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To attain native-like proficiency in second-language word usage, learners have to discover intricate semantic categories in the target language. We investigated the factors influencing the development of two aspects of second-language learners' semantic categories: the category center and category boundary of word meanings. In the experiment, second-language learners of Japanese, whose first language is Mandarin, were asked to produce the best verb for 28 videos depicting various cutting and breaking events. Descriptive analyses were conducted to compare the verb patterns used by second-language learners with those of native speakers. The second-language learners' verb use pattern suggested their struggle in delineating the semantic ranges of breaking verbs in a native-like manner. Model analyses further revealed that different factors contribute to learning two different aspects of word meanings. The learning category center of word meaning depended on the similarity between the lexical domains in the first and second languages. On the contrary, the success of learning the semantic boundaries of verbs required a large input frequency and smaller semantic coverage, and smaller category ambiguity. The results suggest that constructing a semantic domain in the second language should be evaluated from at least two different aspects of semantic representation.

ABSTRACT Translucent post-larvae disease (TPD), caused by Vibrio parahaemolyticus (Vp TPD), has become an emerging shrimp disease, affecting more than 70%–80% of coastal shrimp nurseries in China in spring 2020. Here, we investigated the key virulence factors of Vp TPD by analyzing protein fragments, related genomic information, as well as experimental challenge tests. After investigating the toxic effects of purified protein fragments with different molecular weights (MWs) from Vp TPD, we found that only the protein fragments with MW >100 kDa showed similar lethality to live Vp TPD in the experimental challenge test using post-larvae shrimp. Meanwhile, similar histopathological changes exhibiting in the hepatopancreas and midgut of the diseased individuals were observed in the post-larvae shrimp challenged with either bacterial protein fragments (MW >100 kDa) or live Vp TPD. Based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and mass spectrometry analyses, two novel proteins, Vibrio high virulent protein (VHVP)-1 and VHVP-2, were identified as the candidates of key virulence factors to cause TPD. Moreover, VHVP-1 and VHVP-2 were found to be encoded by two genes (vhvp-1 and vhvp-2) tandemly located on a 187,791-bp plasmid and were predicted to depend on the same promoter following a comparative genomic analysis. Further epidemiological investigation and challenge test indicated that the V. parahaemolyticus isolate carrying only the vhvp-1 gene and lacking vhvp-2 gene could not cause mortality of experimental Penaeus vannamei post-larvae. The mutant (Δvhvp-2) by deleting vhvp-2 gene could only cause 4.92% of accumulative mortality of post-larvae that is similar to the non-Vp TPD Vibrio strain. Additionally, the complemented strains, Δvhvp-2/pBT3-vhvp-2 and Δvhvp-2/pwtCas9-vhvp-2, showed similar virulence to the wild-type Vp TPD. The results demonstrated that V. parahaemolyticus becomes lethal to post-larval shrimp by acquiring the VHVP-2 virulence factor. This study sheds light on further investigations of the pathogenic mechanism of Vp TPD and the development of strategies for early diagnosis of TPD in shrimp hatcheries. IMPORTANCE As a severe emerging shrimp disease, TPD has heavily impacted the shrimp aquaculture industry and resulted in serious economic losses in China since spring 2020. This study aimed to identify the key virulent factors and related genes of the Vp TPD, for a better understanding of its pathogenicity of the novel highly lethal infectious pathogen, as well as its molecular epidemiological characteristics in China. The present study revealed that a novel protein, Vibrio high virulent protein-2 (MW >100 kDa), is responsible to the lethal virulence of V. parahaemolyticus to shrimp post-larvae. The results are essential for effectively diagnosing and monitoring novel pathogenic bacteria, like Vp TPD, in aquaculture shrimps and would be beneficial to the fisheries department in early warning of Vp TPD emergence and developing prevention strategies to reduce economic losses due to severe outbreaks of TPD. Elucidation of the key virulence genes and genomics of Vp TPD could also provide valuable information on the evolution and ecology of this emerging pathogen in aquaculture environments.

Developing and evaluating novel diagnostic assays are crucial components of contemporary diagnostic research. The receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) are frequently used to evaluate diagnostic assays’ performance. The variation in AUC estimation can be quantified nonparametrically using resampling methods, such as bootstrapping, and then used to construct interval estimation for the AUC. When multiple observations are observed from the same subject, which is very common in veterinary diagnostic tests evaluation experiments, a traditional bootstrap-based method can fail to provide valid interval estimations of AUC. In particular, the traditional method does not account for the correlation among data observations and could result in interval estimation that fails to cover the true AUC adequately at the desired confidence level. In this paper, we proposed two novel methods to calculate the confidence interval of the AUC for correlated diagnostic test data based on cluster bootstrapping and hierarchical bootstrapping, respectively. Our simulation studies showed that both proposed methods had adequate coverage probabilities which were higher than the existing traditional method when there were intra-subject correlations. We also discussed applying the proposed methods to evaluate a novel whole-virus ELISA (wv-ELISA) diagnostic assay in detecting porcine parainfluenza virus type-1 antibodies in swine serum.

Summary: Background: Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer with a high incidence in Southern China and Southeast Asia. Patients with remote metastasis and recurrent NPC have poor prognosis. Thus, a better understanding of NPC pathogenesis may identify novel therapies to address the unmet clinical needs. Methods: H3K27ac ChIP-seq and HiChIP was applied to understand the enhancer landscapes and the chromosome interactions. Whole genome sequencing was conducted to analyze the relationship between genomic variations and epigenetic dysregulation. CRISPRi and JQ1 treatment were used to evaluate the transcriptional regulation of SOX2 SEs. Colony formation assay, survival analysis and in vivo subcutaneous patient-derived xenograft assays were applied to explore the function and clinical relevance of SOX2 in NPC. Findings: We globally mapped the enhancer landscapes and generated NPC enhancer connectomes, linking NPC specific enhancers and SEs. We found five overlapped genes, including SOX2, among super-enhancer regulated genes, survival related genes and NPC essential genes. The mRNA expression of SOX2 was repressed when applying CRISPRi targeting different SOX2 SEs or JQ1 treatment. Next, we identified a genetic variation (Chr3:181422197, G > A) in SOX2 SE which is correlated with higher expression of SOX2 and poor survival. In addition, SOX2 was highly expressed in NPC and is correlated with short survival in patients with NPC. Knock-down of SOX2 suppressed tumor growth in vitro and in vivo. Interpretation: Our study demonstrated the super-enhancer landscape with chromosome interactions and identified super-enhancer driven SOX2 promotes tumorigenesis, suggesting that SOX2 is a potential therapeutic target for patients with NPC. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Abstract As a kind of intestinal flora regulator, probiotics show great potential in the treatment of many diseases. However, orally delivered probiotics are often vulnerable to unfriendly gastrointestinal environments, resulting in a low survival rate and decreased therapeutic efficacy. Decorating or encapsulating probiotics with functional biomaterials has become a facile yet useful strategy, and probiotics can be given different functions by wearing different armors. This review systematically discusses the challenges faced by oral probiotics and the research progress of armored probiotics delivery systems. We focus on how various functional armors help probiotics overcome different obstacles and achieve efficient delivery. We also introduce the applications of armor probiotics in disease treatment and analyze the future trends of developing advanced probiotics‐based therapies.

