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SARS-CoV-2 spike protein (SARS-2-S) induced cell-cell fusion in uninfected cells may occur in long COVID-19 syndrome, as circulating SARS-2-S or extracellular vesicles containing SARS-2-S (S-EVs) were found to be prevalent in post-acute sequelae of COVID-19 (PASC) for up to 12 months after diagnosis. Although isolated recombinant SARS-2-S protein has been shown to increase the SASP in senescent ACE2-expressing cells, the direct linkage of SARS-2-S syncytia with senescence in the absence of virus infection and the degree to which SARS-2-S syncytia affect pathology in the setting of cardiac dysfunction are unknown. Here, we found that the senescent outcome of SARS-2-S induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without de novo synthesis of SARS-2-S. However, it is important to note that currently approved COVID-19 mRNA vaccines do not induce syncytium formation or cellular senescence. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNFα. We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by SARS-2-S. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy especially in individuals with post-acute sequelae of COVID-19.

IntroductionInflammation play important roles in the initiation and progression of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), septic shock, clotting dysfunction, or even death associated with SARS-CoV-2 infection. However, the pathogenic mechanisms underlying SARS-CoV-2-induced hyperinflammation are still largely unknown.MethodsThe animal model of septic shock and ALI was established after LPS intraperitoneal injection or intratracheal instillation. Bone marrow-derived macrophages (BMDMs) from WT and BPOZ-2 KO mouse strains were harvested from the femurs and tibias of mice. Immunohistology staining, ELISA assay, coimmunoprecipitation, and immunoblot analysis were used to detect the histopathological changes of lung tissues and the expression of inflammatory factors and protein interaction.Results and conclusionsWe show a distinct mechanism by which the SARS-CoV-2 N (SARS-2-N) protein targets Bood POZ-containing gene type 2 (BPOZ-2), a scaffold protein for the E3 ubiquitin ligase Cullin 3 that we identified as a negative regulator of inflammatory responses, to promote NLRP3 inflammasome activation. We first demonstrated that BPOZ-2 knockout (BPOZ-2 KO) mice were more susceptible to lipopolysaccharide (LPS)-induced septic shock and ALI and showed increased serum IL-1β levels. In addition, BMDMs isolated from BPOZ-2 KO mice showed increased IL-1β production in response to NLRP3 stimuli. Mechanistically, BPOZ-2 interacted with NLRP3 and mediated its degradation by recruiting Cullin 3. In particular, the expression of BPOZ-2 was significantly reduced in lung tissues from mice infected with SARS-CoV-2 and in cells overexpressing SARS-2-N. Importantly, proinflammatory responses triggered by the SARS-2-N were significantly blocked by BPOZ-2 reintroduction. Thus, we concluded that BPOZ-2 is a negative regulator of the NLPR3 inflammasome that likely contributes to SARS-CoV-2-induced hyperinflammation.

Dysregulation of lipid metabolism and transport contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here the authors identify GP73 as a TBC-domain Rab GTPase-activating protein that regulates very low-density lipoprotein export and promotes NAFLD development in mice.

Activation of the NLRP3 inflammasome requires the expression of NLRP3, which is strictly regulated by its capacity to directly recognize microbial-derived substances. Even though the involvement of caspase-1 activation in macrophages via NLRP3 and NLRC4 has been discovered, the accurate mechanisms by which Shigella infection triggers NLRP3 activation remain inadequately understood. Here, we demonstrate that IpaH4.5, a Shigella T3SS effector, triggers inflammasome activation by regulating NLRP3 expression through the E3 ubiquitin ligase activity of IpaH4.5. First, we found that IpaH4.5 interacted with NLRP3. As a result, IpaH4.5 modulated NLRP3 protein stability and inflammasome activation. Bacteria lacking IpaH4.5 had dramatically reduced ability to induce pyroptosis. Our results identify a previously unrecognized target of IpaH4.5 in the regulation of inflammasome signaling and clarify the molecular basis for the cytosolic response to the T3SS effector.

