigen stimulation contributes to the exhaustion of CD8+ T cells. Nevertheless, exhausted CD8+ T (TEX) cells still preserve certain effector function, and maintaining a reservoir of exhausted cells is of vital importance for virus elimination and tumor eradiation. Despite considerable work interrogating the rejuvenation of TEX cells, mechanisms underpinning the clonal deletion of TEX cells remain largely unexplored over the past decade. In this study, we employed mouse models of LCMV infection to demonstrate that excessive accumulation of lipid peroxidation rendered virus-specific TEX cells to ferroptosis, which may correlate with enhanced mitochondria-derived oxidative stress and compromised activity of glutathione peroxidase 4 (GPX4). In addition, either incomplete or complete ablation of GPX4 resulted in exacerbated ferroptosis and aggravated shrunken population of virus-specific TEX cells. On the other hand, inhibiting ferroptosis via administration of a ferroptosis inhibitor or overexpression of GPX4 greatly rectified the cell loss of virus-specific TEX cells. Collectively, we disclosed ferroptosis as a crucial player in the clonal deletion of virus-specific TEX cells and stressed the intervention of ferroptosis as a promising approach to optimize the longevity of virus-specific TEX cells.

Objective: The purpose of our study was to investigate the effect of gender on postoperative pain, sleep quality, and recovery outcomes in patients undergoing VATS surgery under general anesthesia. Method: Perioperative peripheral blood inflammatory markers system inflammation Index (SII) was recorded for perioperative inflammatory response. The visual analog scale (VAS) was used to evaluate pain level. And the Athens Insomnia Scale (AIS) was evaluated on the night before surgery (sleep preop 1), the first night after surgery (sleep POD 1), and the third night after surgery (sleep POD 3) for postoperative sleep. Result: In this prospective cohort study, 79 males and 79 females were consecutively included. Females had significantly higher pain score (both rest and cough pain) compared to the males at 3 h after the surgery (3.85 ± 1.2 vs. 3.16 ± 1.1) (rest) (p

Abstract To meet the needs of energy storage under high temperature and high pressure, a high‐entropy relaxor ferroelectric ceramic, La‐modified (Bi0.2Na0.2Ba0.2Sr0.2Ca0.2)TiO3 is prepared, which has excellent thermal and mechanical stability. At the wide temperature range of 327–689 K (tan δ < 0.01) and below ≈7 GPa, the material shows extraordinary functional performance. Comprehensive study indicates that the ceramic possesses a single‐phase cubic perovskite structure, and as the pressure increases, the material undergoes a transition at ≈8 GPa, in which enormous large grains crack into smaller grains, but the space group Pm3¯m does not change. In addition, with further compression, the grains begin to rotate and re‐orientate at ≈9 GPa. Based on the investigations, it is considered that the suitable doping of multiple cations can effectively improve the stability of ceramics, and it also paves the experimental way to further study thermally and mechanically stable high‐entropy ceramics.

Abstract Since their inception, frequency combs generated in microresonators, known as microcombs, have sparked significant scientific interests. Among the various applications leveraging microcombs, soliton microcombs are often preferred due to their inherent mode-locking capability. However, this choice introduces additional system complexity because an initialization process is required. Meanwhile, despite the theoretical understanding of the dynamics of other comb states, their practical potential, particularly in applications like sensing where simplicity is valued, remains largely untapped. Here, we demonstrate controllable generation of sub-combs that bypasses the need for accessing bistable regime. And in a graphene-sensitized microresonator, the sub-comb heterodynes produce stable, accurate microwave signals for high-precision gas detection. By exploring the formation dynamics of sub-combs, we achieved 2 MHz harmonic comb-to-comb beat notes with a signal-to-noise ratio (SNR) greater than 50 dB and phase noise as low as − 82 dBc/Hz at 1 MHz offset. The graphene sensitization on the intracavity probes results in exceptional frequency responsiveness to the adsorption of gas molecules on the graphene of microcavity surface, enabling detect limits down to the parts per billion (ppb) level. This synergy between graphene and sub-comb formation dynamics in a microcavity structure showcases the feasibility of utilizing microcombs in an incoherent state prior to soliton locking. It may mark a significant step toward the development of easy-to-operate, systemically simple, compact, and high-performance photonic sensors. Graphical Abstract

Abstract Background Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common neurological problems occurring in the perinatal period. However, there still is not a promising approach to reduce long-term neurodevelopmental outcomes of HIE. Recently, itaconate has been found to exhibit anti-oxidative and anti-inflammatory effects. However, the therapeutic efficacy of itaconate in HIE remains inconclusive. Therefore, this study attempts to explore the pathophysiological mechanisms of oxidative stress and inflammatory responses in HIE as well as the potential therapeutic role of a derivative of itaconate, 4-octyl itaconate (4OI). Methods We used 7-day-old mice to induce hypoxic-ischemic (HI) model by right common carotid artery ligation followed by 1 h of hypoxia. Behavioral experiments including the Y-maze and novel object recognition test were performed on HI mice at P60 to evaluate long-term neurodevelopmental outcomes. We employed an approach combining non-targeted metabolomics with transcriptomics to screen alterations in metabolic profiles and gene expression in the hippocampal tissue of the mice at 8 h after hypoxia. Immunofluorescence staining and RT-PCR were used to evaluate the pathological changes in brain tissue cells and the expression of mRNA and proteins. 4OI was intraperitoneally injected into HI model mice to assess its anti-inflammatory and antioxidant effects. BV2 and C8D1A cells were cultured in vitro to study the effect of 4OI on the expression and nuclear translocation of Nrf2. We also used Nrf2-siRNA to further validate 4OI-induced Nrf2 pathway in astrocytes. Results We found that in the acute phase of HI, there was an accumulation of pyruvate and lactate in the hippocampal tissue, accompanied by oxidative stress and pro-inflammatory, as well as increased expression of antioxidative stress and anti-inflammatory genes. Treatment of 4OI could inhibit activation and proliferation of microglial cells and astrocytes, reduce neuronal death and relieve cognitive dysfunction in HI mice. Furthermore, 4OI enhanced nuclear factor erythroid-2-related factor (Nfe2l2; Nrf2) expression and nuclear translocation in astrocytes, reduced pro-inflammatory cytokine production, and increased antioxidant enzyme expression. Conclusion Our study demonstrates that 4OI has a potential therapeutic effect on neuronal damage and cognitive deficits in HIE, potentially through the modulation of inflammation and oxidative stress pathways by Nrf2 in astrocytes.

