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Abstract Background The laccase Lcc9 from Coprinopsis cinerea has optimal catalytic activity at moderate to alkaline pH conditions, making it invaluable for industrial applications. However, C. cinerea naturally secretes Lcc9 at low expression levels, which limits the industrial application of Lcc9 on a large scale. Recombinant production of Lcc9 using Aspergillus niger would be an effective way to achieve its high production. Results This study achieved the secretory production of Lcc9 in A. niger and established an efficient transformation procedure for A. niger by optimizing its protoplast preparation system. The transformation efficiency of A. niger was increased 3.8-fold under the optimal system (cell wall digestion enzyme solution: 2% cellulase, 1% snailase, 1% lyticase, and 0.5% lysozyme; incubation time: 3 h; incubation temperature: 37 ℃; culture time: 48 h). The extracellular yield of Lcc9 was enhanced by optimizing gene expression cassette and bioprocess. First, the strain AnGgcL (containing P gpdA ) mediated by the SPCAT, a signal peptide of the extracellular high abundance protein catalase, had an extracellular laccase activity of 10 U/L after shake flask fermentation. Then, by optimizing promoter and signal peptide combinations that regulate lcc9 expression, the strain AnGcgL mediated by P citA -SPGlaA had an extracellular laccase activity of 20 U/L. Subsequently, the strain AnRcgL1 (containing P citA -SPGlaA) obtained by random integration had an extracellular laccase activity of 86 U/L. Sequencing revealed that the lcc9 expression cassette was integrated into the citrate synthase gene locus in the AnRcgL1 genome in a 9-copy form. By optimizing the microparticle, osmolyte, and Cu2+ in the fermentation medium, the AnRcgL1 extracellular laccase activity was further increased to 1566.7 U/L, which was 156.7-fold higher than that of AnGgcL. Furthermore, its extracellular laccase activity was increased to 1961 U/L in a 1-L fermenter. Conclusions To our knowledge, this study is the first to report the recombinant extracellular production of the C. cinerea laccase Lcc9 in A. niger and to use SPCAT in the A. niger expression system. The results of this study will help accelerate the industrial application of Lcc9. Moreover, the strategy used in this work provides methodological guidance for increasing other exogenous protein yields in A. niger.

Abstract Objectives To evaluate the efficacy and safety of programmed cell death 1 (PD‐1)/programmed cell death ligand 1 (PD‐L1) inhibitors in the treatment of extensive‐stage small‐cell lung cancer (ES‐SCLC), we conducted a systematic review and meta‐analysis that included randomized controlled trials (RCTs) and real‐world studies (RWS). Methods By scanning PubMed, Web of science, Embase, and other relevant clinical information public databases, nine RCTs and eight RWSs involving 5205 patients were included in the study. We directly compared the differences between chemotherapy and PD‐1/PD‐L1 inhibitors plus chemotherapy, and determined the optimal treatment strategy through network meta‐analysis (NMA). Results Compared to chemotherapy, the addition of PD‐1/PD‐L1 inhibitors significantly improves the overall survival (OS), progression‐free survival (PFS), and objective response rate (ORR) in SCLC patients. Regarding safety, both RCTs and RWSs indicated no significant difference in grade 3–4 adverse events between chemotherapy and chemoimmunotherapy. NMA showed serplulimab plus chemotherapy (Serp_Chemo) appears to provide the best OS, PFS, and ORR benefit, while nivolumab plus chemotherapy shows higher toxicity than other regimens. In subgroup analysis, for elderly patients (age ≥65) and non‐elderly (age upper limit of normal (ULN), there is no apparent OS benefit from immune therapy. Conclusions In ES‐SCLC treatment, adding PD‐1/PD‐L1 inhibitors to standard chemotherapy improves OS, PFS, and ORR, with Serp_Chemo shows the most promise. Atez_Chemo and Serp_Chemo provided better survival for elderly and non‐elderly patients, respectively.

Activity of bc1 complex kinase (ABC1K) is an atypical protein kinase (aPK) that plays a crucial role in plant mitochondrial and plastid stress responses, but little is known about the responses of ABC1Ks to stress in cotton (Gossypium spp.). Here, we identified 40 ABC1Ks in upland cotton (Gossypium hirsutum L.) and found that the GhABC1Ks were unevenly distributed across 17 chromosomes. The GhABC1K family members included 35 paralogous gene pairs and were expanded by segmental duplication. The GhABC1K promoter sequences contained diverse cis-acting regulatory elements relevant to hormone or stress responses. The qRT-PCR results revealed that most GhABC1Ks were upregulated by exposure to different stresses. GhABC1K2-A05 and GhABC1K12-A07 expression levels were upregulated by at least three stress treatments. These genes were further functionally characterized by virus-induced gene silencing (VIGS). Compared with the controls, the GhABC1K2-A05- and GhABC1K12-A07-silenced cotton lines exhibited higher malondialdehyde (MDA) contents, lower catalase (CAT), peroxidase (POD) and superoxide dismutase (SOD) activities and reduced chlorophyll and soluble sugar contents under NaCl and PEG stress. In addition, the expression levels of six stress marker genes (GhDREB2A, GhSOS1, GhCIPK6, GhSOS2, GhWRKY33, and GhRD29A) were significantly downregulated after stress in the GhABC1K2-A05- and GhABC1K12-A07-silenced lines. The results indicate that knockdown of GhABC1K2-A05 and GhABC1K12-A07 make cotton more sensitive to salt and PEG stress. These findings can provide valuable information for intensive studies of GhABC1Ks in the responses and resistance of cotton to abiotic stresses.

This paper investigates the closed-loop supply chain decisions of battery manufacturers considering innovation investments and different subsidy methods provided by the government. The analysis encompasses four scenarios: whether battery manufacturers engage in innovation investments and whether the government opts for technology R&D subsidies or production subsidies. The study finds that innovation investments by battery manufacturers can enhance the modularization level of batteries. The reward or penalty measures for recycling quality imposed on automobile manufacturers elevate the quality of battery recycling, and also increase the wholesale price of batteries and the retail price of automobiles. After implementing R&D and production subsidies, both the modularization level of batteries and the profits of supply chain members exceed those without subsidies, though these subsidies do not affect the quality of battery recycling. R&D subsidies more effectively promote innovation capacity and product quality among battery manufacturers, whereas production subsidies more significantly boost the profits of both battery manufacturers and automobile manufacturers. Therefore, subsidy measures should be tailored according to different stages of the power battery industry's development. Regardless of whether battery manufacturers invest in innovation or whether the government provides subsidies, collaboration between battery manufacturers and automobile manufacturers is essential to coordinate the closed-loop supply chain. The research findings offer valuable guidance for formulating subsidy policies in the new energy vehicle industry across different periods, and also provide theoretical insights for decision-making behaviors among related enterprises.