Summary: Recent reports have shown the critical role of the mitochondrial antiviral signaling (MAVS) protein in virus-induced apoptosis, but the involvement of MAVS in tumorigenesis is still poorly understood. Herein, we report that MAVS is a key regulator of p53 activation and is critical for protecting against tumorigenesis. We find that MAVS promotes p53-dependent cell death in response to DNA damage. MAVS interacts with p53 and mediates p53 mitochondrial recruitment under genotoxic stress. Mechanistically, MAVS inhibits p53 ubiquitination by blocking the formation of the p53-murine double-minute 2 (MDM2) complex, leading to the stabilization of p53. Notably, compared with their wild-type littermates, MAVS knockout mice display decreased resistance to azoxymethane (AOM) or AOM/dextran sulfate sodium salt (DSS)-induced colon cancer. MAVS expression is significantly downregulated in human colon cancer tissues. These results unveil roles for MAVS in DNA damage response and tumor suppression. : Zhang et al. show that MAVS interacts with p53 and regulates p53-dependent apoptosis, indicating roles for MAVS in tumor suppression and the DNA damage response. Keywords: MAVS, p53, ubiquitination, tumor suppression

Abstract Background Video-assisted thoracoscopic surgery (VATS) for a relatively large mediastinal tumor (5.0–10.0 cm) remains controversial. In addition, few studies have focused on comparing different surgical approaches for large mediastinal tumors. Therefore, this study aimed to compare the short-term outcomes between subxiphoid approach VATS, intercostal approach VATS, and traditional sternotomy for large-sized anterior mediastinal tumors. Methods The study consecutively enrolled 159 patients with large-sized anterior mediastinal tumors (5.0–10.0 cm) who received surgery in our hospital between January 2018 and July 2022 (subxiphoid approach VATS: 52 patients, intercostal approach VATS: 70 patients, traditional sternotomy: 37 patients). We analyzed the clinical baseline data, intraoperative and postoperative outcomes, and postoperative complications of all patients. Then the patients were further divided into two groups according to whether there was a peripheral organ (such as pericardium, lung, or left innominate vein) invasion: group A, invasion of the surrounding organ, and group B, no invasion of the surrounding organ. Intraoperative and postoperative outcomes and postoperative complications were also analyzed in group A and group B, respectively. Results In all patients, there were significant differences in blood loss (subxiphoid approach: 33.1 ± 46.0 ml, intercostal approach: 36.9 ± 44.1 ml, sternotomy: 113.0 ± 84.9 ml, P

Abstract There is no consensus about whether relatively large mediastinal tumors (≥ 5.0 cm) are suitable for video-assisted thoracoscopic surgery (VATS). Therefore, this study aimed to compare the efficacy and safety of intercostal approach VATS for large-sized anterior mediastinal tumors (5.0–10.0 cm) with no invasion to the surrounding tissues and organs. A total of 129 patients with anterior mediastinal tumors who received surgery in our hospital between January 2018 and July 2022 were consecutively enrolled. Patients were divided into 2 groups based on mediastinal tumor diameter: Group A (tumor size between 1.0 and 4.9 cm) and Group B (tumor size between 5.0 and 10.0 cm). The primary endpoints were operation time, blood loss, and postoperative pain, and the secondary endpoints were the volume of drainage, drainage duration, postoperative hospital stay, and postoperative complications. Significant differences were found in the volume of drainage between the two groups (Group A: 218.4 ± 140.6, Group B: 398.9 ± 369.3, P 0.05). In addition, there existed no significant differences in the postoperative complications. Intercostal approach VATS is regarded as a feasible and safe surgical method for large-sized anterior mediastinal tumors (5.0–10.0 cm) with no invasion to the surrounding tissues and organs.

Abstract Two‐dimensional (2D) non‐layered materials, along with their unique surface properties, offer intriguing prospects for sensing applications. Introducing mechanical degrees of freedom is expected to enrich the sensing performances of 2D non‐layered devices, such as high frequency, high tunability, and large dynamic range, which could lead to new types of high performance nanosensors. Here, we demonstrate 2D non‐layered nanomechanical resonant sensors based on β‐In2S3, where the devices exhibit robust nanomechanical vibrations up to the very high frequency (VHF) band. We show that such device can operate as pressure sensor with broad range (from 10−3 Torr to atmospheric pressure), high linearity (with a nonlinearity factor as low as 0.0071), and fast response (with an intrinsic response time less than 1 μs). We further unveil the frequency scaling law in these β‐In2S3 nanomechanical sensors and successfully extract both the Young's modulus and pretension for the crystal. Our work paves the way towards future wafer‐scale design and integrated sensors based on 2D non‐layered materials.