Zirconia has been extensively used in aerospace, military, biomedical and industrial fields due to its unusual combination of high mechanical, electrical and thermal properties. However, the fundamental and critical phase transition process of zirconia has not been well studied because of its difficult first-order phase transition with formidable energy barrier. Here, we generated a machine learning interatomic potential with ab initio accuracy to discover the mechanism behind all kinds of phase transition of zirconia at ambient pressure. The machine learning potential precisely characterized atomic interactions among all zirconia allotropes and liquid zirconia in a wide temperature range. We realized the challenging reversible first-order monoclinic-tetragonal and cubic-liquid phase transition processes with enhanced sampling techniques. From the thermodynamic information, we gave a better understanding of the thermal hysteresis phenomenon in martensitic monoclinic-tetragonal transition. The phase diagram of zirconia from our machine learning potential based molecular dynamics simulations corresponded well with experimental results.

Objective: To analyze the changing trend of the global burden of thyroid cancer (TC) and its associated risk factors using data from the Global Burden of Disease study 2019 (GBD 2019). Methods: This study utilized the GBD 2019 database to analyze the burden trend of TC in various regions and countries from 1990 to 2019, while also examining the age-period-cohort (APC) effect. Additionally, the study used Bayesian age-period-cohort (BAPC) and predictive models to forecast TC incidence up until 2030. Results: According to data from 2019, there were 233,846.64 (95 % UI 211,636.89–252,806.55) cases of TC worldwide. The burden of TC varies among regions and countries, with higher incidence rates observed in moderate and above SDI regions. Age and gender also play a role, with incidence rates peaking in the >95 age group for men and the 70–74 age group for women. Additionally, women have a higher incidence than men. The APC model revealed that the impact of age was most significant among individuals aged 95 years and older, while it was lowest among those aged 0–14 years. Additionally, the period effect showed a relatively low risk of morbidity with a Period RR 0 during 2005–2019. Furthermore, the cohort effect demonstrated that the relative risk of developing the disease was lower before 1950 and higher after 1950. Predicted values show an increasing trend in thyroid incidence over the next 30 years. Conclusions: The findings of this study highlight the continued significance of thyroid cancer as a global public health issue. It is crucial to develop targeted interventions that address the specific risk factors associated with thyroid cancer. Furthermore, health policies should be customized and adapted to the unique needs of different regions and populations.

Abstract Background Treatment options are limited for recurrent/metastatic adenoid cystic carcinoma of the head and neck (R/M ACCHN). We aimed to evaluate the preliminary results of the efficacy and safety of all‐trans retinoic acid (ATRA) combined with low‐dose apatinib in patients with R/M ACCHN according to a secondary analysis of a phase II study. Methods Patients from a phase II study (NCT02775370) who orally administered 500 milligram (mg) apatinib daily until treatment‐related adverse events (AEs) intolerance or progression occurred were eligible for inclusion. Patients were further treated with combination therapy of ATRA (25 mg/m2/day) and apatinib (250 mg/day) between March 2019 and October 2021 until progression of disease (PD). Results A total of 16 patients were included with nine (56.3%) males and aged 35–69 years old. All recruited patients previously received anti‐angiogenic therapy then withdrew due to toxicities or progression occurred. The objective response rate (ORR) and disease control rate (DCR) were 18.8% and 100%, respectively. During a median follow‐up of 23.9 months (range:17.8–31.7 months), 11 (68.8%) patients developed PD and one of them died in 20.9 months. The median of progression‐free survival (PFS) was 16.3 months (95% CI: 7.2–25.4 months), and the 6‐month, 12‐month, and 24‐month PFS rates were 100%, 81.3%, and 33.3%, respectively. The grade 3 adverse events were albuminuria (n = 2, 12.5%) and hand‐foot syndrome (n = 1, 6.25%). Conclusion All‐trans retinoic acid combined with low‐dose apatinib might be a potential efficacy therapeutic option for patients with R/M ACCHN. This finding will be further confirmed by our registered ongoing trial, the APLUS study (NCT 04433169).

Abstract To investigate the effect of pentoxifylline (PTX) on Chlorine (Cl2)-induced acute lung injury (ALI) by single-cell RNA sequencing (scRNA-seq). Female BALB/c mice were exposed to Cl2 at 400 ppm for 15 min. H&E staining was used to observe the degree of lung injury. scRNA-seq was conducted to analysis of normal and Cl2-exposed mice lung tissues. Immunofluorescence was used to observe genes of interest. Thirty-two mice were randomly divided into four groups: Control, Cl2, Cl2+Fer-1, Cl2+PTX. TEM, WB and ELISA were used to detect ferroptosis-related indicators. The 5, 8, 10, 12, 16, 20 clusters were epithelial cells and 4, 15, 18, 19, 21 clusters were endothelial cells. Pseudo-time analysis revealed the differentiation trajectory of epithelial cells and key regulatory genes (Gclc, Bpifa1, Dnah5 and Dnah9) during the process of injury. Cell–cell communication analysis identified several important receptor–ligand complexes (Nrp1-Vegfa, Nrp2-Vegfa, Flt1-Vegfa and Flt4-Vegfa). Ferroptosis were found up-regulated in epithelial and endothelial cells by GSVA analysis. Highly expressed genes to which closely related ferroptosis were found by SCENIC analysis. PTX could significantly decrease the levels of MDA and abnormal high expression of solute carrier family 7 member 11 (SLC7A11, the key transporter of cystine) as well as increase the expression of GSH/GSSG and glutathione peroxidase 4 (GPX4) (p

Abstract Background Cavernous malformations of the spinal cord are a rare type of vascular malformation, comprising approximately 5 to 16% of all vascular lesions in the spinal cord. Depending on their origin position, these malformations can be distributed in different locations within the spinal canal. Although intramedullary cavernous malformations have been reported in the literature, they are exceedingly rare. Furthermore, highly calcified or ossified intramedullary cavernous spinal malformations are even rarer. Case presentation Here, we present a case report of a 28-year-old woman diagnosed with a thoracic intramedullary cavernous malformation. The patient had been experiencing progressive numbness in her distal limbs for a period of 2 months. During routine lung computed tomography screening for COVID-19, a hyperdense mass was noted in the patient’s spinal canal. Magnetic resonance imaging revealed a mulberry-shaped intramedullary mass at the T1-2 level. The patient underwent surgical treatment, during which the entire lesion was successfully removed, resulting in a gradual improvement of her symptoms. Histological examination confirmed the presence of cavernous malformations with calcification. Conclusions Intramedullary cavernous malformations with calcification are rare and special type that should be treated surgically in the early stage without significant neurological impairment before rebleeding or enlargement of the lesion can occur.

Abstract Background In network meta-analysis, estimation of a comparative effect can be performed for treatments that are connected either directly or indirectly. However, disconnected trial networks may arise, which poses a challenge to comparing all available treatments of interest. Several modeling approaches attempt to compare treatments from disconnected networks but not without strong assumptions and limitations. Conducting a new trial to connect a disconnected network can enable calculation of all treatment comparisons and help researchers maximize the value of the existing networks. Here, we develop an approach to finding the best connecting trial given a specific comparison of interest. Methods We present formulas to quantify the variation in the estimation of a particular comparative effect of interest for any possible connecting two-arm trial. We propose a procedure to identify the optimal connecting trial that minimizes this variation in effect estimation. Results We show that connecting two treatments indirectly might be preferred to direct connection through a new trial, by leveraging information from the existing disconnected networks. Using a real network of studies on the use of vaccines in the treatment of bovine respiratory disease (BRD), we illustrate a procedure to identify the best connecting trial and confirm our findings via simulation. Conclusion Researchers wishing to conduct a connecting two-arm study can use the procedure provided here to identify the best connecting trial. The choice of trial that minimizes the variance of a comparison of interest is network dependent and it is possible that connecting treatments indirectly may be preferred to direct connection.