Abstract Earth’s lower mantle is a potential water reservoir. The physical and chemical properties of the region are in part controlled by the Fe3+/ΣFe ratio and total iron content in bridgmanite. However, the water effect on the chemistry of bridgmanite remains unclear. We carry out laser-heated diamond anvil cell experiments under hydrous conditions and observe dominant Fe2+ in bridgmanite (Mg, Fe)SiO3 above 105 GPa under the normal geotherm conditions corresponding to depth > 2300 km, whereas Fe3+-rich bridgmanite is obtained at lower pressures. We further observe FeO in coexistence with hydrous NiAs-type SiO2 under similar conditions, indicating that the stability of ferrous iron is a combined result of H2O effect and high pressure. The stability of ferrous iron in bridgmanite under hydrous conditions would provide an explanation for the nature of the low-shear-velocity anomalies in the deep lower mantle. In addition, entrainment from a hydrous dense layer may influence mantle plume dynamics and contribute to variations in the redox conditions of the mantle.

Sertoli cells (SCs) maintain testicular homeostasis and promote spermatogenesis by forming the blood-testis barrier (BTB) and secreting growth factors. The pro-proliferative and anti-apoptotic effects of nerve growth factor (NGF) on SCs have been proved previously. It is still unclear whether the damage effect of arsenic on testis is related to the inhibition of NGF expression, and whether NGF can mitigate arsenic-induced testicular damage by decreasing the damage of SCs induced by arsenic. Here, the lower expression of NGF in testes of arsenic exposed mice (freely drinking water containing 15 mg/l of NaAsO2) was observed through detection of Western blot and Real-time PCR. Subsequently, hematoxylin and eosin (HE) staining, Evans blue staining and transmission electron microscopy were used to evaluate the pathology, BTB permeability and tight junction integrity in testes of control mice, arsenic exposed mice (freely drinking water containing 15 mg/l of NaAsO2) and arsenic + NGF treated mice (freely drinking water containing 15 mg/l of NaAsO2 + intraperitoneal injection with 30 μg/kg of NGF), respectively. Evidently, spermatogenic tubule epithelial cells in testis of arsenic exposed mice were disordered and the number of cell layers was reduced, accompanied by increased permeability and damaged integrity of the tight junction in BTB, but these changes were less obvious in testes of mice treated with arsenic + NGF. In addition, the sperm count, motility and malformation rate of mice treated with arsenic + NGF were also improved. On the basis of the above experiments, the viability and apoptosis of primary cultured SCs treated with arsenic (10 μM NaAsO2) or arsenic + NGF (10 μM NaAsO2 + 100 ng/mL NGF) were detected by Cell counting kit-8 (CCK8) and transferase-mediated DUTP-biotin nick end labeling (TUNEL) staining, respectively. It is found that NGF ameliorated the decline of growth activity and the increase of apoptosis in arsenic-induced SCs. This remarkable biological effect that NGF inhibited the increase of Bax expression and the decrease of Bcl-2 expression in arsenic-induced SCs was also determined by western blot and Real-time PCR. Moreover, the decrease in transmembrane resistance (TEER) and the expression of tight junction proteins ZO-1 and occludin was mitigated in SCs induced by arsenic due to NGF treatment. In conclusion, the above results confirmed that NGF could ameliorate the injury effects of arsenic on testis, which might be related to the function of NGF to inhibit arsenic-induced SCs injury.

Objective: Pulmonary cavity lesion is one of the commonly seen lesions in lung caused by a variety of malignant and non-malignant diseases. Diagnosis of a cavity lesion is commonly based on accurate recognition of the typical morphological characteristics. A deep learning-based model to automatically detect, segment, and quantify the region of cavity lesion on CT scans has potential in clinical diagnosis, monitoring, and treatment efficacy assessment. Methods: A weakly-supervised deep learning-based method named CSA2-ResNet was proposed to quantitatively characterize cavity lesions in this paper. The lung parenchyma was firstly segmented using a pretrained 2D segmentation model, and then the output with or without cavity lesions was fed into the developed deep neural network containing hybrid attention modules. Next, the visualized lesion was generated from the activation region of the classification network using gradient-weighted class activation mapping, and image processing was applied for post-processing to obtain the expected segmentation results of cavity lesions. Finally, the automatic characteristic measurement of cavity lesions (e.g., area and thickness) was developed and verified. Results: the proposed weakly-supervised segmentation method achieved an accuracy, precision, specificity, recall, and F1-score of 98.48%, 96.80%, 97.20%, 100%, and 98.36%, respectively. There is a significant improvement (P < 0.05) compared to other methods. Quantitative characterization of morphology also obtained good analysis effects. Conclusions: The proposed easily-trained and high-performance deep learning model provides a fast and effective way for the diagnosis and dynamic monitoring of pulmonary cavity lesions in clinic. Clinical and Translational Impact Statement: This model used artificial intelligence to achieve the detection and quantitative analysis of pulmonary cavity lesions in CT scans. The morphological features revealed in experiments can be utilized as potential indicators for diagnosis and dynamic monitoring of patients with cavity lesions