Due to the increasing number of international exchanges, foreign users have gradually become a significant consumer segment. Many of them are not proficient in the local language. Providing them with native language services will be an important trend, both from a business and a humanistic perspective. The purpose of this study is to investigate the fast-food restaurant ordering system that can provide multilingual services for foreigners, and to investigate factors that influence fast food restaurant consumers to adopt multilingual self-service ordering systems. Based on the characteristics of foreign users, we have proposed experience factors such as convenience, translation quality, social anxiety, and the Flow. According to research, the convenience of the service has a strong direct impact on consumers' intention to use, social anxiety has a weak direct impact on consumers' intention to use, and translation quality has a weak direct impact on consumers' intention to use through the intermediate variable of social anxiety. Particularly, Flow experience is not associated with intention to use. The Flow state is one in which users are completely immersed and do not notice time or the surroundings when the perceived difficulty of a task matches their abilities. The purpose of this study is to improve our understanding of the customer evaluation criteria for multilingual self-service systems, as well as to establish the MSSS model for future research on multilingual self-service systems.

This study adopts a cross-linguistic perspective and investigates how musical expertise affects the perception of duration and pitch in language. Native speakers of Chinese (N = 44) and Estonian (N = 46), each group subdivided into musicians and non-musicians, participated in a mismatch negativity (MMN) experiment where they passively listened to both Chinese and Estonian stimuli, followed by a behavioral experiment where they attentively discriminated the stimuli in the non-native language (i.e., Chinese to Estonian participants and Estonian to Chinese participants). In both experiments, stimuli of duration change, pitch change, and duration plus pitch change were discriminated. We found higher behavioral sensitivity among Chinese musicians than non-musicians in perceiving the duration change in Estonian and higher behavioral sensitivity among Estonian musicians than non-musicians in perceiving all types of changes in Chinese, but no corresponding effect was found in the MMN results, which suggests a more salient effect of musical expertise on foreign language processing when attention is required. Secondly, Chinese musicians did not outperform non-musicians in attentively discriminating the pitch-related stimuli in Estonian, suggesting that musical expertise can be overridden by tonal language experience when perceiving foreign linguistic pitch, especially when an attentive discrimination task is administered. Thirdly, we found larger MMN among Chinese and Estonian musicians than their non-musician counterparts in perceiving the largest deviant (i.e., duration plus pitch) in their native language. Taken together, our results demonstrate a positive effect of musical expertise on language processing.

Abstract In vitro and in vivo models play integral roles in preclinical drug research, evaluation, and precision medicine. In vitro models primarily involve research platforms based on cultured cells, typically in the form of two‐dimensional (2D) cell models. However, notable disparities exist between 2D cultured cells and in vivo cells across various aspects, rendering the former inadequate for replicating the physiologically relevant functions of human or animal organs and tissues. Consequently, these models failed to accurately reflect real‐life scenarios post‐drug administration. Complex in vitro models (CIVMs) refer to in vitro models that integrate a multicellular environment and a three‐dimensional structure using bio‐polymer or tissue‐derived matrices. These models seek to reconstruct the organ‐ or tissue‐specific characteristics of the extracellular microenvironment. The utilization of CIVMs allows for enhanced physiological correlation of cultured cells, thereby better mimicking in vivo conditions without ethical concerns associated with animal experimentation. Consequently, CIVMs have gained prominence in disease research and drug development. This review aimed to comprehensively examine and analyze the various types, manufacturing techniques, and applications of CIVM in the domains of drug discovery, drug development, and precision medicine. The objective of this study was to provide a comprehensive understanding of the progress made in CIVMs and their potential future use in these fields.

Long-term consumption of high-carbohydrate feed may adversely affect intestinal health of fish; however, the underlying roles remain ambiguous. This study examined the effects of varying carbohydrate levels on the intestinal flora of common carp and assessed how microbial metabolites influence intestinal health. Two hundred seventy common carps were chosen and distributed randomly into three groups that fed diets containing starch at levels of 15% (low-carbohydrate diet [LCD]), 28% (medium-carbohydrate diet [MCD]), and 45% (high-carbohydrate diet [HCD]) for 60 days. A significant increase in final body weight, weight gain rate, and specific growth rate within the MCD group, while feed conversion ratio exhibited a decrease in comparison to the other groups (p