ABSTRACT Background Bullous pemphigoid (BP) and atopic dermatitis (AD) are currently thought to be tightly related, yet studies of the mechanisms of co‐morbidities are lacking. Methods We obtained GWAS data for BP (N = 376,274) and AD (N = 796,661) from the Finnish Genetic Research Program dataset and the UK Biobank, separately. Then, the following four analyses were performed: (1) cross‐trait linkage disequilibrium score regression (LDSC) to assess the genetic correlation between BP and AD, (2) cross‐phenotype association analysis (CPASSOC) to identify multiple effector loci shared by BP and AD, (3) transcriptome‐wide association study (TWAS) to determine whether their cross‐organizational expression patterns share genes with a common biological mechanism of relevance, and (4) bidirectional Mendelian randomization (MR) analysis to assess bidirectional causal effects of BP and AD. Results We found a positive genetic association between BP and AD (rg = 0.5476, p = 0.0495) as well as identified four pleiotropic loci and 59 common genes affecting BP and AD. Bidirectional MR analysis suggested that BP promotes the risk of AD. Conclusions We revealed a genetic link between BP and AD, which is associated with biological pleiotropy and causality. Awareness of the association between BP and AD helps dermatologists manage patients with these illnesses.

Abstract TMEFF1 is a new protein involved in the physiological functions of the central nervous system, and we previously reported TMEFF1 can promote ovarian cancer. ST14 was determined to be involved in the processes of epidermal differentiation, epithelial cell integrity, and vascular endothelial cell migration, etc. The relationship between ST14 and TMEFF1 in the ovary remains unknown. In this study, we detected the expression of ST14 and TMEFF1 in 130 different ovarian cancer tissues through immunohistochemistry. We determined ST14 and TMEFF1 were highly expressed in ovarian cancer, indicating a higher degree of tumor malignancy and a worse prognosis. Tissues significantly expressing ST14 also highly expressed TMEFF1, and the expression of the two proteins was positively correlated. Consistently, immunofluorescence double staining demonstrated the co-localization of ST14 and TMEFF1 in the same region, and immunoprecipitation confirmed the interaction between ST14 and TMEFF1. TMEFF1 expression was also reduced after knocking down ST14 through Western blot. MTT, wound healing and Transwell assays results determined that knockdown of ST14 inhibited proliferation, migration and invasion of ovarian cancer cells in vitro, but the inhibitory effect was restored after adding TMEFF1 exogenous protein. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways analysis showed that ST14 and its related genes were enriched in the processes of epithelial formation, intercellular adhesion, protein localization, and mitosis regulation. We also clarified the kinase, microRNA, and transcription factor target networks and the impact of genetic mutations on prognosis. Overall, high expression of ST14 and TMEFF1 in ovarian cancer predicts higher tumor malignancy and a worse prognosis. ST14 and TMEFF1 co-localize and interact with each other in ovarian cancer. ST14 can regulate TMEFF1 expression to promote proliferation, migration and invasion of ovarian cancer cells. We speculate that the relationship between ST14 and TMEFF1 in ovarian cancer could become a potential target for anti-cancer therapy.

Abstract Small cell lung cancer (SCLC) is one of the highly aggressive malignancies characterized by rapid growth and early metastasis, but treatment options are limited. For SCLC, carboplatin or cisplatin in combination with etoposide chemotherapy has been considered the only standard of care, but the standard first‐line treatment only results in 10‐month survival. The majority of patients relapse within a few weeks to months after treatment, despite the relatively sensitive response to chemotherapy. Over the past decade, immunotherapy has made significant progress in the treatment of SCLC patients. However, there have been limited improvements in survival rates for SCLC patients with the current immune checkpoint inhibitors PD‐1/PD‐L1 and CTLA‐4. In the face of high recurrence rates, small beneficiary populations, and low survival benefits, the exploration of new targets for key molecules and signals in SCLC and the development of drugs with novel mechanisms may provide fresh hope for immunotherapy in SCLC. Therefore, the aim of this review was to explore four new targets, DLL3, TIGIT, LAG‐3, and GD2, which may play a role in the immunotherapy of SCLC to find useful clues and strategies to improve the outcome for SCLC patients.

Distilled grain waste (DGW) is rich in nutrients and can be a potential resource as animal feed. However, DGW contains as much as 14% lignin, dramatically reducing the feeding value. White-rot fungi such as Pleurotus ostreatus could preferentially degrade lignin with high efficiency. However, lignin derivatives generated during alcohol distillation inhibit P. ostreatus growth. Thus, finding a new strategy to adjust the DGW properties to facilitate P. ostreatus growth is critical for animal feed preparation and DGW recycling. In this study, three dominant indigenous bacteria, including Sphingobacterium thermophilum X1, Pseudoxanthomonas byssovorax X3, and Bacillus velezensis 15F were chosen to generate single and compound microbial inoculums for DGW composting to prepare substrates for P. ostreatus growth. Compared with non-inoculated control or single microbial inoculation, all composite inoculations, especially the three-microbial compound, led to faster organic metabolism, shorter composting process, and improved physicochemical properties of DGW. P. ostreatus growth assays showed the fastest mycelial colonization (20.43 μg·g−1 ergosterol) and extension (9 mm/d), the highest ligninolytic enzyme activities (Lac, 152.68 U·g−1; Lip, 15.56 U·g−1; MnP, 0.34 U·g−1; Xylanase, 10.98 U·g−1; FPase, 0.71 U·g−1), and the highest lignin degradation ratio (30.77%) in the DGW sample after 12 h of composting with the three-microbial compound inoculation when compared to other groups. This sample was relatively abundant in bacteria playing critical roles in amino acid, carbohydrate, energy metabolism, and xenobiotic biodegradation, as suggested by metagenomic analysis. The feed value analysis revealed that P. ostreatus mycelia full colonization in composted DGW led to high fiber content retention and decreased lignin content (final ratio of 5% lignin) but elevated protein concentrations (about 130 g·kg−1 DM). An additional daily weight gain of 0.4 kg/d was shown in cattle feeding experiments by replacing 60% of regular feed with it. These findings demonstrate that compound inoculant consisting of three indigenous microorganisms is efficient to compost DGW and facilitate P. ostreatus growth. P. ostreatus decreased the lignin content of composted DGW during its mycelial growth, improving the quality of DGW for feeding cattle.

Abstract In this study, a method for assimilating FY4A advanced geostationary radiance imager (AGRI) cirrus‐effected radiances (CER) is investigated, and the impact of this method on water vapor analysis and rainstorm forecasting is examined through observing system simulation experiments and actual case experiments. The high proportion of inverted humidity profiles in the cirrus‐effected pixels is the main reason for the negative effect of assimilation in the mid‐to‐lower troposphere. To address this, relevant constraint conditions are incorporated into the cost function. The statistical results reveal that the addition of a CER assimilation improves the analysis increment of water vapor, with pattern correlation coefficients of 0.33, 0.35, and 0.20 at 200, 300, and 400 hPa, respectively, which are greater than those of a clear‐sky radiance assimilation (0.28, 0.33, and 0.17, respectively). Moreover, the inclusion of a CER assimilation greatly improves data utilization, and has a neutral to positive effect on precipitation forecasting.