The accurate prediction of carbon dioxide (CO2) emissions in the building industry can provide data support and theoretical insights for sustainable development. This study proposes a hybrid model for predicting CO2 emissions that combines a multi-strategy improved particle swarm optimization (MSPSO) algorithm with a long short-term memory (LSTM) model. Firstly, the particle swarm optimization (PSO) algorithm is enhanced by combining tent chaotic mapping, mutation for the least-fit particles, and a random perturbation strategy. Subsequently, the performance of the MSPSO algorithm is evaluated using a set of 23 internationally recognized test functions. Finally, the predictive performance of the MSPSO-LSTM hybrid model is assessed using data from the building industry in the Yangtze River Delta region as a case study. The results indicate that the coefficient of determination (R2) of the model reaches 0.9677, which is more than 10% higher than that of BP, LSTM, and CNN non-hybrid models and demonstrates significant advantages over PSO-LSTM, GWO-LSTM, and WOA-LSTM hybrid models. Additionally, the mean square error (MSE) of the model is 2445.6866 Mt, and the mean absolute error (MAE) is 4.1010 Mt, both significantly lower than those of the BP, LSTM, and CNN non-hybrid models. Overall, the MSPSO-LSTM hybrid model demonstrates high predictive accuracy for CO2 emissions in the building industry, offering robust support for the sustainable development of the industry.

Abstract Background The non-invasive imaging of leukocyte trafficking to assess inflammatory areas and monitor immunotherapy is currently generating great interest. There is a need to develop more robust cell labelling and imaging approaches to track living cells. Positron emission tomography (PET), a highly sensitive molecular imaging technique, allows precise signals to be produced from radiolabelled moieties. Here, we developed a novel leukocyte labelling approach with the PET radioisotope zirconium-89 (89Zr, half-life of 78.4 h). Experiments were carried out using human leukocytes, freshly isolated from whole human blood. Results The 89Zr-leukocyte labelling efficiency ranged from 46 to 87% after 30–60 min. Radioactivity concentrations of labelled cells were up to 0.28 MBq/1 million cells. Systemically administered 89Zr-labelled leukocytes produced high-contrast murine PET images at 1 h–5 days post injection. Murine biodistribution data showed that cells primarily distributed to the lung, liver, and spleen at 1 h post injection, and are then gradually trafficked to liver and spleen over 5 days. Histological analysis demonstrated that exogenously 89Zr-labelled human leukocytes were present in the lung, liver, and spleen at 1 h post injection. However, intravenously injected free [89Zr]Zr4+ ion showed retention only in the bone with no radioactivity in the lung at 5 days post injection, which implied good stability of radiolabelled leukocytes in vivo. Conclusions Our study presents a stable and generic radiolabelling technique to track leukocytes with PET imaging and shows great potential for further applications in inflammatory cell and other types of cell trafficking studies.

IntroductionAutism Spectrum Disorder (ASD) is a common neurodevelopmental disorder emerging in early childhood, with heterogeneous clinical outcomes across individuals. This study aims to recognize neuroimaging genetic factors associated with outcomes of ASD after a 4-year follow-up.MethodsA total of 104 ASD children were included in this study; they underwent clinical assessments, MRI data acquisition, and the whole exome sequencing (WES). Exome functional risk score (EFRS) was calculated based on WES; and two modalities of brain connectivity were constructed based on MRI data, that is functional connectivity (FC) for functional MRI (fMRI), and individual differential structural covariance network (IDSCN) for structural MRI (sMRI), to explore the neuroimaging genetic biomarker of outcomes of ASD children.ResultsRegression analysis found EFRS predicts social adaptability at the 4-year follow-up (Y = -0.013X + 9.29, p = 0.003). We identified 19 pairs of FC associated with autism symptoms severity at follow-up, 10 pairs of FC and 4 pairs of IDSCN associated with social adaptability at follow-up, and 10 pairs of FC associated with ASD EFRS by support vector regression (SVR). Related brain regions with prognostic predictive effects are mainly distributed in superior frontal gyrus, occipital cortex, temporal cortex, parietal cortex, paracentral lobule, pallidum, and amygdala for FC, and temporal cortex, thalamus, and hippocampus for IDSCN. Mediation model showed that ASD EFRS affects the social communication of ASD children through the mediation of FC between left middle occipital gyrus and left pallidum (RMSEA=0.126, CMIN=80.66, DF=42, p< 0.001, CFI=0.867, AIC=152). DiscussionOur findings underscore that both EFRS and brain connectivity can predict social adaptability, and that brain connectivity serving as mediator in the relationship of EFRS and behaviors of ASD, suggesting the intervention targets in the future clinical application.

Since the model parameters of the shaking table exist in a non-linear form, this leads to distortion of the reproduced waveforms and can even lead to bias in the ground vibration test results. Therefore, the selection of the controller is particularly critical. Multi-variable (MVC) controllers are often used in shaking table control, to improve the control effect of MVC controllers. In this paper, a multi-parametric (BP-MVC) controller based on BP neural network is proposed. The BP neural network is applied to the multi-parameter (MVC) controller to identify the shaking table model, adjust the parameters in real-time, accelerate the convergence speed, and reduce the system error. The simulation results show that the correlation coefficient (CC) of the BP-MVC controller is greater than 0.985, and the root-mean-square error (RMSE) and mean absolute error (MAE) are less than 0.04 and 0.25, respectively, in a nonlinear, time-varying hydraulic system. This suggests that the BP-MVC controller has a better control performance and parameter adaptivity, which can provide a reference for the subsequent ground vibration tests.