Among the polyphenolic compounds commonly found in green tea, (-)-epigallocatechin-3-gallate (EGCG) is known to have various functions, including the promotion of antioxidant and myofiber growth in mammals. However, the effect of EGCG on common carp (Cyprinus carpio L.) remains poorly understood. To evaluate the role of EGCG on juvenile common carp, 255 fish (initial weight 17.33 ± 0.34 g) were fed with five experimental diets containing 0, 0.05, 0.25, 0.5, and 1 g/kg EGCG. The results showed that diet supplementation with 0.05–0.5 g/kg EGCG supplementation significantly enhanced the specific growth rate (SGR) and reduced the feed conversion ratio (FCR). Weight gain rate (WGR) was significantly enhanced in the 0.25 and 0.5 g/kg EGCG groups. As for antioxidants, 0.25–1 g/kg EGCG significantly reduced protein carbonyl (PC) content and upregulated superoxide dismutase (sod) gene expression in the muscle. As for muscle nutritional composition, 0.05–0.5 g/kg EGCG increased total amino acid (TAA) and flavor amino acid (FAA) contents, likely via the rapamycin (mTOR) signaling pathway. Muscle n-3 polyunsaturated fatty acids (n-3 PUFA) content was increased with 0.5 g/kg EGCG, presumably owing to the upregulation of fatty acyl elongase 5 (elovl5), long-chain fatty acyl-CoA synthetase 6 (acsl6), and peroxisome proliferator-actiated receptor α (pparα). Dietary EGCG (0.05–1 g/kg) significantly increased muscle hardness and chewiness, accompanied by an increase in myofiber density. EGCG supplementation (0.25–1 g/kg) increased the pH value and reduced lactate contents in the muscle. However, muscle crude lipid and hydroxyproline contents significantly decreased with 1 g/kg EGCG. Overall, quadratic regression analysis of WGR, SGR, TAA, and FAA showed that optimal EGCG (0.46–0.52 g/kg) dietary supplementation improved the growth and nutritional composition of juvenile common carp.

Real-time visual-aided navigation and path strategy for pneumonoconiosis and efficient 3D visualization of pulmonary vessels are of great research and clinical significance in the treatment of lung diseases. The complex structure of lung tissue limits the application of deep learning in pulmonary vascular visualization due to the lack of vascular labeling datasets. Also, the existing methods have large computational complexity and are low efficiency. This study proposes a method for high-quality 3D visualization of pulmonary vessels based on low-cost segmentation and fast reconstruction, consisting of three steps: 1) Pulmonary vessel feature extraction from lung CT images using self-supervised learning, 2) Segmentation of pulmonary sparse vessels in lung CT images using self-supervised transfer learning, and 3) 3D reconstruction of pulmonary vessels based on segmentation results of step (2) using interpolation. The accuracy of pulmonary vascular contour segmentation was improved from 91.31% using the sparse coding to 98.65% using our proposed method (27,270 test sample points); the classifier evaluation accuracy was improved from 95.33% to 98.26%, and the average running time of the model with the test set data was 44 ms per slice. the segmentation results can automatically generate a complete vascular tree model with an average time of 10.8s ± 1 1.6s. The results demonstrate that the proposed method provides fast and accurate 3D visualization of pulmonary vessels, and is promising for more precise and reliable information for pneumonoconiosis patients.

Soil amelioration in coastal saline areas plays an important role in alleviating land resource shortages, improving regional ecological environments, ensuring food security, and promoting economic development. Plastic mulching (M) and the combination of freezing saline water irrigation and plastic mulching (WIM) are successful amelioration practices that dramatically reduce the salinity of surface soil and facilitate plant growth in coastal saline soil. However, the bacterial responses that are closely related to these amelioration practices in coastal saline soil remain poorly understood. In this study, bacterial richness and diversity, community composition, and potential ecological functions in the rhizosphere and bulk soils of cotton in M and WIM treatments, along with a control treatment, were investigated using high-throughput sequencing in a coastal saline field. The results showed that both the M and WIM treatments increased bacterial richness and alpha diversity, which were in general significantly higher in bulk soil than in rhizosphere soil. Non-metric multidimensional scaling and the Bray–Curtis dissimilarity analysis revealed that the bacterial community in rhizosphere soil was assembled far from those in the control and bulk soils and behaved more specifically in rhizosphere soil than in bulk soil. The relative abundances of most of the dominant phyla showed opposite trends of variation in bulk and rhizosphere soils compared to those in control soil in both M and WIM treatments; in particular, the specific bacterial groups of Proteobacteria and Actinobacteria decreased in bulk soil but significantly increased in rhizosphere soil. Functional groups of chemoheterotrophy, aerobic chemoheterotrophy, and nitrate reduction were predominant in rhizosphere rather than bulk soil, according to the Functional Annotation of Prokaryotic Taxa. These findings improve the understanding of the mechanism of bacterial responses to amelioration practices M and WIM in coastal saline soils and provide valuable information for the development of amelioration techniques based on agricultural practices and soil microbiome to enhance plants’ adaptability to saline soil in the future.