Abstract Soundscapes have played an important role in the design and building of classical Chinese gardens. In Chinese classical poetry, biophonies such as bird calls, and geophonies such as wind, are the preferable sound sources. Although these major sound sources have been categorized and summarized by scholars extensively, little research has been conducted to analyze the physical characteristics and preference matrix of these preferred sound sources. Moreover, the perceived loudness of sound in classical Chinese gardens has received more attention from scholars than acoustic frequency. In this study, we selected 12 sound sources that are most typically present in classical Chinese gardens based on extensive literature research on Chinese classical poetry, and acquired respective audio samples from the BBC’s library of Sound Effects. Through the spectrogram analyses, pitch detection algorithm and LSTM audio classification methods, the sound sources were classified into discrete sound sources with pitch variation and continuous sound sources with spectral characteristics of white noise or pink noise. The reasoning behind the preference for these two types of sound sources was then discussed from physical and mental healing perspectives, which aims to help provide perspectives on the associated implications in the planning of urban green spaces.

As a concept that emerged in Europe, a bio-district is an area where different actors work together for the innovative and integrated transformation of rural food systems and the sustainable management of local resources, based on the principles of organic farming and with farmers playing a central role. Traditional Chinese villages represent sustainable models for the management of rural food systems and natural resources, developed by indigenous peoples who have been in “dialogue” with the land over millennia and adapted to specific geographical and ecological environments. These models encompass well-established edible green infrastructure (EGI) ecological structures, rich in indigenous knowledge and understanding of the environment that support food supply and regional ecological sustainability. Our case study focuses on a well-preserved village of the Dong ethnic group in southwest China, which maintains traditional livelihoods and a local food system. We used field surveys, interviews, participatory mapping to propose an EGI model of the traditional Dong village, which comprises the following key elements: the “rice-fish-duck” cycle as a key factor of traditional livelihoods, the hierarchical ecological structure of “households-groups-village,” and corresponding management models. This study aims to comprehensively understand the knowledge of sustainable food systems and natural resource management derived from traditional China. It achieves this by theoretically analyzing the traditional village EGI that has evolved over China’s thousand-year agricultural civilization. The objective is to apply this understanding to the construction of bio-districts in rural China. EGI model in traditional villages worldwide have the potential to offer lessons from millennium-old indigenous agricultural systems, which may have relevance for current environmental and food crises faced by our industrialized world, the construction of bio-districts and organic regions, and the sustainable management of local resources.

Abstract Background Position transition training for general practitioners in Zhejiang Province started in 2017 and has since been held once a year. By the beginning of 2022, four training sessions were completed. The purpose of this survey was to establish the current situation of trainees after their graduation and provide reference for the evaluation of the training effect. Methods Of the 738 trainees who completed the training, 253 were contacted and followed up. A self-designed questionnaire was used to conduct the survey through online filling in. The content included questions to elucidate the following information: whereabouts after the training, registration as a general practitioner, undertaken general practice teaching and scientific research work, current occupational environment, improvement of post competence after receiving position transition training, willingness to complete survey, willingness to participate in future training programs, etc. Results A number of 253 valid questionnaires were collected with a recovery rate of 100%. Notably, 93.68% of the participants successfully completed their training and obtained the Training Certificate of General Practitioners. Further, 83.4% were registered as general practitioners, 82.94% of which added on the basis of the original registered scope of practice. Currently, most of them work in primary health care institutions, primarily occupied with medical treatment, chronic disease management, COVID-19 prevention and control, health education, and prevention and health care. Of them, 27.01% were currently undertaking teaching work, and only 3.32% of them were conducting scientific research work related to general practice. The overall satisfaction of the trainees in the three theoretical training bases was above 90%, with no statistically significant difference among them (P > 0.05). Importantly, 84.11% of the followed-up personnel hoped to continue to participate in similar training in the future to improve their general practitioner core competences. Conclusion The position transition training in Zhejiang Province has achieved good results, but the details of training and the implementation of policies in individual regions need to be improved. Most of the graduates were willing to continue their education, especially in general practitioners with special interests.

Moldy corn produces aflatoxin and gibberellin, which can have adverse effects on human health if consumed. Mold is a significant factor that affects the safe storage of corn. If not detected and controlled in a timely manner, it will result in substantial food losses. Understanding the infection patterns of mold on corn kernels and the changing characteristics of the internal structure of corn kernels after infection is crucial for guiding innovation and optimizing detection methods for moldy corn. This knowledge also helps maintain corn storage and ensure food safety. This study was based on X-ray tomography technology to non-destructively detect changes in the structural characteristics of moldy corn kernels. It used image processing technology and model reconstruction algorithms to obtain the 3D model of the embryo, pores and cracks, endosperm and seed coat, and kernels of moldy corn kernels; qualitative analysis of the characteristic changes of two-dimensional slice grayscale images and 3D models of moldy corn kernels; and quantitative analysis of changes in the volume parameters of corn kernels, embryos, endosperm, and seed coats as a whole. It explored the detection method of moldy corn kernels based on a combination of X-ray tomography technology and deep learning algorithms. The analysis concluded that mold infection in maize begins in the embryo and gradually spreads and that mold damage to the tissue structure of maize kernels is irregular in nature. The overall volume parameter changes of corn kernels, embryos, endosperm, and seed coats in the four stages of 0 d, 5 d, 10 d, and 15 d showed a trend of first increasing and then decreasing. The ResNet50 model was enhanced for detecting mold on maize kernels, achieving an accuracy of over 93% in identifying mold features in sliced images of maize kernels. This advancement enabled the non-destructive detection and classification of the degree of mold in maize kernel samples. This article studies the characterization of the characteristic changes of moldy corn kernels and the detection of mildew, which will provide certain help for optimizing the monitoring of corn kernel mildew and the development of rapid detection equipment.