Ionizing radiation has garnered considerable attention as a combination partner for immunotherapy due to its potential immunostimulatory effects. In contrast to the more commonly used external beam radiation, we explored the feasibility of combining chimeric antigen receptor (CAR) T cell therapy with targeted radionuclide therapy (TRT), which is achieved by delivering β-emitting 177Lu-DOTATATE to tumor via tumor-infiltrating CAR T cells that express somatostatin receptor 2 (SSTR2). We hypothesized that the delivery of radiation to tumors could synergize with CAR T therapy, resulting in enhanced antitumor immunity and tumor response. To determine the optimal dosage and timing of 177Lu-DOTATATE treatment, we measured CAR T cell infiltration and expansion in tumors longitudinally through positron emission tomography (PET) using a SSTR2-specific positron-emitting radiotracer,18F-NOTA-Octreotide. In animals receiving CAR T cells and a low–dose (2.5 Gy) of TRT following the administration of 177Lu-DOTATATE, we observed a rapid regression of large subcutaneous tumors, which coincided with a dramatic increase in serum proinflammatory cytokines. Tumor burden was also reduced when a higher radiation dose (6 Gy) was delivered to the tumor. However, this higher dose led to cell death in both the tumor and CAR T cells. Our study suggests that there may exist an optimum range of TRT dosage that can enhance T cell activity and sensitize tumor cells to T cell killing, which may result in more durable tumor control compared to a higher radiation dose.

Abstract The Chinese tapertail anchovy, Coilia nasus, is a socioeconomically important anadromous fish that migrates from near ocean waters to freshwater to spawn every spring. The analysis of genomic architecture and information of C. nasus were hindered by the previously released versions of reference genomes with gaps. Here, we report the assembly of a chromosome-level gap-free genome of C. nasus by incorporating high-coverage and accurate long-read sequence data with multiple assembly strategies. All 24 chromosomes were assembled without gaps, representing the highest completeness and assembly quality. We assembled the genome with a size of 851.67 Mb and used BUSCO to estimate the completeness of the assembly as 92.5%. Using a combination of de novo prediction, protein homology and RNA-seq annotation, 21,900 genes were functionally annotated, representing 99.68% of the total predicted protein-coding genes. The availability of gap-free reference genomes for C. nasus will provide the opportunity for understanding genome structure and function, and will also lay a solid foundation for further management and conservation of this important species.

Human papillomavirus (HPV) is a prevalent cause of mucosal and cutaneous infections and underlying conditions ranging from benign warts to anogenital and oropharyngeal cancers affecting both males and females, notably cervical cancer. Cervical cancer is the fourth leading cause of cancer deaths among women globally and is the most impactful in low- and middle-income countries (LMICs), where the costs of screening and licensed L1-based HPV vaccines pose significant barriers to comprehensive administration. Additionally, the licensed L1-based HPV vaccines fail to protect against all oncogenic HPV types. This study generated three independent lots of an L2-based target antigen (LBTA), which was engineered from conserved linear L2-protective epitopes (aa11–88) from five human alphapapillomavirus genotypes in E. coli under cGMP conditions and adjuvanted with aluminum phosphate. Vaccination of rabbits with LBTA generated high neutralizing antibody titers against all 17 HPV types tested, surpassing the nine types covered by Gardasil®9. Passive transfer of naïve mice with LBTA antiserum revealed its capacity to confer protection against vaginal challenge with all 17 αHPV types tested. LBTA shows stability at room temperature over >1 month. Standard in vitro and in vivo toxicology studies suggest a promising safety profile. These findings suggest LBTA’s promise as a next-generation vaccine with comprehensive coverage aimed at reducing the economic and healthcare burden of cervical and other HPV+ cancers in LMICs, and it has received regulatory approval for a first-in-human clinical study (NCT05672966).

Abstract Background Removal of tonsils and adenoids is among the most common surgical procedures worldwide. Evidence of increased risk of cancer following such surgery is, however, inconclusive. Methods We conducted a population-based, sibling-controlled cohort study of 4,953,583 individuals in Sweden with a follow-up during 1980–2016. History of tonsillectomy, adenotonsillectomy, and adenoidectomy was identified from the Swedish Patient Register whereas incident cases of cancer during follow-up were identified from the Swedish Cancer Register. We used Cox models to calculate hazard ratios (HR) with 95% confidence intervals (CI) of cancer in both a population and a sibling comparison. The sibling comparison was used to assess the potential impact of familial confounding, due to shared genetic or non-genetic factors within a family. Results We found a modestly increased risk for any cancer following tonsillectomy, adenoidectomy, or adenotonsillectomy in both the population (HR 1.10; 95%CI 1.07–1.12) and sibling (HR 1.15; 95%CI 1.10–1.20) comparisons. The association did not differ greatly by type of surgery, age at surgery, or potential indication for surgery, and persisted more than two decades after surgery. An excess risk was consistently observed for cancer of the breast, prostate, thyroid, and for lymphoma in both population and sibling comparisons. A positive association was observed for pancreatic cancer, kidney cancer, and leukemia in the population comparison whereas a positive association was observed for esophageal cancer in the sibling comparison. Conclusions Surgical removal of tonsils and adenoids is associated with a modestly increased risk of cancer during the decades following the surgery. The association is unlikely attributed to confounding due to shared genetic or non-genetic factors with a family.