Abstract Purpose The purpose of this study was to describe and evaluate the use of a specially designed hollow trephine to create the entry point through the femoral condyle during retrograde interlocking intramedullary nailing for femoral fractures. Methods From June 2019 to December 2021, we treated 11 patients (5 men, 6 women; mean age, 64 years; age range 40–77 years) with mid-distal femoral fractures by retrograde intramedullary femoral nailing using a self-designed hollow trephine for femoral condyle reaming and cancellous bone harvesting. The mode of all the nails is static. Patients were followed up at 1, 4, 8, and 12 weeks and for at least 6 months after surgery. The healing process and heterotopic ossification were evaluated by imaging. Partial weight bearing was permitted during the recovery period and complete weight bearing was permitted after clinical healing of the fracture displayed by X-ray. Results The operation was successful in all patients. Over mean follow-up of 9.3 months (range, 6.0–12.0 months), all patients achieved clinical healing within three months. There were no complications such as knee joint infection, heterotopic ossification, knee joint adhesion and wedge effect. Conclusion The use of the hollow trephine during femoral retrograde intramedullary nailing helps avoid postoperative complications such as heterotopic ossification, knee joint adhesions, and wedge effect. It also facilitates bone graft harvesting.

Abstract Introduction Increasing evidence has revealed the key activity of protein disulfide isomerase A4 (PDIA4) in the endoplasmic reticulum stress (ERS) response. However, the role of PDIA4 in regulating glioblastoma (GBM)-specific pro-angiogenesis is still unknown. Methods The expression and prognostic role of PDIA4 were analyzed using a bioinformatics approach and were validated in 32 clinical samples and follow-up data. RNA-sequencing was used to search for PDIA4-associated biological processes in GBM cells, and proteomic mass spectrum (MS) analysis was used to screen for potential PDIA4 substrates. Western blotting, real-time quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assays (ELISA) were used to measure the levels of the involved factors. Cell migration and tube formation assays determined the pro-angiogenesis activity of PDIA4 in vitro. An intracranial U87 xenograft GBM animal model was constructed to evaluate the pro-angiogenesis role of PDIA4 in vivo. Results Aberrant overexpression of PDIA4 was associated with a poor prognosis in patients with GBM, although PDIA4 could also functionally regulate intrinsic GBM secretion of vascular endothelial growth factor-A (VEGF-A) through its active domains of Cys-X-X-Cys (CXXC) oxidoreductase. Functionally, PDIA4 exhibits pro-angiogenesis activity both in vitro and in vivo, and can be upregulated by ERS through transcriptional regulation of X-box binding protein 1 (XBP1). The XBP1/PDIA4/VEGFA axis partially supports the mechanism underlying GBM cell survival under ER stress. Further, GBM cells with higher expression of PDIA4 showed resistance to antiangiogenic therapy in vivo. Conclusions Our findings revealed the pro-angiogenesis role of PDIA4 in GBM progression and its potential impact on GBM survival under a harsh microenvironment. Targeting PDIA4 might help to improve the efficacy of antiangiogenic therapy in patients with GBM.

The dynamic and temporal changes of host genome architecture during Epstein-Barr virus (EBV) transformation are not well known. Here the authors transform human primary B lymphocyte into lymphoblastoid cell lines (LCLs) with EBV and show that the host 3D genome is rewired to facilitate expression of key oncogenes.

Abstract Precancerous lesions of the oral mucosa, especially those accompanied by moderate to severe dysplasia, contribute to the initiation of oral squamous cell carcinoma (OSCC). However, the cellular compositions and spatial organization of the precancerous stage and how these factors promote human OSCC initiation remain unclear. Here, we built a single-cell transcriptome atlas and a spatial transcriptome map after obtaining data from pairwise human oral mucosal biopsies of 9 individuals consisting of very early-stage OSCC, adjacent precancerous lesions with moderate to severe dysplasia, as well as a matched normal region. An altered epithelial gene-expression profile was identified which favored OSCC initiation. This observation was coupled with distinct fibroblast, monocytic, and regulatory T-cell subclusters involved in reshaping the microenvironment. In particular, a unique immune-inhibitory monocyte subtype and spatial-switching regulation of VEGF signaling were observed surrounding precancerous lesions, concertedly strengthening activities in promoting cancer initiation. Collectively, our work elucidated the cellular landscapes and roles of precancerous lesions underlying OSCC initiation, which is essential for understanding the entire OSCC initiation process and helps inform therapeutic strategies for cancer intervention.

Abstract Maleic acid polymer scale inhibitor is a new domestic seawater desalination scale inhibitor. This study tested the acute oral toxicity, sub-chronic toxicity and genotoxicity of this new inhibitor. The LD50 obtained from the acute oral toxicity test was 6810 and 9260 mg/kg·BW for male and female rats, as well as 1/5, 1/10 and 1/20 LD50 were as the dose for sub-chronic toxicity test. It showed the weight of male rats with high dose was significantly lower than the control group during the exposure period (p

Nanomedicine proofed to be efficient in cancer therapy but rapid clearance from blood circulation by reticuloendothelial system (RES) severely limits the antitumor efficacy. Here, the authors design a series of nanogels with distinctive stiffness and investigate how nanogel mechanical properties could be leveraged to overcome RES.

Objective: To investigate the clinical value of laparoscopic cytoreductive surgery (CRS) in treating of appendiceal pseudomyxoma peritonei with limited disease and low tumor burden. Methods: The clinical data of patients with appendiceal pseudomyxoma peritonei treated by surgery with CRS at the Aerospace Center Hospital from January 2018 to December 2021 were retrospectively analyzed. The patients were divided into laparoscopic or open CRS groups according to the operation method. A propensity score-matched (PSM) analysis (1:1) was performed, the related clinical variables were compared between the two groups, and the effect on progression-free survival (PFS) was also analyzed. Results: One hundred and eight patients were included in this study. After PSM, 33 patients were selected from each group and the age and peritoneal cancer index were matched between the two groups. There were significant differences in operation time (P

Porphyra polysaccharide is a special kind of nutrient showing multiple physiological functions including regulating cell proliferation, but the detailed mechanisms are not fully revealed, impairing its further development and applications. This work was to purify and characterize the Porphyra haitanensis polysaccharide (PH), investigate its physiological function, and demonstrate the underlying mechanisms. The purified PH was first characterized by Fourier-transform infrared spectroscopy. Then an intestinal epithelial cell model was established, in which PH significantly suppressed cell hyperplasia. Specifically, PH activated the Hippo/YAP pathway, which subsequently activated mTOR pathway, however mTOR activated Hippo in the absence of PH. Moreover, both the inhibition of Hippo by YAP1 knock-down and the suppression of mTOR by rapamycin impaired PH function. These results indicated that PH attenuated hyperplasia activity by remodeling the cross-talk between Hippo/YAP and mTOR pathways, which revealed potential targets and approaches for treating hyperplasia-related diseases and provided novel ways to utilize P. haitanensis as well as other related functional foods.