ABSTRACT: With increasing challenges towards continued scaling and improvement in performance faced by electronic computing, mechanical computing has started to attract growing interests. Taking advantage of the mechanical degree of freedom in solid state devices, micro/nano-electromechanical systems (MEMS/NEMS) could provide alternative solutions for future computing and memory systems with ultralow power consumption, compatibility with harsh environments, and high reconfigurability. In this review, MEMS/NEMS-enabled memories and logic processors were surveyed, and the prospects and challenges for future on-chip mechanical computing were also analyzed.

Atherosclerosis, the main pathological basis of cardiovascular disease, is a chronic inflammatory disease that severely affects the quality of human life. Resveratrol (Res) is a natural polyphenol that is a major component of many herbs and foods. The present study analyzed resveratrol from the perspective of visualization and bibliometric analysis and found that resveratrol is closely related to the inflammatory response in cardiovascular diseases (associated with atherosclerosis). To explore the specific molecular mechanism of resveratrol, network pharmacology and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used, in which HIF-1α signaling may be a key pathway in the treatment of AS. Furthermore, we induced the polarization of macrophage RAW264.7 to M1 type to generate inflammatory response by the combination of lipopolysaccharide (LPS) (200 ng/mL) + interferon-γ (IFN-γ) (2.5 ng/mL). LPS and IFN-γ increased the inflammatory factor levels of IL-1β, TNF-α, and IL-6 in RAW264.7, and the proportion of M1-type macrophages also increased, but the expression of inflammatory factors decreased after resveratrol administration, which confirmed the anti-inflammatory effect of resveratrol in AS. In addition, we found that resveratrol downregulated the protein expression of toll-like receptor 4 (TLR4)/NF-κB/hypoxia inducible factor-1 alpha (HIF-1α). In conclusion, resveratrol has a significant anti-inflammatory effect, alleviates HIF-1α-mediated angiogenesis, and prevents the progression of AS through the TLR4/NF-κB signaling pathway.

A 56-day feeding trial was conducted to investigate the effects of genistein on growth, lipid metabolism, antioxidant capacity, and immunity of common carp fed with high-carbohydrate or high-fat diets. Five diets were used to feed fish: control diet (5% fat; CO), high-fat diet (11% fat; HF), high-carbohydrate diet (45% carbohydrate; HC), and HF or HC diet with 500 mg/kg genistein (FG or CG). Results showed that final body weight (FW) and specific growth rate (SGR) were significantly reduced, but the supplementation with genistein resulted in higher values of FW and SGR than the HF or HC group. Both high carbohydrate and high fat belong to high-energy diets, which may promote lipid deposition. Genistein obviously decreased liver triglyceride (TG) content and alleviated hepatic fat vacuolation in the HF and HC groups. The expression of lipid metabolism genes (cpt-1 and atgl) was markedly higher in the FG group than in the HF group. The lipid synthesis-related genes (fas, acc, and pparγ) were elevated in high-energy diets but recovered to the control level or reduced after genistein treatments. With respect to fatty acid transporter genes, fatp increased in the FG group, and cd36 increased in the CG group. Furthermore, the antioxidant and immune indexes, such as total antioxidant capacity (T-AOC), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), acid phosphatase (ACP), and lysozyme (LZM) activities, were decreased, while malonate aldehyde (MDA) content, activities of alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were enhanced in the HF and HC groups. The antioxidant and immunity values could be ameliorated by treatment with genistein. Moreover, the transcript levels of antioxidant-related genes (cat, gr, and nrf2) in the liver and anti-inflammatory factors (tgf-β and il-10) and lyz in the head kidney tissue were promoted, although the expression levels of proinflammatory factors (tnf-α and il-6) declined in the genistein supplementation group, which confirmed the antioxidant and immune-enhancing effects of genistein. Therefore, 500 mg/kg genistein could ameliorate the negative effects of high-energy diets on immunity.