Abstract The limited number of targetable tumor-specific antigens and the immunosuppressive nature of the microenvironment within solid malignancies represent major barriers to the success of chimeric antigen receptor (CAR)-T cell therapies. Here, using epithelial cell adhesion molecule (EpCAM) as a model antigen, we used alanine scanning of the complementarity-determining region to fine-tune CAR affinity. This allowed us to identify CARs that could spare primary epithelial cells while still effectively targeting EpCAMhigh tumors. Although affinity-tuned CARs showed suboptimal antitumor activity in vivo, we found that inducible secretion of interleukin-12 (IL-12), under the control of the NFAT promoter, can restore CAR activity to levels close to that of the parental CAR. This strategy was further validated with another affinity-tuned CAR specific for intercellular adhesion molecule-1 (ICAM-1). Only in affinity-tuned CAR-T cells was NFAT activity stringently controlled and restricted to tumors expressing the antigen of interest at high levels. Our study demonstrates the feasibility of specifically gearing CAR-T cells towards recognition of solid tumors by combining inducible IL-12 expression and affinity-tuned CAR.

According to the static aeroelastic characteristics of Solar-Powered UAV (SP-UAV) with large aspect ratio, this paper develops a nolinear aeroelastic analysis method which takes into account both the calculation accuracy and efficiency. Firstly, we establish the finite element model of the geometric nonlinear structure, which is verified by the static test of the whole UAV to reduce the calculation error caused by the simplified method of structure model. Then, the aerodynamic model of SP-UAV is established by using Curved Vortex Lattice (CVL), and the structure-aerodynamic coupling interpolation is realized by the Thin Plate Spline-interpolation (TPS) method, so as to complete the full static aeroelastic analysis. The analysis indicate that the calculated results of the longitudinal trim are well match the first flight condition. In particular, considering the elevator efficiency loss occurred in longitudinal trim analysis of the UAV, we design an optimization scheme to improve the efficiency of the elevator by about 15%. The simulation results show that the loss of elevator efficiency of flexible solar UAV with high aspect ratio is non-negligible, with the maximum value higher than 40% under high dynamic pressure. In actual flight, the speed of UAV must be reduced as much as possible to minimize the loss of rudder efficiency, while the elastic control method should be considered in flight control.

Abstract The ability to image adoptively transferred T cells in the body and to eliminate them to avoid toxicity will be vital for chimeric antigen receptor (CAR) T cell therapy, particularly against solid tumors with higher risk of off-tumor toxicity. Previously, we have demonstrated the utility of somatostatin receptor 2 (SSTR2) for CAR T cell imaging, illustrating the expansion and contraction of CAR T cells in tumor as well as off-tumor expansion. Using intercellular adhesion molecule 1 (ICAM-1)-specific CAR T cells that secrete interleukin (IL)-12 as a model, herein we examined the potential of SSTR2 as a safety switch when combined with the SSTR2-specific maytansine-octreotate conjugate PEN-221. Constitutive secretion of IL-12 led to continuous expansion of CAR T cells after rapid elimination of tumors, causing systemic toxicity in mice with intact MHC expression. Treatment with PEN-221 rapidly reduced the abundance of CAR T cells, decreasing the severity of xenogeneic graft-versus-host disease (GvHD), and prolonged survival. Our study supports the development of SSTR2 as a single genetic marker for CAR T cells that is readily applicable to humans both for anatomical detection of T cell distribution and an image-guided safety switch for rapid elimination of CAR T cells.

BackgroundInflammation is critically involved in the development of human cancer, and blood inflammatory biomarkers have been proposed to indicate the risk of different cancer types.MethodsUsing the Swedish Apolipoprotein-Related Mortality Risk (AMORIS) Cohort (N=812,073), we first performed a time-to-event analysis to evaluate the association of the baseline level of 12 blood inflammatory biomarkers measured during 1985-1996 with the subsequent risk of head and neck cancer (HNC) identified through the nationwide Swedish Cancer Register until end of 2020. A nested case-control study was further conducted to demonstrate the longitudinal trends of the studied biomarkers during the 30-year period prior to diagnosis of HNC.ResultsIn the time-to-event analysis, we identified a total of 2,510 newly diagnosed HNC cases. There was an increased risk of HNC per standard deviation (SD) increase of haptoglobin (hazard ratio [HR]: 1.25; 95% confidence interval [CI]: 1.21-1.30), leukocytes (HR: 1.22; 95%CI: 1.17-1.28), sedimentation rate (HR: 1.17; 95%CI: 1.07-1.29), and monocytes (HR: 1.34; 95%CI: 1.07-1.68) at baseline, after adjustment for age, sex, fasting status, occupational status, and country of birth. In contrast, there was a decreased risk of HNC per SD increase of lymphocytes in % (HR: 0.85; 95%CI: 0.73-0.99) and lymphocyte-to-monocyte ratio (LMR) (HR: 0.81; 95%CI: 0.69-0.95) at baseline. In the nested case-control study using repeatedly measured biomarker levels, we found that individuals with HNC had consistently higher levels of haptoglobin, leukocytes, sedimentation rate, and monocytes, as well as consistently lower levels of lymphocytes in % and LMR, during the 30-year period prior to diagnosis, compared to controls.ConclusionBased on a cohort of more than half a million participants with up to 35 years of follow-up, our findings provide solid evidence supporting the presence of alterations in blood inflammatory biomarkers during the decades before diagnosis of HNC.

Cancer is a global leading cause of death, with nearly 10 million people dying from cancer in 2020. Photodynamic therapy (PDT) has emerged as a promising cancer treatment modality; however, the potential molecular mechanisms remain obscure. Herein, we designed a near-infrared (NIR) light-activated nanoplatform (TPBC-PEG) to explore the therapeutic effects and mechanisms of PDT by using a model of intratibial primary and pulmonary metastasis osteosarcoma. Under laser irradiation, TPBC-PEG photosensitizer dose-dependently inhibited proliferative and metastatic capabilities while promoting apoptosis of osteosarcoma cells in vitro, and also effectively suppressed carcinogenesis and pulmonary metastasis in osteosarcoma xenograft mouse model. Moreover, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis after high-throughput mRNA-seq indicated that the HIPPO signaling pathway was one of the 20 most significantly related signaling pathways. And a series of experiments for determining the HIPPO signaling activity were conducted to reconfirm the specificity. Collectively, PDT of TPBC-PEG micelles against carcinogenesis and pulmonary metastasis of deep-seated intratibial osteosarcoma was achieved by activating HIPPO signaling pathway. Our study identified a hitherto uncharacterized molecular mechanism of PDT, which may provide new insights to understand and design promising nanoplatforms for future cancer therapies.