Background: Salvia miltiorrhiza (Salvia miltiorrhiza Radix et Rhizoma) is the dried root and rhizome of Salvia miltiorrhiza Bge., a plant of the labiate family. It is a type of traditional Chinese medicine that can promote blood circulation for removing blood stasis. It is often used to treat cardiovascular and cerebrovascular diseases in a clinic.Aim of the study: High-quality Chinese herbal medicines are the premise of the safe and effective use of Traditional Chinese Medicine (TCM) in clinics. We aim to prove the rationality of the traditional identification method, namely, ‘the redder the root colour and the thicker the root, the better is the quality’, to use the morphological features of Salvia miltiorrhiza as the main index to quickly and directly evaluate its quality. Materials and methods: By referring to relevant ancient books, domestic and foreign literature, and academic papers, we summarised the research progress regarding the morphological features, functional substances, pharmacological action, and clinical efficacy of Salvia miltiorrhiza. Results: The redder the colour, the thicker the root, and the denser the texture, the better is the quality of Salvia miltiorrhiza. In Salvia miltiorrhiza, tanshinone ⅡA and salvianolic acid B are the main functional substances that protect the cardiovascular and cerebrovascular functions. The higher the content of these two functional substances, the better is the clinical efficacy of Salvia miltiorrhiza. Conclusion: The research idea of the correlation between the ‘morphological features, functional substances, pharmacological action, and clinical efficacy’ can be applied to evaluate the quality of Salvia miltiorrhiza. This research idea and method can also be applied to more Chinese herbal medicines.

Enzymatic, acidic, and alkaline treatments were applied to extract insoluble dietary fiber (IDF) from mycoprotein. The structural properties of IDFs were elucidated using scanning electron microscopy, molecular weight analysis, Fourier transform infrared spectroscopy, and monosaccharide composition analysis. The results indicated that all three treatment methods led to IDFs with higher water holding capacity and oil holding capacity compared to untreated mycoprotein. Moreover, the alkali and enzymatic treated IDFs displayed more loose and porous structures, resulting in higher water holding capacity, oil holding capacity, and emulsifying activity compared to citric acid treated IDFs. The findings of this study can help for better understanding of the application of mycoprotein IDFs and optimizing the IDFs extraction from filamentous fungi.

Abstract Objective To investigate the predictive value of deep learning-based cardiac ultrasound flow imaging for hypertrophic cardiomyopathy (HCM) complicated by arrhythmias. Methods The clinical data of 158 patients with hypertrophic cardiomyopathy were retrospectively collected from July 2019 to December 2021, and additionally divided into training group 106 cases, validation group 26 cases and test group 26 cases according to the ratio of 4:1:1, and divided into concurrent and non-concurrent groups according to whether they were complicated by arrhythmia or not, respectively. General data of patients (age, gender, BMI, systolic blood pressure, diastolic blood pressure, HR) were collected, a deep learning model for cardiac ultrasound flow imaging was established, and image data, LVEF, LAVI, E/e', vortex area change rate, circulation intensity change rate, mean blood flow velocity, and mean EL value were extracted. Results The differences in general data (age, gender, BMI, systolic blood pressure, diastolic blood pressure, HR) between the three groups were not statistically significant, P > 0.05. The differences in age, gender, BMI, systolic blood pressure, diastolic blood pressure, HR between the patients in the concurrent and non-concurrent groups in the training group were not statistically significant, P > 0.05. Conclusions Deep learning-based cardiac ultrasound flow imaging can identify cardiac ultrasound images more accurately and has a high predictive value for arrhythmias complicating hypertrophic cardiomyopathy, and vortex area change rate, circulation intensity change rate, mean flow velocity, mean EL, LAVI, and E/e' are all risk factors for arrhythmias complicating hypertrophic cardiomyopathy.

Abstract Mannosyl compounds have been widely used in nutrition, fodder, and vaccine adjuvant industries. In our previous study, the engineered strains for the biosynthesis of three mannosyl compounds including β‐1,2‐mannobiose (M2‐β‐1,2), β‐1,2‐mannotriose (M3‐β‐1,2), and mannosylglycerate (MG) have been developed. However, their biological activities have not been reported. Here, those three compounds were successfully purified after fermentation of the engineered strains, and their potential immunomodulatory activities on RAW264.7 macrophages were investigated with commercialized β‐1,4‐mannotriose (M3‐β‐1,4) as control. Our results showed that M3‐β‐1,2 and MG promoted the viability and phagocytic function of RAW264.7. Meanwhile, the cytokine TNF‐α and interleukin‐6 (IL‐6) level of RAW264.7 macrophages were significantly enhanced upon the stimulation of M3‐β‐1,2 and MG compared with M3‐β‐1,4. Moreover, MG significantly stimulated macrophages to secrete IL‐10 compared with other mannan oligosaccharides. Finally, this study proved that the immunomodulatory activity of M3‐β‐1,2 and MG on RAW 264.7 cells was mainly through mitogen‐activated protein kinases and myeloid differentiation protein 88 (MyD88)‐dependent signaling pathways. All these findings suggested that M3‐β‐1,2 and MG exhibited immunomodulatory activities in the innate and adaptive immune systems, thus facilitating the application potential in developing of mannosyl compounds as an immunomodulator available for food and pharmaceutical area.

ABSTRACT The function of Seryl-tRNA synthetase in fungi during gene transcription regulation beyond translation has not been reported. Here, we report a seryl-tRNA synthetase, ThserRS, which can negatively regulate laccase lacA transcription in Trametes hirsuta AH28-2 under exposure to copper ion. ThserRS was obtained through yeast one-hybrid screening using a bait sequence of lacA promoter (−502 to −372 bp). ThserRS decreased while lacA increased at the transcription level in T. hirsuta AH28-2 in the first 36 h upon CuSO4 induction. Then, ThserRS was upregulated, and lacA was downregulated. ThserRS overexpression in T. hirsuta AH28-2 resulted in a decrement in lacA transcription and LacA activity. By comparison, ThserRS silencing led to increased LacA transcripts and activity. A minimum of a 32-bp DNA fragment containing two putative xenobiotic response elements could interact with ThserRS, with a dissociation constant of 919.9 nM. ThserRS localized in the cell cytoplasm and nucleus in T. hirsuta AH28-2 and was heterologously expressed in yeast. ThserRS overexpression also enhanced mycelial growth and oxidative stress resistance. The transcriptional level of several intracellular antioxidative enzymes in T. hirsuta AH28-2 was upregulated. Our results demonstrate a noncanonical activity of SerRS that acts as a transcriptional regulation factor to upregulate laccase expression at an early stage after exposure to copper ions. IMPORTANCE Seryl-tRNA synthetase is well known for the attachment of serine to the corresponding cognate tRNA during protein translation. In contrast, its functions beyond translation in microorganisms are underexplored. We performed in vitro and cell experiments to show that the seryl-tRNA synthetase in fungi with no UNE-S domain at the carboxyl terminus can enter the nucleus, directly interact with the promoter of the laccase gene, and negatively regulate the fungal laccase transcription early upon copper ion induction. Our study deepens our understanding of the Seryl-tRNA synthetase noncanonical activities in microorganisms. It also demonstrates a new transcription factor for fungal laccase transcription.