Appropriate deep application of fertilizer is the key basis for improving nitrogen use efficiency (NUE). However, the effects of different deep application methods and fertilizer types on nutrient migration, NUE and biomass in wheat season are unclear. Therefore, in this study, a barrel planting test with multilayer fertilization (15N labeled urea (U) and coated urea (CU)) was conducted in a long-term positioning trial of winter wheat in the North China Plain (NCP). We quantified the migration of fertilizer N (Ndff) in soil–plant–atmosphere and its effects on wheat biomass and NUE based on surface (Usur, CUsur), layered-strip (Ustr, CUstr) and layered-mix fertilization (Umix, CUmix) of U and CU. Compared with surface fertilization, the concentration of mineral N in root zone (0–40 cm) was increased by Ustr and Umix (8.6–50.3%), and the concentration of ammonium N was decreased by CUstr and CUmix (49.6–76.0%), but there was no change in the nitrate N. The biomass and total N absorption of wheat tissues (straw and root) were increased by 12.3–38.9% under Ustr and CUstr. Meanwhile, the distribution of Ndff in the 0–10 cm soil was decreased under Ustr and CUstr, but it was increased in the 10–30 cm soil, thereby promoting the absorption of Ndff in wheat tissues by 12.3–28.7%. The rates of absorption and loss of Ndff were the highest (57.6–58.5%) and the lowest (4.5%) under Ustr and CUstr, respectively, compared with other treatments. Consequently, layered-strip fertilization optimized the migration and utilization of Ndff within the soil–plant–atmosphere system. This approach equalized distribution, enhanced absorption and minimized losses of Ndff, resulting in an increase in NUE by 9.6–16.7%. Under the same treatment, CU was more suitable for crop nutrient requirements than U, which was more conducive to the improvement of NUE. Our findings will provide a scientific basis for the precise directional fertilization of winter wheat in the NCP.

Interpersonal verbs like disappoint and praise in Lucy disappointed/praised Mary because she… bias the potential cause of the event to one of the antecedent noun phrases (henceforth NPs) (e.g., Lucy for disappoint whereas Mary for praise). Using Chinese as its materials, this study investigated how verb-based implicit causality affects online pronoun resolution in backward concession (e.g., Lucy disappointed/praised Mary although she…), an intersubjective discourse relation where the subordinate although-clause forms an indirect relationship with the preceding main clause. Experiment 1 was a baseline experiment with the typical structure where implicit causality is found to be effective, i.e., backward causality. Results showed a clear modulation effect of implicit causality on pronoun resolution such that as verb bias strength decreases, participants were faster in processing sentences that disambiguate the pronoun to the verb-inconsistent NP. However, this modulation effect was not observed in Experiment 2 where we used the same verbs but replaced because with although. There was no preference for the pronoun to be disambiguated toward the verb-consistent NP or the verb-inconsistent NP in backward concession. The results of Experiments 1 and 2 were replicated in Experiment 3 where we directly compared causal and concessive relations. We suggest that the absent effect of verb-based implicit causality in backward concession could be attributed to the intersubjective nature of the concessive relation. Discourse devices such as although indicate speakers’ subjective perspective and comprehenders are able to quickly accommodate the speaker’s point of view during online discourse processing.

In future data centers, applications will make heavy use of far memory (including disaggregated memory pools and NVM). The access latency of far memory is more widely distributed than that of local memory accesses. This makes the efficiency of traditional out-of-order load/store mechanism in most general-purpose processors decrease in this scenario. Therefore, this work proposes an in-core asynchronous memory access unit to fully utilize the far memory resources.

Abstract Background The gonad is the major factor affecting animal reproduction. The regulatory mechanism of the expression of protein-coding genes involved in reproduction still remains to be elucidated. Increasing evidence has shown that ncRNAs play key regulatory roles in gene expression in many life processes. The roles of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in reproduction have been investigated in some species. However, the regulatory patterns of miRNA and lncRNA in the sex biased expression of protein coding genes remains to be elucidated. In this study, we performed an integrated analysis of miRNA, messenger RNA (mRNA), and lncRNA expression profiles to explore their regulatory patterns in the female ovary and male testis of Pelodiscus sinensis. Results We identified 10,446 mature miRNAs, 20,414 mRNAs and 28,500 lncRNAs in the ovaries and testes, and 633 miRNAs, 11,319 mRNAs, and 10,495 lncRNAs showed differential expression. A total of 2814 target genes were identified for miRNAs. The predicted target genes of these differentially expressed (DE) miRNAs and lncRNAs included abundant genes related to reproductive regulation. Furthermore, we found that 189 DEmiRNAs and 5408 DElncRNAs showed sex-specific expression. Of these, 3 DEmiRNAs and 917 DElncRNAs were testis-specific, and 186 DEmiRNAs and 4491 DElncRNAs were ovary-specific. We further constructed complete endogenous lncRNA-miRNA-mRNA networks using bioinformatics, including 103 DEmiRNAs, 636 DEmRNAs, and 1622 DElncRNAs. The target genes for the differentially expressed miRNAs and lncRNAs included abundant genes involved in gonadal development, including Wt1, Creb3l2, Gata4, Wnt2, Nr5a1, Hsd17, Igf2r, H2afz, Lin52, Trim71, Zar1, and Jazf1. Conclusions In animals, miRNA and lncRNA as master regulators regulate reproductive processes by controlling the expression of mRNAs. Considering their importance, the identified miRNAs, lncRNAs, and their targets in P. sinensis might be useful for studying the molecular processes involved in sexual reproduction and genome editing to produce higher quality aquaculture animals. A thorough understanding of ncRNA-based cellular regulatory networks will aid in the improvement of P. sinensis reproductive traits for aquaculture.