A Chinese Compilation of Physical Activities was compiled to estimate the energy costs of physical activities (PAs) using data on adults aged 18–64. Data were obtained from published articles and laboratory measurements. Databases, including PubMed, Embase, Scopus, Ebsco, Web of Science, Chinese National Knowledge Infrastructure, Wan Fang Data, National Science and Technology Report Service, Public Health Scientific Data were searched to collect data from inception to January 2022, on energy expenditure associated with PA in the healthy Chinese population. Two reviewers independently screened the literature and extracted, classified, and summarized data. Data were measured for 36 PAs using indirect calorimetry. Detailed descriptions of specific activities and metabolic equivalent values were provided by summarizing 241 physical activities in 13 categories. The first edition of the Chinese Compilation of PAs in Healthy Adults Aged 18–64(CCPA) was created. It provides valuable resources for people who regularly engage in physical exercise, researchers, educators, fitness professionals, and health or commercial sectors to quickly obtain various PA MET intensities. In the future, the energy expenditure of various PAs of different ages within the Chinese population can be measured based on the CCPA.

Objective: In this paper, we obtained the NOT5 gene from Saccharomyces uvarum by transcriptome analysis. Analysis of its biological information can lay the foundation for the later study of the role of the gene. Methods: The primary structure, secondary structure, tertiary structure, and structural domains of the encoded protein were predicted using online analysis tools such as COILS Server, SOPMA, and Alpha Fold. Results: The length of the NOT5 gene was 1446 bp, encoding 481 amino acids, and it was located on chromosome XVI 690107~691789. The genetic relationship analysis showed that this gene was the closest to Saccharomyces eubayanus NOT5 like protein XP018219088.1, and had high homology. Its molecular formula was C2493H3848N654O795S19, and its molecular mass was 56311.02. It was an unstable hydrophilic protein. The protein encoded by this gene did not contain a signal peptide, had no transmembrane region, had a coiled helix region, and was subcellularly localized on the mitochondria in the cytoplasm. The secondary structure of the protein was dominated by random coils. Pfam Not3 and Pfam NOT2_3_5 domains were predicted. Yeast Not1-Not2-Not5 (4by6.1.C) was used as the template to construct the tertiary structure of NOT5 protein, and the sequence consistency between the two could reach 89.88%. Conclusion: The structure of the protein encoded by the NOT5 gene was unstable, and would interconnect translation and transcription in the cell.

BackgroundsPD-1 inhibitors and TKIs have been used to treat advanced osteosarcoma, but there is still a lack of intuitive data for the comparison of their efficacy. We conducted a meta-analysis to evaluate their therapeutic benefits.MethodsA systematic methodological search of five primary electronic databases was performed. Studies with a randomized design of any type about PD-1 inhibitors or TKIs for the treatment of advanced osteosarcoma were included. The primary outcomes mainly included CBR, PFS, OS and ORR, The CR, PR, SD and AEs were the secondary outcomes. The survival period (months) of patients was taken as the main analysis data. Random-effects models were used for meta-analysis.ResultsEight immunocheckpoint inhibitors in 327 patients from 10 clinical trials were finally evaluated. For OS, TKIs [11.67 months (95% CI, 9.32-14.01)] show more obvious advantages than PD-1 inhibitors [6.37 months (95% CI, 3.96-8.78)]. For PFS, TKIs [4.79 months (95% CI, 3.33-6.24)] are longer than PD-1 inhibitors [1.46 months (95% CI, 1.23-1.69)]. Although there was no fatal event, attention should still be paid, especially during the combined application of PD-1 inhibitors with TKIs since their obvious AEs.ConclusionsThe findings of this study suggest that patients with advanced osteosarcoma, TKIs may be more beneficial than PD-1 inhibitors. TKIs combined with PD-1 inhibitors has a bright future in the treatment of advanced osteosarcoma, but we should always pay attention to the strong side effects.

Background: Several autoimmune and inflammatory disorders, including autoimmune thyroid diseases (AITD), have been linked to Th17 cells and the IL-23/IL-17 axis. Current data suggest that genetic variation contributes greatly to disease susceptibility to AITD. Objectives: To study the role of single nucleotide polymorphisms (SNPs) of IL-23/IL-17 pathway in AITD predisposition and test the gene-gene/gene-sex interactions in these loci. Methods: A total of 1051 patients with AITD, including 657 patients with Graves' disease (GD) and 394 patients with Hashimoto's thyroiditis (HT), and 874 healthy controls were enrolled in this case-control association study. Six SNPs were selected and genotyped by multiplex PCR combined with high-throughput sequencing. Interactions were tested by the general multifactor dimensionality reduction (GMDR) method. Results: Allele C and combinational genotype AC+CC of rs3212227 within IL-23 were significantly associated with GD with goiter (p=0.003 and 0.014, respectively). Allele G and combinational genotype AG+GG of rs4819554 within IL-17RA were significantly related to HT with family history and the severity of HT (p=0.011 and 0.027; p=0.041 and 0.035). Also, allele T and genotype CT+TT of rs9463772 within IL-17F were significantly correlated with the severity of HT (p=0.001 and 0.027, respectively). Moreover, high dimensional gene-sex interaction (IL-23R-IL-23-IL-17RA-IL-17F-sex) was identified in AITD, GD, and HT patients with GMDR analysis. Conclusions: Our study identified the novel loci and gene-sex interaction in AITD. This evidence, from another perspective, suggests that sex, IL-23/IL-17 pathway, and Th17 cells play an important role in the pathogenesis of AITD.