Numerous studies were published in the last two decades to evaluate and project the permafrost changes in its thermal state, mainly based on the soil temperature datasets from the Coupled Model Intercomparison Project (CMIP), and discuss the impacts of permafrost changes on regional hydrological, ecological and climatic systems and even carbon cycles. However, limited monitored soil temperature data are available to validate the CMIP outputs, resulting in the over-projection of future permafrost changes in CMIP3 and CMIP5. Moreover, future permafrost changes in CMIP6, particularly over the Qinghai–Tibet Plateau (QTP), where permafrost covers more than 40% of its territory, are still unknown. To address this gap, we evaluated and calibrated the monthly ground surface temperature (GST; 5 cm below the ground surface), which was often used as the upper boundary to simulate and project permafrost changes derived from 19 CMIP6 Earth System Models (ESMs) against in situ measurements over the QTP. We generated the monthly GST series from 1900 to 2014 for five sites based on the linear calibration models and validated them through the three other sites using the same calibration methods. Results showed that all of the ESMs could capture the dynamics of in situ GST with high correlations (r > 0.90). However, large errors were detected with a broad range of centred root-mean-square errors (1.14–4.98 °C). The Top 5 model ensembles (MME5) performed better than most individual ESMs and averaged multi-model ensembles (MME19). The calibrated GST performed better than the GST obtained from MME5. Both annual and seasonal GSTs exhibited warming trends with an average annual rate of 0.04 °C per decade in the annual GST. The average seasonal warming rate was highest in winter and spring and lowest in summer. This reconstructed GST data series could be used to simulate the long-term permafrost temperature over the QTP.

Abstract Cancer cell membrane (CCM) derived nanotechnology functionalizes nanoparticles (NPs) to recognize homologous cells, exhibiting translational potential in accurate tumor therapy. However, these nanoplatforms are majorly generated from fixed cell lines and are typically evaluated in cell line-derived subcutaneous-xenografts (CDX), ignoring the tumor heterogeneity and differentiation from inter- and intra- individuals and microenvironments between heterotopic- and orthotopic-tumors, limiting the therapeutic efficiency of such nanoplatforms. Herein, various biomimetic nanoplatforms (CCM-modified gold@Carbon, i.e., Au@C-CCM) were fabricated by coating CCMs of head and neck squamous cell carcinoma (HNSCC) cell lines and patient-derived cells on the surface of Au@C NP. The generated Au@C-CCMs were evaluated on corresponding CDX, tongue orthotopic xenograft (TOX), immune-competent primary and distant tumor models, and patient-derived xenograft (PDX) models. The Au@C-CCM generates a photothermal conversion efficiency up to 44.2% for primary HNSCC therapy and induced immunotherapy to inhibit metastasis via photothermal therapy-induced immunogenic cell death. The homologous CCM endowed the nanoplatforms with optimal targeting properties for the highest therapeutic efficiency, far above those with mismatched CCMs, resulting in distinct tumor ablation and tumor growth inhibition in all four models. This work reinforces the feasibility of biomimetic NPs combining modular designed CMs and functional cores for customized treatment of HNSCC, can be further extended to other malignant tumors therapy.

Abstract Background Common chronic infections induced low-grade inflammation has been correlated with atherosclerosis as supported by strong evidence. The balance between pro-and anti-inflammatory factors was exploited to elucidate the effects of chronic periodontitis on diabetes-associated atherosclerosis. Methods Study subjects encompassed 30 SPF male rats randomly divided into four groups: A group (NC), B group (T2DM), C group (CP), D group (DM + CP). After developing the model, blood samples were collected from the angular vein analyze serum APN, hs-CRP, and blood lipid. the carotid artery was isolated for HE staining. Result Compared with group A, the serum APN in group B, C and D decreased gradually with the progression of the disease. Serum hs-CRP in group B, C and D was significantly increased. At T3, T4 and T5 in group B, C and D, APN/hs-CRP significantly decreased. TC, LDL and TG significantly increased in group B, D; HDL significantly decreased in group C. Carotid artery HE staining showed: compared with group A, different degrees of endothelial defect, destruction of elastic fibers in the middle membrane, disorder of smooth muscle arrangement, and partial dissolution 、 fragmentation and Calcium salt deposition necrosis occurred in group B, C and D. Conclusion Enhanced systemic inflammation, decreased adiponectin level, and disorganized lipid metabolism with or without type 2 diabetes attributed to local inflammation of periodontitis can result in an imbalance of pro-inflammatory and anti-inflammatory effects. Therefore, it’s more meaningful to predict the progression of DAA with anti-inflammatory/pro-inflammatory variation.

In order to explore the development and application of edible dock, the main nutrients and functional components contents were measured, and the antioxidant and hypoglycemic activities were evaluated by measuring the free radical scavenging ability, reducing power and α-glucosidase inhibitory of extract from edible dock. The results showed that the value of total protein reached about 34.70 mg/100 mg (dry weight), the ratios of essential amino acids and medicinal amino acids to total amino acids were respectively 45% and 65%, and the score of amino acid ratio coefficient (SRC) was over 68, indicating that the edible dock was a kind of plant of high nutritional value. The contents of total phenol, total flavonoid and the specific activity of superoxide dismutase were 11.35 mg GAE/g (dry weight), 3.56 mg RE/g (dry weight) and 15.24±3.40 U/mg pro, respectively. Malic acid and oxalic acid were the main organic acid in edible dock (~89.24%). The values corresponding to the extract concentration required to scavenge 50% (IC50) of 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical and 2,2-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) free radical were respectively 0.465 mg/mL and 0.066 mg/mL, and the extract concentration providing reducing power (absorbance) of 0.5 (IC0.5) was about 0.528 mg/mL, which indicated that the edible dock possessed good antioxidant activity. Moreover, the extract of edible dock significantly inhibited α-glucosidase activity in experimental ranges, thus proving its favorable hypoglycemic activity. The above results can enrich the scientific research of edible dock and provide the theoretical foundation for its further development and utilization.

This paper introduces a refractive index sensor based on Fano resonance, utilizing a metal–insulator–metal (MIM) waveguide structure with an Anchor-like cavity. This study utilizes the finite element method (FEM) for analyzing the propagation characteristics of the structure. The evaluation concentrated on assessing how the refractive index and the structure’s geometric parameters affect its sensing characteristics. The designed structure demonstrates optimum performance, achieving a maximum sensitivity of 2440 nm/RIU and an FOM of 63. Given its high sensitivity, this nanoscale refractive index sensor is ideal for detecting hemoglobin concentrations in blood, and the sensor’s sensitivity is 0.6 nm·g/L, aiding in clinical prevention and treatment.

Considering the characteristics of both quality and quantity losses in fresh produce as well as the existence of spot markets, optimal retailer ordering, pricing, and freshness-keeping decisions through the single ordering policy (firm ordering only or option ordering only) and the mixed ordering policy (firm ordering and option ordering simultaneously) are constructed based on option contracts and analyzed for the retailer under different ordering policies. The results show that there is a unique optimal pricing, ordering, and freshness-keeping decision under all three ordering policies, but there is no joint decision. The optimal freshness-keeping and retail price under the mixed ordering policy are lower than those under the option ordering only but higher than those under the firm ordering only. When only a single order can be placed, the retailer’s optimal ordering policy is determined by demand risk. When all three ordering policies are available, the optimal ordering policy for the retailer is the mixed ordering policy. A spot market will weaken the role of option contracts in mitigating supply chain risks, and the larger the risk, the more significant the role of the spot market.