IntroductionThe conflict between cancer cells and the host immune system shapes the immune tumour microenvironment (TME) in hepatocellular carcinoma (HCC). A deep understanding of the heterogeneity and intercellular communication network in the TME of HCC will provide promising strategies to orchestrate the immune system to target and eradicate cancers.MethodsHere, we performed single-cell RNA sequencing (scRNA-seq) and computational analysis of 35786 unselected single cells from 3 human HCC tumour and 3 matched adjacent samples to elucidate the heterogeneity and intercellular communication network of the TME. The specific lysis of HCC cell lines was examined in vitro using cytotoxicity assays. Granzyme B concentration in supernatants of cytotoxicity assays was measured by ELISA.ResultsWe found that VCAN+ tumour-associated macrophages (TAMs) might undergo M2-like polarization and differentiate in the tumour region. Regulatory dendritic cells (DCs) exhibited immune regulatory and tolerogenic phenotypes in the TME. Furthermore, we observed intensive potential intercellular crosstalk among C1QC+ TAMs, regulatory DCs, regulator T (Treg) cells, and exhausted CD8+ T cells that fostered an immunosuppressive niche in the HCC TME. Moreover, we identified that the TIGIT-PVR/PVRL2 axis provides a prominent coinhibitory signal in the immunosuppressive TME. In vitro, antibody blockade of PVR or PVRL2 on HCC cell lines or TIGIT blockade on immune cells increased immune cell-mediated lysis of tumour cell. This enhanced immune response is paralleled by the increased secretion of Granzyme B by immune cells.DiscussionCollectively, our study revealed the functional state, clinical significance, and intercellular communication of immunosuppressive cells in HCC at single-cell resolution. Moreover, PVR/PVRL2, interact with TIGIT act as prominent coinhibitory signals and might represent a promising, efficacious immunotherapy strategy in HCC.

From 17 to 22 July 2021, the “21·7” extreme rainfall event (“21·7” ERE) hit Henan Province, breaking the record for mainland China with a maximum hourly rainfall of 201.9 mm at the Zhengzhou station. The long-lived (20 h) mesoscale Huang-Huai vortex (HHV) was an important system that directly affected the major rainfall stage, including the extreme hourly rainfall. This study investigates the formation and development mechanism of the HHV, as well as its association with the simulation of extreme hourly rainfall through numerical simulations. The simulated rainfall and radar composite reflectivity were in good agreement with the observations, thus effectively reproducing the generation and developmental process of the HHV. The analysis results showed that the HHV initially formed at 850 hPa on 19 July at 1800 UTC and eventually developed to 550 hPa. The positive feedback formed by the horizontal convergence and vertical vorticity transport was the main mechanism leading to the generation and deepening of the HHV. The stretching effect (STR) term played an absolutely dominant role in the increase in the vorticity tendency, and it primarily originated from the coupling effect of boundary layer jets (BLJs) and synoptic-weather-system-related low-level jets (SLLJs). The accurate simulation of the HHV allowed the early rainfall to reasonably reproduce the surface cold pool near the Zhengzhou station, and then the cooperation of the SLLJs, the BLJs, and the cold pool made the simulated extreme hourly rainfall exactly close to the Zhengzhou station, but with a weaker intensity, due to the fact that the HHV moved northeastward after its formation, resulting in a narrow range of southerly flow in southern Henan, which is not conducive to convective triggering in the southerly flow.

Abstract Background Nucleolar and spindle-associated protein 1 (NUSAP1) was shown to be involved in cell cycle regulation in cancer. However, its prognostic value and underlying mechanism in ovarian cancer remain unclear. Methods Oncomine, TCGA, CCLE, and UALCAN databases were used to analyze the expression level of NUSAP1 in ovarian cancer. The Kaplan–Meier plotter database was used to evaluate its prognostic value. The results from these analyses were further validated using immunohistochemical assay. The potential molecular mechanism of NUSAP1 in ovarian cancer was assessed with respect to homologous recombination repair, mismatch repair, and immunology using different databases. Results Database analyses and experimental results demonstrated that NUSAP1 was highly expressed in ovarian cancer, its levels being correlated with the FIGO stage. High NUSAP1 expression was an independent risk factor affecting the prognosis of patients with epithelial ovarian cancer. Moreover, NUSAP1 was associated with cell cycle, DNA replication, homologous recombination, and p53 signaling pathway. A positive correlation was identified between the expression of NUSAP1 and BRCA1/2 in ovarian cancer. In addition, NUSAP1 was associated with the expression of DNA mismatch repair genes and immune cell infiltration. Conclusions NUSAP1 may be a valuable prognostic marker, as well as a novel biomarker for evaluating the response to immunotherapy of patients with ovarian cancer.

Abstract Background Compared to normal cells, cancer cells exhibit a higher level of oxidative stress, which primes key cellular and metabolic pathways and thereby increases their resilience under oxidative stress. This higher level of oxidative stress also can be exploited to kill tumor cells while leaving normal cells intact. In this study we have found that isovalerylspiramycin I (ISP I), a novel macrolide antibiotic, suppresses cancer cell growth and tumor metastases by targeting the nucleolar protein selenoprotein H (SELH), which plays critical roles in keeping redox homeostasis and genome stability in cancer cells. Methods We developed ISP I through genetic recombination and tested the antitumor effects using primary and metastatic cancer models. The drug target was identified using the drug affinity responsive target stability (DARTS) and mass spectrum assays. The effects of ISP I were assessed for reactive oxygen species (ROS) generation, DNA damage, R-loop formation and its impact on the JNK2/TIF-IA/RNA polymerase I (POLI) transcription pathway. Results ISP I suppresses cancer cell growth and tumor metastases by targeting SELH. Suppression of SELH induces accumulation of ROS and cancer cell-specific genomic instability. The accumulation of ROS in the nucleolus triggers nucleolar stress and blocks ribosomal RNA transcription via the JNK2/TIF-IA/POLI pathway, causing cell cycle arrest and apoptosis in cancer cells. Conclusions We demonstrated that ISP I links cancer cell vulnerability to oxidative stress and RNA biogenesis by targeting SELH. This suggests a potential new cancer treatment paradigm, in which the primary therapeutic agent has minimal side-effects and hence may be useful for long-term cancer chemoprevention.

To obtain a safe and efficient β-glucosidase for preparing icariside II from icariin by biocatalytic hydrolysis, a GRAS (generally recognized as safe) strain Bacillus subtilis WB600 was used as the host to produce a thermophilic β-glucosidase from Thermotoga petrophila, by construction of a Escherichia coli-Bacillus subtilis shuttle vector pMA5. Enzymatic properties of the recombinant enzyme and its process conditions of hydrolyzing icariin to prepare icariside II were studied. The result showed that after cultivated in SR culture for 48 h at 30 ℃, the activity of β-glucosidase in the fermented broth reached to 69.68 U/mL. TpBgl3 exhibited the maximal activity at 85 °C and pH4.0. More than 85% of the maximum activity was retained after incubation at 65 °C and pH4.0 for 3 h. Under optimized conditions of 65 °C, pH4.0, and 0.16 U/mg enzyme dosage, the recombinant enzyme could transform 10 g/L icariin into 7.50 g/L icariside II in 20 min with a molar conversion of 98.67%. The successful secretory expression of β-glucosidase in Bacillus subtilis could provide new ways to the industrial safe and efficient biopreparation of icariside II and other high-value-added aglycon compounds.