Coilia nasus is a typical anadromous migratory fish found in the lower reaches of the Yangtze River. Every year, C. nasus clusters offshore and swims upstream along the Yangtze River into the tributaries and lakes in the middle and lower reaches of the Yangtze River to breed. In this study, female C. nasus were collected as study subjects from the Chongming section of Shanghai, the Taizhou section of Jiangsu, and the Anqing section of Anhui. Their ovaries were used to examine tissue sections and investigate gene expression, including the follicle-stimulating hormone receptor (fshr), the luteinizing hormone receptor (lhr), kisspeptin-1 (kiss1), and forkhead box l2 (foxl2), which are related to reproductive development, while the serum levels of estrogen (including estradiol, E2) and progestins (including 17α,20β-dihydroxy-4-pregenen-3-one, 17α,20β-DHP) were also analyzed. Our results showed that, first, the growth period of the oocytes was small in stage II of ovarian development, in which both E2 and 17α,20β-DHP levels and gene expression were low. Then, in stage III, the growth period of the oocytes became large, and the yolk granules and oil droplets began to appear. Simultaneously, E2 and the expression of kiss1 and foxl2 were significantly elevated. Finally, stage IV was the period of a large amount of accumulation of nutrients in the oocytes, and 17α,20β-DHP levels and the expression of fshr and lhr were significantly elevated. These results enrich the theoretical study of ovarian development in the natural population of C. nasus, supplementing the biological basis of C. nasus reproduction and scientifically supporting the study of C. nasus population ecology and resource conservation.

Surface-enhanced Raman scattering (SERS) spectroscopy is a powerful technology in trace analysis. However, the wide applications of SERS in practice are limited by the expensive substrate materials and the complicated preparation processes. Here we report a simple and economical galvanic-replacement-assisted synthesis route to prepare Ag nanoparticles on Cu(0) foil (nanoAg@Cu), which can be directly used as SERS substrate. The fabrication process is fast (ca. 10 min) and easily scaled up to centimeters or even larger. In addition, the morphology of the nanoAg@Cu (with Ag particles size from 30 nm to 160 nm) can be adjusted by various additives (e.g., amino-containing ligands). Finally, we show that the as-prepared nanoAg@Cu can be used for SERS characterization of two-dimensional polymers, and ca. 298 times relative enhancement of Raman intensity is achieved. This work offers a simple and economical strategy for the scalable fabrication of silver-based SERS substrate in thin film analysis.

Key points We observed GAM characteristic in the GAOs enrichment system. Metagenome-based analysis revealed that Candidatus Contendobacter was the dominant GAOs. The EMC pathway was a novel propionyl-CoA synthesis pathway for PHV in Candidatus Contendobacter.

IntroductionThere is no denying the clinical benefits of exogenous pyruvate in the treatment of pathological metabolic acidosis. However, whether it can prevent exercise physiological metabolic acidosis, delay the occurrence of exercise fatigue, and improve the beneficial effects of exercise and its internal mechanism remain unclear.MethodsWe randomly divided 24 male SD rats into 3 groups: one group was a control without exercise (CC, n = 8), and the other two groups were supplemented with 616 mg/kg/day pyruvate (EP, n = 8) or distilled water of equal volume (EC, n = 8). These groups completed acute high-intensity interval exercise (HIIE) after 7 days of supplementation. The acid metabolism variables were measured immediately after exercise including blood pH (pHe), base excess (BE), HCO3−, blood lactic acid and skeletal muscle pH (pHi). The redox state was determined by measuring the oxidized coenzyme I/reduced coenzyme I (nicotinamide adenine dinucleotide [NAD+]/reduced NAD+ [NADH]) ratio and lactate/pyruvate (L/P) ratio. In addition, the activities of lactate dehydrogenase A (LDHA), hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) were determined by ELISA.ResultsPyruvate supplementation significantly reversed the decrease of pHe, BE, HCO3− and pHi values after HIIE (p < 0.001), while significantly increased the activities of LDHA (p = 0.048), HK (p = 0.006), and PFK (p = 0.047). Compared with the CC, the NAD+/NADH (p = 0.008) ratio and the activities of LDHA (p = 0.002), HK (p < 0.001), PFK (p < 0.001), and PK (p = 0.006) were significantly improved in EP group.DiscussionThis study provides compelling evidence that oral pyruvate attenuates HIIE-induced intracellular and extracellular acidification, possibly due to increased activity of LDHA, which promotes the absorption of H+ in the LDH reaction. The beneficial effects of improving the redox state and glycolysis rate were also shown. Our results suggest that pyruvate can be used as an oral nutritional supplement to buffer HIIE induced metabolic acidosis.

Maximizing the absorption and utilization of solar energy is a bottleneck issue and hot research concern for high-altitude long-endurance (HALE) solar-powered UAVs (SP-UAVs). This paper investigates the overall design and task optimization for a deformable/reconfigurable SP-UAV platform that utilizes its modular characteristics to optimize the overall solar absorption and structural weight while maximizing its mission utility. First, we establish the energy absorption/consumption model, the aerodynamic model, and the subsystem mass prediction model. Based on these models, the overall parameter design and optimization scheme of a modular SP-UAV is proposed by using heuristic intelligence algorithms. The results show that the loading ratio of the deformable modular SP-UAV increases from 8.2% to 9.8%. Then, the flight processes in both the deformed and the reconfigured cases are verified under task-oriented scenarios. Simulation results indicate that compared with comparable benchmarks with conventional layouts, deformable SP-UAVs are capable of increasing the feasible zone from 72 to 142 days. Additionally, the separation and recombination points are optimized and determined at specific latitudes and dates. A performance analysis shows that separation in the daytime can multiply, thereby increasing the flight range, although the feasible zone shrinks with increasing UAV unit number.