To enhance the physical and mechanical characteristics of steam-cured concrete, an orthogonal experimental design was utilized to examine the effects of varying contents of fly ash (0 wt%, 10 wt%, 15 wt%, 20 wt%), silica fume (0 wt%, 5 wt%, 10 wt%, 15 wt%), basalt fiber (0 vol%, 0.05 vol%, 0.1 vol%, 0.2 vol%), and polypropylene fiber (0 vol%, 0.05 vol%, 0.1 vol%, 0.2 vol%) on its mechanical properties. Utilizing range and variance analyses, this study identified four preliminary optimized compositions of concrete incorporating fly ash, silica fume, basalt fiber, and polypropylene fiber. On this basis, in order to determine the optimal mix proportion, the mechanical performances, the pore characteristics, and the microstructure of four optimized mix proportions were analyzed. According to the results of macroscopic, fine, and microscopic multi-scale tests, the addition of 15 wt% fly ash, 10 wt% silica ash, 0.2 vol% basalt fiber, and 0.1 vol% polypropylene fiber to the steamed concrete is the best to improve the performance of the steamed concrete. Compared to ordinary concrete, the compressive strength increases by 28%, the tensile strength increases by 40%, and the porosity decreases by 47.2%.

The synergistic effects of boron (B) and rare earth (RE) elements on the microstructure and stress rupture properties were investigated in a Ni-based superalloy. The stress rupture lifetime at 650 °C/873 MPa significantly increased with the addition of B as a single element. Furthermore, the stress rupture lifetime reached its peak (303 h), with a certain amount of B and RE added together in test alloys. Although the grain size and morphology of the γ′ phase varied a little with the change in B and RE addition, they were not considered to be the main reasons for stress rupture performance. The enhancement in stress rupture lifetime was mostly attributed to the segregation of the B and RE elements, which increased the binding force of the grain boundary and improved its strength and plasticity. In addition, the enrichment of B and RE inhabited the precipitation of carbides along grain boundaries. Furthermore, nano-scale RE precipitates containing sulfur (S) and phosphorus (P) were observed to be distributed along the grain boundaries. The purification of grain boundaries by B and RE elements was favorable to further improve the stress rupture properties.

Steel slag is a by-product of the steel industry and usually contains a high amount of f-CaO and f-MgO, which will result in serious soundness problems once used as a binding material and/or aggregates. To relieve this negative effect, carbonation treatment was believed to be one of the available and reliable methods. By carbonation treatment of steel slag, the phases of f-CaO and f-MgO can be effectively transformed into CaCO3 and MgCO3, respectively. This will not only reduce the expansive risk of steel slag to improve the utilization of steel slag further but also capture and store CO2 due to the mineralization process to reduce carbon emissions. In this study, based on the physical and chemical properties of steel slag, the carbonation mechanism, factors affecting the carbonation process, and the application of carbonated steel slag were reviewed. Eventually, the research challenge was also discussed.

Nanoindentation measurements were conducted to investigate the high-cycle response of 316L stainless steel in bending fatigue. Hardness variation owing to the gradient flexure stress amplitude for different curvatures was plotted along with the thickness and length, respectively. Scanning electron microscopy (SEM) was subsequently conducted to explore the deformation characteristics in multiple layers, which had cyclic gradient stress, on the cross-section of specimens. The nanoindentation results indicated that the cyclic hardening response of 316L stainless steel is correlated with the level of stress amplitude in the high-cycle fatigue (HCF) regime. Furthermore, an analytical model was proposed to clarify the relationship between nanohardness and stress amplitude. Finally, the evolution of damage accumulation due to irreversible plastic deformation is continuous during stress reduction up to the neighboring zone at the neutral surface of the flexure beam in some individual grains.

Following publication, concerns relating to the relevance of a number of citations recommend by a peer reviewer were brought to the attention of the Editorial Office [...]

Pooled sample testing is an effective strategy to reduce the cost of disease surveillance in human and animal medicine. Testing pooled samples commonly produces matched observations with dichotomous responses in medical and epidemiological research. Although standard approaches exist for one-to-one paired binary data analyses, there is not much work on one-to-two or one-to-N matched binary data in the current statistical literature. The existing Miettinen’s test assumes that the multiple observations from the same matched set are mutually independent. In this paper, we propose exact and asymptotic tests for one-to-two matched binary data. Our methods are markedly different from the previous studies in that we do not rely on the mutual independence assumption. The emphasis on the interdependence of observations within a matched set is inherent and attractive in both human health and veterinary medicine. It can be applied to all kinds of diagnostic studies with a one-to-two matched data structure. Our methods can be generalized to the one-to-N matched case. We discuss applications of the proposed methods to the environmental testing of salmonella in the United States.

Accurate line parameters are the basis for the optimal control and safety analysis of distribution networks. The lack of real-time monitoring equipment in grids has meant that data-driven identification methods have become the main tool to estimate line parameters. However, frequent network reconfigurations increase the uncertainty of distribution network topologies, creating challenges in the data-driven identification of line parameters. In this paper, a line parameter identification method compatible with an uncertain topology is proposed, which simplifies the model complexity of the joint identification of topology and line parameters by removing the unconnected branches through noise reduction. In order to improve the solving accuracy and efficiency of the identification model, a two-stage identification method is proposed. First, the initial values of the topology and line parameters are quickly obtained using a linear power flow model. Then, the identification results are modified iteratively based on the classical power flow model to achieve a more accurate estimation of the grid topology and line parameters. Finally, a simulation analysis based on IEEE 33- and 118-bus distribution systems demonstrated that the proposed method can effectively realize the estimation of topology and line parameters, and is robust with regard to both measurement errors and grid structures.

Starting from the theoretical mechanism of the impact of financial agglomeration on regional green innovation efficiency, and using panel data from 30 provinces in China from 2009 to 2017, this study calculates a financial agglomeration index and green innovation efficiency applying principal component analysis and the slacks-based measure (SBM) of super-efficiency. The study then constructs static and dynamic spatial Durbin models using two different spatial weight matrices to empirically test the spatial spillover effect of financial agglomeration on regional green innovation efficiency. The results reveal a significant positive spatial correlation between China's inter-provincial green innovation efficiency and financial agglomeration. Both static and dynamic models demonstrate that financial agglomeration has a significant spatial spillover effect on the green innovation efficiency of adjacent provinces, but the static model overestimates the impact of spatial spillover. In addition, human capital level, technology market activity, and environmental regulation all have significant positive impacts on the green innovation efficiency of provinces and adjacent provinces.