Fabricating heterostructures with abundant interfaces and delicate nanoarchitectures is an attractive approach for optimizing photocatalysts. Herein, we report the facile synthesis of BiOCl nanoflake/FeOCl nanospindle heterostructures through a solution chemistry method at room temperature. Characterizations, including XRD, SEM, TEM, EDS, and XPS, were employed to investigate the synthesized materials. The results demonstrate that the in situ reaction between the Bi precursors and the surface Cl− of FeOCl enabled the bounded nucleation and growth of BiOCl on the surface of FeOCl nanospindles. Stable interfacial structures were established between BiOCl nanoflakes and FeOCl nanospindles using Cl− as the bridge. Regulating the Bi-to-Fe ratios allowed for the optimization of the BiOCl/FeOCl interface, thereby facilitating the separation of photogenerated carriers and accelerating the photocatalytic degradation of RhB. The BiOCl/FeOCl heterostructures with an optimal composition of 15% BiOCl exhibited ~90 times higher visible-light photocatalytic activity than FeOCl. Based on an analysis of the band structures and reactive oxygen species, we propose an S-scheme mechanism to elucidate the significantly enhanced photocatalytic performance observed in the BiOCl/FeOCl heterostructures.

In the original publication [...]

Membrane transporters encoded by NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER (NPF) genes, which play crucial roles in plant growth, development and resistance to various stresses, are involved in the transport of nitrate (NO3-) and peptides. In several plant species, NPF genes are involved in the resistance to abiotic stresses; however, whether the whole NPF gene family in cotton contributes to this resistance has not been systematically investigated. Here, 201 genes encoding NPF proteins with a peptide transporter (PTR) domain were confirmed in three different Gossypium species, namely, Gossypium hirsutum, Gossypium arboreum and Gossypium raimondii. The NPF proteins in these three Gossypium species and Arabidopsis thaliana were classified into three different subfamilies via phylogenetic analysis. Among the genes that encode these proteins, most GhNPF genes in the same subfamily contained similar gene structures and conserved domains. Predictions of the promoters of these genes revealed that the cis-acting elements included phytohormone- and light-responsive elements, indicating that some of these genes might be expressed in response to abiotic stress. Furthermore, 52 common potential candidate genes in 98 GhNPFs were predicted to exhibit specific spatiotemporal expression patterns in different tissues based on two RNA sequencing (RNA-seq) datasets. Finally, the gene expression profiles of abiotic stress indicated that 31 GhNPF genes were upregulated in at least one treatment period. Under abiotic stress for 12 and 24 h, the expression of GhNPF8 was upregulated upon cold treatment but downregulated with heat treatment, salt treatment and drought treatment. Furthermore, the expression of genes GhNPF8, GhNPF54 and GhNPF43 peaked at 6 h after heat and salt treatment. These results indicated that these genes exhibit underlying characteristics related to responses to abiotic stress. The verification of NPFs and analysis of their expression profiles in different tissues and in response to different abiotic stresses of cotton provide a basis for further studying the relationship between abiotic stress resistance and nitrogen (N) transport in cotton, as well as identifying candidate genes to facilitate their functional identification.

Summary: Influenza A virus poses a constant challenge to human health. The highly conserved influenza matrix-2 (M2) protein is an attractive target for the development of a universal antibody-based drug. However, screening using antigens with subphysiological conformation in a nonmembrane environment significantly reduces the generation of efficient antibodies. Here, M2(1-46) was incorporated into nanodiscs (M2-nanodiscs) with M2 in a membrane-embedded tetrameric conformation, closely resembling its natural physiological state in the influenza viral envelope. M2-nanodisc generation, an antigen, was followed by Chiloscyllium plagiosum immunization. The functional vNARs were selected by phage display panning strategy from the shark immune library. One of the isolated vNARs, AM2H10, could specifically bind to tetrameric M2 instead of monomeric M2e (the ectodomain of M2 protein). Furthermore, AM2H10 blocked ion influx through amantadine-sensitive and resistant M2 channels. Our findings indicated the possibility of developing functional shark nanobodies against various influenza viruses by targeting the M2 protein.

Abstract Background Pleurotus ostreatus is an edible mushroom popularly cultivated worldwide. Distilled grain waste (DGW) is a potential substrate for P. ostreatus cultivation. However, components in DGW restrict P. ostreatus mycelial growth. Therefore, a cost-effective approach to facilitate rapid P. ostreatus colonization on DGW substrate will benefit P. ostreatus cultivation and DGW recycling. Results Five dominant indigenous bacteria, Sphingobacterium sp. X1, Ureibacillus sp. X2, Pseudoxanthomonas sp. X3, Geobacillus sp. X4, and Aeribacillus sp. X5, were isolated from DGW and selected to develop a consortium-based microbial agent to compost DGW for P. ostreatus cultivation. Microbial agent inoculation led to faster carbohydrate metabolism, a higher temperature (73.2 vs. 71.2 °C), a longer thermophilic phase (5 vs. 3 days), and significant dynamic changes in microbial community composition and diversity in composts than those of the controls. Metagenomic analysis showed the enhanced microbial metabolisms, such as xenobiotic biodegradation and metabolism and terpenoid and polyketide metabolism, during the mesophilic phase after microbial agent inoculation, which may facilitate the fungal colonization on the substrate. In accordance with the bioinformatic analysis, a faster colonization of P. ostreatus was observed in the composts with microbial inoculation than in control after composting for 48 h, as indicated from substantially higher fungal ergosterol content, faster lignocellulose degradation, and higher lignocellulase activities in the former than in the latter. The final mushroom yield shared no significant difference between composts with microbial inoculation and control, with 0.67 ± 0.05 and 0.60 ± 0.04 kg fresh mushroom/kg DGW, respectively (p > 0.05). Conclusion The consortium-based microbial agent comprised indigenous microorganisms showing application potential in composting DGW for providing substrate for P. ostreatus cultivation and will provide an alternative to facilitate DGW recycling.