Abstract High tumor mutation burden (TMB), which is associated with increased tumor immunogenicity, has been identified to predict improved response to immune checkpoint inhibitors (ICIs) therapy in non-small cell lung cancer (NSCLC). As host immunity is also significant to eliminate cancer cells, however, its clinical impact on cancer immunotherapy is still largely unknown. Here we explored the influence of age, which is an important characteristic to evaluate immune response of patients, on TMB-based predictive system for ICIs therapy in NSCLC. Our results showed that high TMB was capable of predicting better durable clinical benefit (DCB) in agelow group, while it was insignificant in agehigh group. Besides, the predictive power of TMB for progression-free survival (PFS) and overall survival (OS) was better in agelow group than in agehigh group. Our study illustrated that the predictive value of TMB for ICIs therapy was better in young patients than in elderly patients in NSCLC.

Summary: The differentiation of lymphatic progenitors is a crucial step in lymphangiogenesis. However, its underlying mechanism remains unclear. Here, we found that noncanonical protease-activated receptor 1 (par1) regulates the differentiation of lymphatic progenitors in zebrafish embryos. Loss of par1 function impaired lymphatic differentiation by downregulating prox1a expression in parachordal lymphangioblasts and caused compromised thoracic duct formation in zebrafish. Meanwhile, the G protein gnai2a, a par1 downstream effector, was selectively required for lymphatic development in zebrafish, and its mutation mimicked the lymphatic phenotype observed in par1 mutants. Interestingly, mmp13, but not thrombin, was required for lymphatic development in zebrafish. Furthermore, analyses of genetic interactions confirmed that mmp13b serves as a par1 upstream protease to regulate lymphatic development in zebrafish embryos. Mechanistically, par1 promotes flt4 expression and phospho-Erk1/2 activity in the posterior cardinal vein. Taken together, our findings highlight a function of par1 in the regulation of lymphatic differentiation in zebrafish embryos.

The complete mitochondrial genome of Notonecta amplifica Kiritshenko, 1930 (Hemiptera: Notonectidae) was sequenced by high-throughput sequencing (HTS). The whole length is 15,150 bp, including 13 protein-coding genes (PCGs), 22 transfer RNA (tRNAs), two ribosomal RNA (rRNAs) and a 528 bp control region (D-loop). The nucleotide is with a base composition of A (43.01%), G (10.32%), C (13.87%) and T (32.80%). The total length of the coding sequences encoding 3,694 amino acids is 11,113 bp, accounting for 73.35%. The lengths of 12S rRNA and 16S rRNA are 800 and 1,251 bp, respectively. The Bayesian phylogenetic analysis of 20 taxa indicate that N. amplifica is closely related to Notonecta montandoni, with posterior probability value of 1.00. The complete mitochondrial genome sequence would provide useful genetic information for future taxonomic and phylogenetic classification of N. amplifica.

Abstract Background This study evaluated the individual and combined diagnostic performance of the bacterial artificial chromosomes (BACs)-on-Beads (BoBs™) assay and conventional karyotyping for the prenatal detection of chromosomal abnormalities in pregnant women who were 35 or more years-old. Method The primary outcome was concordance of any numerical, structural, or submicroscopic chromosomal abnormalities between BoBs™ and conventional karyotyping of amniotic fluid specimens from pregnant women at 17 to 22 weeks gestation. Results We examined samples from 4852 pregnant women. BoBs™ indicated that 4708 samples were normal (97.03%), and 144 were abnormal (2.97%); conventional karyotyping indicated that 4656 (95.96%) samples were normal and 196 (4.04%) were abnormal. The combined use of both methods indicated that 4633 of 4852 samples were normal (95.49%) and 219 of 4852 samples (4.51%) were abnormal. The kappa coefficient of the combined test was 0.70, indicating substantial consistency between BoBs™ and conventional karyotyping (95% CI = 0.65–0.76, P