Swine nursery mortality is one of the most important key performance indicators (KPIs) for commercial swine production systems and, for the purpose of this study, refers to the number of pigs that died during the first 60 days during the post-weaning phase (approximately 170-day period). Likewise, nursery mortality accounts for almost 50% of the mortality that occurs throughout the post-weaning phase. Despite being a metric concerning the post-weaning phase of production, previous studies have demonstrated that nursery mortality is highly correlated with the previous performance of the piglets in the pre-weaning phase and to stocking conditions at placement in nursery sites. However, there is no evidence of that predictive models are currently routinely utilized in the swine industry to predict the nursery performance of individual groups of pigs based on their previous performance in the pre-weaning phase. One obstacle to building such predictive models is that health and management data as well as production data for the pre and post-weaning phases are collected with separate record-keeping programs and stored in unconnected databases.Thus, the objective of this study was to measure and compare the performance of 5 forecasting models for predicting nursery mortality using a master table containing data collected from a single swine production system for 1,831 groups of pigs. An automated model was built to integrate information for 48 variables included in the master table that was previously disconnected within the production system. After the model and parameter tuning process, the model with the best overall prediction performance was the Support Vector Machine (SVM) in terms of Root Mean Squared Error (RMSE=0.3929), Mean Absolute Error (MAE=0.2956), and coefficient of determination (R2=0.7761). This study demonstrated the ability to use an integrated master table containing whole-herd information until the placement event of nursery groups to predict their downstream nursery mortality through the initial 60 days of the post-weaning phase.

Background and objectivesTo investigate the application of intelligent puncture blood collection robots in anticoagulated blood specimens, the satisfaction of subjects with the two blood collection methods, and the feasibility of intelligent blood collection devices to replace manual blood collection methods in clinical work.Materials and methodsA total of 154 volunteers from Zhongshan Hospital Fudan University were recruited to compare the test results of anticoagulant blood samples between blood collection robot and manual blood collection, a questionnaire was used to inquire about the volunteers’ feelings about the two blood collection methods; the blood collection data of 6,255 patients willing to use the robot for blood collection were collected to analyze the success rate of blood collection.ResultsThe blood collection robot is superior to manual specimen collection in terms of volume and pain of specimen collection, and the puncture success rate is 94.3%. The anticoagulated blood specimens collected by the robot had 11 indexes statistically different from the results of manual blood collection, but the differences did not affect the clinical diagnosis and prognosis.ConclusionThe intelligent robotic blood collection is less painful and has better acceptance by patients, which can be used for clinical anticoagulated blood specimen collection.

Iron is a trace metal element that is essential for the survival of cells and parasites. The role of iron in cerebral toxoplasmosis (CT) is still unclear. Deferiprone (DFP) is the orally active iron chelator that binds iron in a molar ratio of 3:1 (ligand:iron) and promotes urinary iron excretion to remove excess iron from the body. The aims of this experiment were to observe the alterations in iron in brains with Toxoplasma gondii (T. gondii) acute infections and to investigate the mechanism of ferroptosis in CT using DFP. We established a cerebral toxoplasmosis model in vivo using TgCtwh3, the dominant strains of which are prevalent in China, and treated the mice with DFP at a dose of 75 mg/kg/d. Meanwhile, we treated the HT-22 cells with 100 μM DFP for half an hour and then infected cells with TgCtwh3 in vitro. A qRT-PCR assay of TgSAG1 levels showed a response to the T. gondii burden. We used inductively coupled plasma mass spectrometry, an iron ion assay kit, Western blot analysis, glutathione and glutathione disulfide assay kits, a malonaldehyde assay kit, and immunofluorescence to detect the ferroptosis-related indexes in the mouse hippocampus and HT-22 cells. The inflammatory factors interferon-γ, tumor necrosis factor-α, transforming growth factor-β, and arginase 1 in the hippocampus and cells were detected using the Western blot assay. Hematoxylin and eosin staining, electron microscopy, and the Morris water maze experiment were used to evaluate the brain injuries of the mice. The results showed that TgCtwh3 infection is followed by the activation of ferroptosis-related signaling pathways and hippocampal pathological damage in mice. The use of DFP led to ferroptosis resistance and attenuated pathological changes, inflammatory reactions and T. gondii burden of the mice, prolonging their survival time. The HT-22 cells with TgCtwh3 activated the ferroptosis pathway and was inhibit by DFP in vitro. In TgCtwh3-infected cells, inflammatory response and mitochondrial damage were severe, but these effects could be reduced by DFP. Our study elucidates the mechanism by which T. gondii interferes with the host's iron metabolism and activates ferroptosis, complementing the pathogenic mechanism of CT and further demonstrating the potential value of DFP for the treatment of CT.

ABSTRACT Wall-less bacteria are broadly distributed in diverse habitats. They evolved from a common ancestor within the Firmicutes phylum through reductive evolution. Here, we report the cultivation, characterization, and polyphasic taxonomic analysis of the novel free-living wall-less bacterium, Hujiaoplasma nucleasis zrk29. We demonstrated that strain zrk29 had a strong ability to degrade DNA and RNA both under laboratory conditions and in the deep sea. We found that nucleic acids induced strain zrk29 to release chronic bacteriophages which supported strain zrk29 and other marine bacteria to metabolize nucleic acids without lysing host cells. We also showed that strain zrk29 tolerated high hydrostatic pressure via two pathways: (i) by transporting cations into its cells to increase intracellular osmotic pressure and (ii) by adjusting the unsaturated fatty acid chain content in its cell membrane phospholipids to increase cell membrane fluidity. This study extends our understanding of free-living wall-less bacteria and provides a useful model to explore the unique adaptation mechanisms of deep-sea microbes. IMPORTANCE The unique physiology and survival strategies of the Tenericutes bacterium—a typical wall-less bacterium—have fascinated scientists and the public, especially in extreme deep-sea environments where there is high hydrostatic pressure (HHP) and limited availability of nutrients. Here, we have isolated a novel free-living Tenericutes strain from deep-sea sediment and have found that it metabolizes nucleic acids with the support of chronic bacteriophages. This Tenericutes strain tolerates HHP stress by increasing intracellular osmotic pressure and the unsaturated fatty acid chain content of phospholipids in its cell membrane. Our results provide insights into the unique physiology of deep-sea free-living Tenericutes bacteria and highlight the significant role that chronic bacteriophages play in assisting wall-less bacteria to adapt to harsh conditions.

BackgroundPain management is critical to equine welfare with non-steroidal anti-inflammatory drugs (NSAID) commonly used in horses. However, systemic NSAID use is limited by harmful gastrointestinal and renal side effects. Intravenous regional limb perfusion (IVRLP) is a technique used in horses that produces high, local antibiotic concentrations while limiting systemic circulation. NSAID-IVRLP would be a novel method of local pain management while limiting systemic NSAID side effects. To date, NSAID-IVRLP administration has not been reported in horses. This study aimed to identify the pharmacokinetics and local complications associated with using the NSAID phenylbutazone (PBZ) for IVRLP in six standing adult horses.MethodsPBZ-IVRLP, at a dose of 2.2 mg/kg PBZ, was performed in a randomly assigned forelimb cephalic vein in 6 standing, healthy adult horses. A placebo-IVRLP was performed in the contralateral forelimb for comparison. Systemic serum and radiocarpal joint synovial fluid PBZ concentrations were identified at various timepoints (before IVRLP T-0 h, just after tourniquet removal T-0.5, 1.5, 3, 5, 12, 16, and 24 h post IVRLP) for non-compartmental pharmacokinetic analysis and concentration over time curves. Local complications associated with PBZ-IVRP were evaluated for up to 7 days following PBZ-IVRLP using physical and ultrasonographic assessment. On day 7 horses were humanely euthanized with histology performed on both forelimbs at PBZ-IVRLP and placebo-IVRLP administration sites.ResultsNon-compartmental pharmacokinetics for PBZ, and its major metabolite oxyphenbutazone (OBZ), were determined for serum and synovial fluid. Synovial PBZ concentrations (mean ± SD; 1.9 ± 2.1 μg/mL) were significantly lower (p = 0.03; CI,0.46–7.36) than serum PBZ concentrations (5.8 ± 5.1 μg/mL) at any time point. Physical and ultrasonographic measurements were not significantly different between PBZ- and placebo-IVRLP forelimbs. The most common histologic findings included focal deep dermal/subcutaneous hemorrhage and edema. Two horses showed perivasculitis and one horse showed a resolving thrombus in the cephalic vein of the PBZ-IVRLP limb. This horse also had severe perivasculitis and fibrinosuppurative dermatitis/panniculitis in the placebo-IVRLP limb.ConclusionPBZ-IVRLP pharmacokinetics at a 2.2 mg/kg dose showed no benefit compared to systemic PBZ administration in standing adult horses. Local complications associated with PBZ-IVRLP were similar to placebo-IVRLP on physical and ultrasonographic evaluation.