Abstract Background HAdV is one of the common pathogens in hospitalized children with acute respiratory infections (ARIs). We aim to describe the clinical and laboratory features, epidemiological characteristics, and HAdV species and/or types of inpatients with HAdV respiratory infections. Methods Respiratory samples were gathered from inpatients diagnosed ARIs in Children’s Hospital, Zhejiang University School of Medicine, and were detected by using Direct Immunofluorescence Assay from 2018 to 2019. PCR amplification and sequencing of the hypervariable zone of hexon gene were used for genotyping. The clinical and laboratory features, and HAdV genotyping, and epidemiological characteristic analysis were retrospectively performed. Results Of 7072 samples collected, 488 were identified as HAdV-positive. The overall detection rate was 6.9%. The peaked detection rate was 14.1% in January 2019. HAdV-positive cases with ARIs mainly appeared in winter. The detection rate was highest among children between 6 months and 2 years (8.7%, 123/1408). Clinical diagnosis included pneumonia (70.3%, 343/488), bronchitis (7.0%, 34/488) and acute upper respiratory tract infection (22.7%, 111/488). The common clinical manifestations were fever (93.4%, 456/488), cough (94.7%, 462/488), wheezing (26.2%, 128/488), and shortness of breath (14.8%, 72/488). 213 (43.6%) cases had co-infection and 138 (28.3%) cases had extrapulmonary symptoms. 96(19.7%) cases had intrapulmonary and intrathoracic complications.78 (16.0%) had an underlying condition, most of which were congenital heart diseases (20.5%, 16/78). The proportions of hyperpyrexia, duration of fever > 10 days, severe pneumonia, and wheezing in the co-infection group were remarkably higher than those in HAdV single-infection group (all p 10 days, wheezing, shortness of breath, change in level of consciousness, serosal fluids, extrapulmonary symptoms, co-infections and underlying diseases were significantly higher in severe pneumonia group than those in the mild pneumonia group (all p

Metal/oxide interface is of fundamental significance to heterogeneous catalysis. Here, the authors construct a nanometer Pd/Bi2O3 interface by grafting Pd clusters onto Bi2O3 clusters and demonstrate its essential roles in the low-temperature semi-hydrogenation of acetylene.

There will be great damage in the process of harvesting, transporting, and storing after grain matures. The injury rate is as high as 8% to 12%. After damage, the germination rate of the grain becomes lower, the quality decreases, and it is easily infected with pests and molds. This study of the grain-crushing characteristics is of great significance to ensure grain quality, and an accurate crushing model is a prerequisite for effectively simulating crushing characteristics. This paper studies the shattering characteristics of wheat grains. Two-dimensional slices of wheat grain were obtained using X-ray tomography technology. Then, an accurate three-dimensional outer contour model of the wheat particle was constructed using image filtering and segmentation algorithms. The particle filling process was conducted using EDEM 2018 software to establish a wheat particle simulation model based on the Hertz–Mindlin with a Bonding contact model. Using the DOE experimental design method, single-factor experiments, Plackett–Burman experiments, steepest-climb experiments, and Box–Behnken were designed to study the fragmentation characteristics of wheat particles combined with parameter calibration and physical experiments. The test results show that the normal stiffness per unit area is 7.392 × 1010 N/m3, critical normal stress is 5.293 × 106 Pa, critical tangential stress is 5.001 × 106 Pa, and the relative error about 3%, which verifies the reliability of the simulation parameters in the discrete-element crushing model of wheat grain. This study focuses on two essential aspects: 1. establishing an accurate wheat-grain contour model; and 2. calibrating the bonding parameters of the discrete-element simulation model of wheat grain. The wheat grain discrete-element crushing model and the calibration of its bonding parameters are constructed to provide a foundation for the study of wheat-grain crushing characteristics. It is of great significance to study the situation of wheat grains and where cracks are produced. In this paper, an accurate model of the wheat-grain contour is established, and the bonding parameters of the discrete-element simulation model of the wheat grain are calibrated. The calibration of the model of the discrete elements of wheat-grain fragmentation and its bonding parameters will provide a basis for studying the crushing characteristics of wheat grain. Understanding the condition of wheat grains and the causes of cracks carries significant academic significance.

Many ensemble-based data assimilation (DA) methods use observation space localization to mitigate the sampling errors due to the insufficient ensemble members. Observation space localization is simpler and more timesaving than model space localization in implementation, but more difficult to directly assimilate satellite radiance observations, a kind of non-local observations. The vertical locations of radiance observations are undetermined and the transmission of observational information is thereby obstructed. To determine the vertical coordinates of radiance observations, a weighted average hypsometry is proposed. Using this hypsometry, AMSU-A radiance observations are directly assimilated with an ensemble four-dimensional variational (En4DVar) DA system. It consists of a four-dimensional ensemble-variational (4DEnVar) system providing ensemble covariance and a 4DVar system. Observing system simulation experiments show that the hypsometry alleviates the degradations in the late period of medium-range forecast in the Northern Extratropics that occur in the traditional peak-based hypsometry. It obviously improves the analysis qualities and forecast skills of the En4DVar system and its two components, especially in the Southern Extratropics, when incorporating AMSU-A radiance observations. The improvement in the En4DVar-initialized forecast is comparable to that in the 4DVar-initialized forecast in the Southern Extratropics and Tropics. It indicates that a proper hypsometry enables efficient extraction of useful information from AMSU-A radiance observations by 4DEnVar with observation space localization. Therefore, the 4DEnVar provides high-quality ensemble covariances for En4DVar.

The atmospheric temperature profiles (ATPs) retrieved through the geostationary Interferometric Infrared Sounder (GIIRS) onboard the FY-4A satellite (GIIRS/FY-4A) can effectively fill the gap of the scarce conventional sounding data in the Taklimakan Desert (TD), the second largest desert in the world, with an area of 330,000 square kilometers. In this study, we take the experimental radiosonde observations (RAOB) from one RAOB station in the hinterland of TD and seven conventional radiosondes in the oasis region around the desert as the true values and analyze the bias distribution characteristics of GIIRS/FY-4A ATPs with quality control (QC) flags 0 or 1 for this region. In addition, a bias comparison is made with GIIRS/FY-4A ATPs, and the fifth generation ECMWF atmospheric reanalysis of the global climate (ERA5) ATPs. The results show that (1) Missing measurements in GIIRS/FY-4A ATPs are the most frequent in the near-surface layer, accounting for more than 80% of all the retrieved grid points. The averaged total proportion of GIIRS/FY-4A ATPs with QC marks 0 or 1 is about 33.06%. (2) The root mean square error (RMSE) of GIIRS/FY-4A ATPs is less than 3 K, smaller than that of ERA5 ATPs. The RMSE of ERA5 ATPs can exceed 10 K in the desert hinterland. The absolute mean biases of GIIRS/FY-4A ATPs and ERA5 ATPs are, respectively, smaller than 3 K and 2 K, the former being slightly larger. The correlation coefficients of GIIRS/FY-4A ATPs with ERA5 ATPs and RAOB ATPs are higher than 0.98 and 0.99, respectively, and the correlation between GIIRS/FY-4A ATPs and RAOB ATPs is inferior to the latter. (3) The overall atmospheric temperature retrieved by GIIRS/FY-4A is 0.08 K higher than the temperature of RAOB, on average, while the overall temperature from ERA5 is 0.13 K lower than that of RAOB, indicating that the temperature profile obtained by integrating GIIRS/FY-4A ATPs and ERA5 ATPs may be much closer to RAOB ATPs. (4) The probability density of the GIIRS/FY-4A ATP biases in the TD region generally follows the Gaussian distribution so that it can be effectively assimilated in the 3-D variational assimilation modules. The probability density distribution characteristics of the GIIRS/FY-4A ATP biases in the desert hinterland and oasis are not much different. However, due to the fusion analysis of the relatively rich multi-source conventional observation data from the oasis stations, the probability density of ERA5 ATPs biases at the oasis stations is nearer to Gaussian distribution than that of the GIIRS/FY-4A ATPs. In the desert hinterland, where conventional observation is not enough, the probability density distributions of the ATPs biases from ERA5 and GIIRS/FY-4A are alike. Therefore, the GIIRS FY4A can contribute to a more accurate estimation of ERA5 ATPs in the TD region.