Lung adenocarcinoma (LUAD) is the main histological type of lung cancer with an unfavorable survival rate. Metastasis is the leading LUAD-related death with Epithelial-Mesenchymal Transition (EMT) playing an essential role. The anticancer efficacies of the active ingredients in Chonglou have been widely reported in various cancers. However, the potential therapeutic targets of the Chonglou active ingredients in LUAD patients remain unknown. Here, the network pharmacology and bioinformatics were performed to analyze the associations of the clinical characteristics, immune infiltration factors and m6A-related genes with the EMT-related genes associated with LUAD (EMT-LUAD related genes), and the molecular docking, STRING, GO, and KEGG enrichment for the drug targets of Chonglou active ingredients associated with EMT (EMT-LUAD-Chonglou related genes). And, cell viability analysis and cell invasion and infiltration analysis were used to confirm the theoretical basis of this study. A total of 166 EMT-LUAD related genes were identified and a multivariate Cox proportional hazards regression model with a favorable predictive accuracy was constructed. Meanwhile, the immune cell infiltration, immune cell subsets, checkpoint inhibitors and the expression of m6A-related genes were significantly associated with the risk scores for EMT-LUAD related genes with independent significant prognostic value of all included LUAD patients. Furthermore, 12 EMT-LUAD-Chonglou related genes with five core drug targets were identified, which participated in LUAD development through extracellular matrix disassembly, collagen metabolic process, collagen catabolic process, extracellular matrix organization, extracellular structure organization and inflammatory response. Moreover, we found that the active ingredients of Chonglou could indeed inhibit the progression of lung adenocarcinoma cells. These results are oriented towards EMT-related genes to achieve a better understanding of the role of Chonglou and its targets in osteosarcoma development and metastasis, thus guiding future preclinical studies and facilitating clinical translation of LUAD treatment.

As flipped classroom has received much attention from researchers and educators, some scholars have investigated the effectiveness of this teaching mode in various English as a foreign language (EFL) settings; however, such an instruction mode has been under-investigated in the Chinese EFL context. Therefore, the current study examined a flipped course’s impact on Chinese EFL learners’ writing performance and anxiety utilizing a pretest-posttest non-equivalent group quasi-experimental design. First, it selected a sample of 50 Chinese EFL learners from two intact language school classes as the participants via the convenience sampling method. Then, it randomly assigned participants of these two intact classes to a control group (n = 24), taught based on the traditional method of writing instruction, and an experimental group (n = 26), instructed based on social media-supported flipped instruction. The study used two writing tasks and a writing anxiety inventory to gather the data from the participants. The descriptive and inferential statistics results showed that the experimental group—taught based on flipped writing instruction—significantly enhanced their writing performance. Moreover, they revealed that the flipped course substantially reduced participants’ writing anxiety. Implications of such findings have been elaborated for EFL research and practice.

It is beneficial for breeding and boosting the flower value of ornamental plants such as orchids, which can take several years of growth before blooming. Over the past few years, in vitro flowering of Cymbidium nanulum Y. S. Wu et S. C. Chen has been successfully induced; nevertheless, the production of many abnormal flowers has considerably limited the efficiency of this technique. We carried out transcriptomic analysis between normal and abnormal in vitro flowers, each with four organs, to investigate key genes and differentially expressed genes (DEGs) and to gain a comprehensive perspective on the formation of abnormal flowers. Thirty-six DEGs significantly enriched in plant hormone signal transduction, and photosynthesis-antenna proteins pathways were identified as key genes. Their broad upregulation and several altered transcription factors (TFs), including 11 MADS-box genes, may contribute to the deformity of in vitro flowers. By the use of weighted geneco−expression network analysis (WGCNA), three hub genes, including one unknown gene, mitochondrial calcium uniporter (MCU) and harpin-induced gene 1/nonrace-specific disease resistance gene 1 (NDR1/HIN1-Like) were identified that might play important roles in floral organ formation. The data presented in our study may serve as a comprehensive resource for understanding the regulatory mechanisms underlying flower and floral organ formation of C. nanulum Y. S. Wu et S. C. Chen in vitro.

In the present note, we develop Hermite-Hadamard type inequality and He's inequality for exponential type convex fuzzy interval-valued functions via fuzzy Riemann-Liouville fractional integral and fuzzy He's fractional integral. Moreover, we establish Hermite-Fejér inequality via fuzzy Riemann-Liouville fractional integral.

The vertex arboricity a(G) of a graph G is the minimum number of colors required to color the vertices of G such that no cycle is monochromatic. The list vertex arboricity al(G) is the list version of this concept. In this paper, we prove that if G is a planar graph without 5-cycles intersecting with 6-cycles, then al(G)≤2.

A case of eruptive lichen planus is reported. A 69-year-old man had generalized dark red erythema and papules with pruritus for 5 months. Dermatological examination showed dark red erythema on the head, face, trunk and limbs, some of which were hypertrophic lichenoid and flat papules covered by fine scales. Dandruff was present on the scalp, with no hair bundles. Wickham marks were seen on oral buccal mucosa, and white macules were seen on genital mucosa. Histopathology of skin lesions showed epidermal defect, band-like lymphocytic infiltration and pigment incontinence in the superficial dermis. PAS staining was negative. The diagnosis was eruption lichen planus. After 1 month of treatment with low dose glucocorticoid combined with hydroxychloroquine, hyperpigmentation was left with no new rash.