Abstract Solar cells formed by spin‐coating organic absorber layers on silicon have attracted widespread attention due to their simple processes and high photovoltaic conversion efficiency (PCE). In typical organic/Si solar cells, however, surface defects or unsatisfactory carrier separation are inadequate to yield excellent device performance. Here, the Au@MoS2 nanocomposites are well synthesized and doped into the organic layer of poly (3,4‐ethylenedioxythiophene)/polystyrene sulfonate (PEDOT:PSS) to improve its work function and the performance of PEDOT:PSS/Si HSCs consequently. By optimizing the doping level of Au@MoS2, the PCE significantly improved from 11.48% to 14.0% by tuning the work function of the PEDOT:PSS layer to more appropriate values. The calculated results based on the Mott–Schottky model indicate that the built‐in field in the PEDOT:PSS/Si interface of HSCs is significantly enhanced due to the increase of work function by the PEDOT:PSS thin films. The enhancement of the built‐in field results in the reduction of the electron–hole recombination loss effectively. The work provides a feasible method for preparing high‐performance PEDOT:PSS/Si HSCs.

Lung squamous cell carcinoma (LSCC) accounts for approximately 30% of non-small cell lung cancer (NSCLC) cases and is the second most common histological type of lung cancer. Anaplastic lymphoma kinase (ALK)-positive NSCLC accounts for only 2%-5% of all NSCLC cases, and is almost exclusively detected in patients with lung adenocarcinoma. Thus, ALK testing is not routinely performed in the LSCC population, and the efficacy of such treatment for ALK-rearranged LSCC remains unknown. Echinoderm microtubule associated protein like 4 (EML4)-ALK (V1) and TP53 co-mutations were identified by next generation sequencing (NGS) in this patient with advanced LSCC. On December 3, 2020, Ensatinib was taken orally and the efficacy was evaluated as partial response (PR). The progression-free survival (PFS) was 19 months. When the disease progressed, the medication was changed to Loratinib. To our knowledge, Enshatinib created the longest PFS of ALK-mutant LSCC patients treated with targeted therapy since literature review. Herein, we described one case treated by Enshatinib involving a patient with both EML4-ALK and TP53 positive LSCC, and the relevant literatures were reviewed for discussing the treatment of this rare disease.

Cardiac-resident macrophages (CRMs) play important roles in homeostasis, cardiac function, and remodeling. Although CRMs play critical roles in cardiac regeneration of neonatal mice, their roles are yet to be fully elucidated. Therefore, this study aimed to investigate the dynamic changes of CRMs during cardiac ontogeny and analyze the phenotypic and functional properties of CRMs in the promotion of cardiac regeneration. During mouse cardiac ontogeny, four CRM subsets exist successively: CX3CR1+CCR2–Ly6C–MHCII– (MP1), CX3CR1lowCCR2lowLy6C–MHCII– (MP2), CX3CR1–CCR2+Ly6C+MHCII– (MP3), and CX3CR1+CCR2–Ly6C–MHCII+ (MP4). MP1 cluster has different derivations (yolk sac, fetal liver, and bone marrow) and multiple functions population. Embryonic and neonatal-derived-MP1 directly promoted cardiomyocyte proliferation through Jagged-1–Notch1 axis and significantly ameliorated cardiac injury following myocardial infarction. MP2/3 subsets could survive throughout adulthood. MP4, the main population in adult mouse hearts, contributed to inflammation. During ontogeny, MP1 can convert into MP4 triggered by changes in the cellular redox state. These findings delineate the evolutionary dynamics of CRMs under physiological conditions and found direct evidence that embryonic and neonatal-derived CRMs regulate cardiomyocyte proliferation. Our findings also shed light on cardiac repair following injury.

Abstract At present, attacks based on the vulnerability of the controller and flooding attacks still constitute a principal threat for hierarchical Software Defined Network (SDN), such as flow table tampering, malicious Application attacks, Distributed Denial of Service (DDoS) etc., due to the limitation against attacks based on known or unknown vulnerabilities for traditional cyber defence technology. Therefore, this study proposes an active defence architecture based on Mimic Defence (MD)–Mimic Hierarchical SDN Framework (MHSDN). Then endogenous security of MHSDN is theoretically analysed. Simultaneously, the attack surface measurement of MD is innovatively proposed, further improving the security and usability measurement standards of the MD system. Finally, to speed up detection and reduce defence cost of DDoS, this research proposes the Random Forest Feature Extract (RFFE) and tolerable switch migration. Simulation shows that RFFE has achieved a faster detection speed at the cost of less detection accuracy, and MHSDN can better improve the reliability of hierarchical SDN.

Abstract Background Acute thoracic aortic dissection (ATAD) is a fatal condition characterized by tear of intima, formation of false lumen and rupture of aorta. However, the subpopulations of normal and dissected aorta remain less studied. Methods Single-cell RNA sequencing was performed including 5 patients with ATAD and 4 healthy controls. Immunohistochemistry and immunofluorescence were used to verify the findings. Results We got 8 cell types from human ascending aorta and identified 50 subpopulations including vascular smooth muscle cells (VSMCs), endothelial cells, fibroblasts, neutrophils, monocytes and macrophages. Six transmembrane epithelial antigen of prostate 4 metalloreductase (STEAP4) was identified as a new marker of synthetic VSMCs. CytoTRACE identified subpopulations with higher differentiation potential in specified cell types including synthetic VSMCs, enolase 1+ fibroblasts and myeloid-derived neutrophils. Synthetic VSMCs-derived C-X-C motif chemokine ligand 12 (CXCL12) might interact with neutrophils and fibroblasts via C-X-C motif chemokine receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3), respectively, which might recruit neutrophils and induce transdifferentitation of fibroblasts into synthetic VSMCs. Conclusion We characterized signatures of different cell types in normal and dissected human ascending aorta and identified a new marker for isolation of synthetic VSMCs. Moreover, we proposed a potential mechanism that synthetic VSMCs might interact with neutrophils and fibroblasts via CXCL12-CXCR4/ACKR3 axis whereby deteriorating the progression of ATAD, which might provide new insights to better understand the development and progression of ATAD.