The porous aerostatic bearing is a new supporting structure that is widely used in precision and ultraprecision engineering and the aerospace and other fields. The aerostatic bearing has a good bearing capacity and static stiffness. In this work, the numerical and experimental research on the static characteristics of an aerostatic bearing based on a porous SiC ceramic membrane is presented. The porous ceramic membrane prepared by reactive sintering, with a porosity of 25.8% and a pore size of 20.55 μm, was used as the restrictor to fabricate the aerostatic bearing. It was found that the ceramics have good permeability, and the permeability coefficient reached 2.78 × 10−13 m2 using permeability-test experiments. The effects of the gas-supply pressure and permeability coefficient on the static characteristics of the aerostatic bearing based on porous ceramics were analyzed using Fluent simulation calculation. When the gas-supply pressure was 0.5 MPa and the gas-film thickness was 6 μm, the static stiffness of the aerostatic bearing reached a maximum of 20.9 N/μm, while the bearing capacity was 632.5 N. The numerical results of the static characteristics of the aerostatic bearing are highly consistent with the experimental results, which verifies the accuracy of the Fluent simulation, and provides convenience for studying the static characteristics of aerostatic bearings.

In the preparation of (Ba,Ca)(Zr,Ti)O3 lead-free piezoelectric ceramics, different Ca2+ and Zr4+ contents will greatly affect the phase structure, microstructure, and electrical properties of the ceramics. XRD shows that all samples have pure perovskite phase structure, and the (Ba0.85Ca0.15)(ZryTi1−y)O3 ceramics morphotropic phase boundary region from tetragonal phase to rhombohedral phase near 0.08 ≤ y ≤ 0.1. From the dielectric temperature curve, the phase transition temperature (TO-T) was found near room temperature at 0.12 ≤ x ≤ 0.18 for the (Ba1−xCax)(Zr0.1Ti0.9)O3 ceramics. Both Ca2+ and Zr4+ increase have a significant decrease on the Curie temperature Tc. All samples were revealed as relaxers with diffusivities in the range 1.29 ≤ γ ≤ 1.82. Different from the undoped ceramics, ceramics doped with Ca and Zr ions exhibit saturated P–E hysteresis loops, and their ferroelectric properties are significantly optimized. In particular, the (Ba0.85Ca0.15)(Zr0.1Ti0.9)O3 ceramic demonstrated optimal properties, namely d33 = 330 pC/N, kp = 0.41, εr = 4069, Pr = 4.8 μC/cm2, and Ec = 3.1 kV/cm, indicating that it is a viable lead-free piezoelectric contender. Variations in Ca and Zr content have a significant effect on the crystal grain sizes and densities of ceramics, which is strongly associated with their piezoelectricity.

The present study assessed the effects of different ratios of dietary linolenic acid (LNA) to linoleic acid (LA) from vegetable oils on growth performance, ovarian steroidogenesis, plasma sex steroid hormone, and tissue fatty acids accumulation in juvenile common carp (Cyprinus carpio). With fish oil, peanut oil, and perilla oil as lipid source, five experimental diets containing 32% crude protein and 8% crude lipid were formulated with LNA/LA ratios of 0.97 (control diet), 0.02, 0.46, 1.09, and 1.53, respectively. The diets were assigned to 15 tanks (50 L) of carp, and the fish (8.10 ± 0.11 g, n = 25) were manually fed to apparent satiation twice daily in triplicate groups for 16 weeks. The survival rate and feed conversion ratio were not significantly different among treatments (P > 0.05). Results demonstrated that fish fed diet with LNA/LA ratio of 1.09 exhibited the highest body weight gain, and was no significantly different with fish fed control diet. Fish fed diet with LNA/LA ratio of 1.53 showed the highest gonadosomatic index (P < 0.05). The expression of StAR, 17β-HSD and Cyp19a1a in ovary were up-regulated, and plasma E2 increased with increasing of dietary LNA/LA ratios (P < 0.05). Fish fed diet with LNA/LA ratio of 0.02 showed the lowest plasma E2 and T. The expression of Fads6-a and Elovl5-a in liver expressed higher in fish fed with dietary LNA/LA ratio of 1.09. LNA, LA, Docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) contents in liver were significantly affected by dietary LNA/LA ratios. LNA content in liver and LNA and ARA content in ovary increased with the increasing of dietary LNA/LA ratios. Results of this study indicated that dietary LNA/LA ratios alter both growth and ovarian development, and provided evidence that balanced LNA/LA ratio was beneficial for growth and ovarian development of juvenile common carp.