Abstract Background Acute myeloid leukemia (AML) patients with normal karyotype (NK-AML) have significant variabilities in outcomes. The European Leukemia Net stratification system and some prognostic models have been used to evaluate risk stratification. However, these common standards still have some limitations. The biological functions and mechanisms of Small Integral Membrane Protein 3 (SMIM3) have seldomly been investigated. To this date, the prognostic value of SMIM3 in AML has not been reported. This study aimed to explore the clinical significance, biological effects and molecular mechanisms of SMIM3 in AML. Methods RT-qPCR was applied to detect the expression level of SMIM3 in bone marrow specimens from 236 newly diagnosed adult AML patients and 23 healthy volunteers. AML cell lines, Kasumi-1 and THP-1, were used for lentiviral transfection. CCK8 and colony formation assays were used to detect cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. Western blot was performed to explore relevant signaling pathways. The biological functions of SMIM3 in vivo were validated by xenograft tumor mouse model. Survival rate was evaluated by Log-Rank test and Kaplan–Meier. Cox regression model was used to analyze multivariate analysis. The correlations between SMIM3 and drug resistance were also explored. Results Through multiple datasets and our clinical group, SMIM3 was shown to be significantly upregulated in adult AML compared to healthy subjects. SMIM3 overexpression conferred a worse prognosis and was identified as an independent prognostic factor in 95 adult NK-AML patients. Knockdown of SMIM3 inhibited cell proliferation and cell cycle progression, and induced cell apoptosis in AML cells. The reduced SMIM3 expression significantly suppressed tumor growth in the xenograft mouse model. Western blot analysis showed downregulation of p-PI3K and p-AKT in SMIM3-knockdown AML cell lines. SMIM3 may also be associated with some PI3K-AKT and first-line targeted drugs. Conclusions SMIM3 was highly expressed in adult AML, and such high-level expression of SMIM3 was associated with a poor prognosis in adult AML. Knockdown of SMIM3 inhibited the proliferation of AML through regulation of the PI3K-AKT signaling pathway. SMIM3 may serve as a potential prognostic marker and a therapeutic target for AML in the future.

Positive relationships between biodiversity and temporal stability through species asynchrony are well-documented, but the underlying mechanisms remain debated. Here, the authors show that statistical averaging is the main mechanism of plant diversity effects on community stability.

Abstract Clinical symptoms of spinal arteriovenous malformations (AVMs) combined with acute spontaneous hemorrhage lack specificity, which leads to misdiagnosis and delays treatment. The current study aimed to analyze the causes of misdiagnosis and review the key points of diagnosis and treatment. We presented an extremely rare case of a 25‐year‐old man whose clinical characteristics mimicked acute transverse myelitis, suffering from rapidly and repeatedly progressive myelopathy with a mass. The pathological diagnosis of the mass was AVM; symptom‐based surgical treatment with posterior decompression and the removal of epidural AVMs during the postoperative 12‐month follow‐up period were performed. The manual muscle testing grade score of the proximal and distal muscles in both lower limbs improved from 1 to 5, and the American Spinal Injury Association motor and sensation grade score improved from B to E. In the case of sudden or progressive spinal cord injury of unknown cause and acute spinal cord dysfunction, there might be a misdiagnosis. The key to a differential diagnosis is to take into account AVMs, and spontaneous hemorrhages and hematomas should also be suspected. Angiography and magnetic resonance imaging are very important for the diagnosis of AVM, and we hope to enhance clinicians' understanding of and vigilance for such diseases.

Abstract Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in Cmpk2-knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the Cmpk2-KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous Cmpk2-KO mice thalamus region as well as in the Cmpk2-knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of CMPK2 as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification.

Abstract Background A critical step in trial design is determining the sample size and sample allocation to ensure the proposed study has sufficient power to test the hypothesis of interest: superiority, equivalence, or non-inferiority. When data are available from prior trials and leveraged with the new trial to answer the scientific questions, the value of society’s investment in prior research is increased. When prior information is available, the trial design including the sample size and allocation should be adapted accordingly, yet the current approach to trial design does not utilize such information. Ensuring we maximize the value of prior research is essential as there are always constraints on resources, either physical or financial, and designing a trial with adequate power can be a challenge. Methods We propose an approach to increasing the power of a new trial by incorporating evidence from a network meta-analysis into the new trial design and analysis. We illustrate the methodology through an example network meta-analysis, where the goal is to identify the optimal allocation ratio for the new three-arm trial, which involves the reference treatment, the new treatment, and the negative control. The primary goal of the new trial is to show that the new treatment is non-inferior to the reference treatment. It may also be of interest to know if the new treatment is superior to the negative control. We propose an optimal treatment allocation strategy which is derived from minimizing the standard error of the log odds ratio estimate of the comparison of interest. We conducted a simulation study to assess the proposed methods to design a new trial while borrowing information from the existing network meta-analysis and compare it to even allocation methods. Results Using mathematical derivation and simulations, we document that our proposed approach can borrow information from a network meta-analysis to modify the treatment allocation ratio and increase the power of the new trial given a fixed total sample size or to reduce the total sample size needed to reach a desired power. Conclusions When prior evidence about the hypotheses of interest is available, the traditional equal allocation strategy is not the most powerful approach anymore. Our proposed methodology can improve the power of trial design, reduce the cost of trials, and maximize the utility of prior investments in research.

ABSTRACT: Amino acids are primarily absorbed in the ruminant small intestine, and the small intestine is a target organ prone to oxidative stress, causing intestinal disfunction. Previous study suggested that l-Trp could benefit intestinal function and production performance. This study aimed to explore the effects of l-Trp on hydrogen peroxide (H2O2)-induced oxidative injury in bovine intestinal epithelial cells (BIEC) and the potential mechanism. The effects of l-Trp on cell apoptosis, antioxidative capacity, AA transporters, and the mammalian target of rapamycin (mTOR) signaling pathway were evaluated in BIEC treated with 0.8 mM l-Trp for 2 hours combined with or without H2O2 induction. In addition, to explore whether the effects of 0.8 mM l-Trp on oxidative stress were related to mTOR, an mTOR-specific inhibitor was used. The percentage of apoptosis was measured using flow cytometry. The relative gene abundance and protein expression in BIEC were determined using real-time PCR and Western blot assay, respectively. Results showed l-Trp at 0.4 and 0.8 mM enhanced the cell viability, and it was inhibited by l-Trp at 6.4 mM. l-Tryptophan at 0.4, 0.8, and 1.6 mM remarkably decreased the percentage of apoptosis and enhanced antioxidative capacity in H2O2-mediated BIEC. Moreover, l-Trp at 0.8 mM increased the relative gene abundance and protein expression of antioxidative enzymes and AA transporters, and the mTOR signaling pathway. The mTOR inhibitor lowered the protein expression of large neutral amino acid transporter 1, but the inhibition of mTOR did not alter the activities of catalase and superoxide dismutase or protein expression of alanine-serine-cysteine transporter 2 with or without H2O2 induction. l-Tryptophan increased catalase and superoxide dismutase activities in H2O2-mediated BIEC, although not with a present mTOR inhibitor. l-Tryptophan increased the protein expression of large neutral amino acid transporter 1 and alanine-serine-cysteine transporter 2 in H2O2-mediated BIEC with or without the presence of an mTOR inhibitor. The present work suggested that l-Trp supplementation could alleviate oxidative injury in BIEC by promoting antioxidative capacity and inhibiting apoptosis, and the mTOR signal played vital roles in the alleviation.