Abstract Background Malignant tumours of the female reproductive system threaten the lives and health of women worldwide, with ovarian cancer having the highest mortality rate. Based on previous work, this study analysed the expression and role of YWHAE in ovarian epithelial tumours. Methods The interaction between YWHAE and HE4 was evaluated via immunoprecipitation, western blot analysis, and cellular immunofluorescence. Immunohistochemistry was used to address the relationship between YWHAE expression, clinicopathological parameters, and patient prognosis. Changes in cell invasion, epithelial–mesenchymal transition, migration, proliferation, apoptosis, and cell cycle before and after differential expression of YWHAE were also explored in ovarian cancer cell lines and via in vivo experiments. Results YWHAE was found to interact with HE4, and its expression was positively correlated with HE4 expression. Moreover, YWHAE upregulation was associated with advanced stages of ovarian cancer and poor patient prognosis. In addition, YWHAE enhanced invasion, migration, and proliferation, but inhibited the apoptosis of ovarian cancer cells. These biological effects were found to be mediated by the AKT and MAPK signalling pathways. Conclusions Altogether, this study demonstrates that YWHAE is substantially upregulated in ovarian cancer tissues, representing a risk factor for the prognosis of ovarian cancer that is positively correlated with HE4 expression. Furthermore, YWHAE and its downstream pathways may represent new therapeutic targets for ovarian cancer.

BackgroundThis study aimed to investigate the serial changes in left ventricular (LV) myocardial deformation in patients with sepsis using three-dimensional (3D) and two-dimensional (2D) speckle tracking echocardiography (STE).MethodsIn this single-center, prospective, and observational study, we included 59 patients diagnosed with sepsis or septic shock in the intensive care unit and 40 healthy controls. Left ventricular ejection fraction (LVEF), left ventricular global longitudinal strain (GLS), and global circumferential strain (GCS) assessed by 3D STE and 2D STE were obtained on the first, third, fifth, seventh to the tenth day after sepsis or septic shock.ResultsIn patients with sepsis or septic shock, 3D and 2D LVEF were not different at each time point. GLS and GCS obtained by 3D STE and 2D STE decreased on the first day compared with the healthy group (all P < 0.01). Compared with the values on the first day, GLS and GCS further decreased on the third day, while 3D and 2D LVEF did not differ. 3D and 2D STE strains were lowest on the third day and gradually improved on the seventh to the tenth day compared with values on the third day. When compared with values on the first day, 3D and 2D GLS gradually improved on the seventh to the tenth day, whereas 3D and 2D GCS on the seventh to the tenth day was not different. Although 3D and 2D STE strains were significantly increased on the seventh to the tenth day, they were not fully recovered to normality.ConclusionAlthough patients with sepsis or septic shock demonstrated gradual improvements in 3D and 2D STE parameters during the ten-day period, LV myocardial strain was not fully recovered to normality by the seventh to the tenth days. 3D and 2D strain imaging, used as a helpful tool for monitoring the evolution of myocardial deformation, can provide clinicians with a useful additional imaging parameter.

ObjectiveTo search for the immunological risk factors of Psoriatic arthritis (PsA) combined with nonalcoholic fatty liver disease (NAFLD), development and assessment of predictive nomograms for NAFLD risk in patients with PsA, and to further explore the correlation between risk factors and dyslipidemia.MethdsA total of 127 patients with PsA (46 with NAFLD and 81 without NAFLD) were included in this retrospective study. The clinical and serological parameters of the patients were collected. The percentage and the absolute number of lymphocytes and CD4+T cells were determined by Flow cytometry. Univariate and multivariate binary logistic regression analysis was used to screen independent risk factors of PsA complicated with NAFLD in the model population, and a nomogram prediction model was developed and assessed.Results(1) Univariate and multivariate logistic regression analysis of the modeling population showed that the percentage of peripheral blood T helper 1 cells (Th1%) (OR=1.12, P=0.001), body mass index (BMI) (OR=1.22, P=0.005) and triglycerides (TG) (OR=4.78, P=0.003) were independent risk factors for NAFLD in patients with PsA, which were incorporated and established a nomogram prediction model. The model has good discrimination and calibration, and also has certain clinical application value. (2) The number of peripheral blood NK cells in PsA patients was significantly positively correlated with serum triglyceride (TG) (r=0.489, P

BackgroundPoly(ADP-ribose)polymerase (PARP) inhibitors are a class of molecular-targeted cancer drugs. Synthetic lethality is a phenomenon that renders homologous recombination repair defective cells more sensitive to PARP inhibitors. As a component of the cohesin complex, RAD21 regulates DNA damage repair. However, the biological roles of RAD21 in ovarian cancer and their underlying mechanisms remain unclear.MethodsAn immunohistochemical assay was used to validate the expression of RAD21 in ovarian cancer and its correlation with prognosis. The effects of RAD21 were evaluated through Cell Counting Kit-8 (CCK8), wound-healing, and invasion assays in vitro and the tumor growth in vivo. Furthermore, CCK8 assay and immunofluorescence assay were used to detect the effect of RAD21 on cell sensitivity to PARP inhibitors and their mechanism. The pathway changes were detected by Western blotting.ResultsRAD21 was markedly upregulated in ovarian cancer samples. High RAD21 expression was correlated with poor differentiation and poor prognosis in patients with ovarian cancer. Functionally, RAD21 overexpression promoted cancer cell proliferation, migration, and invasion. Moreover, RAD21 knockdown increased the sensitivity of ovarian cancer cells to three kinds of PARP inhibitors by affecting DNA damage repair. In vivo experiments indicated that RAD21 promoted tumor growth. Mechanistically, the overexpression of RAD21 led to increased phosphorylation levels of Akt and mTOR. Blocking the Akt/mTOR signaling pathway reversed RAD21 overexpression-induced cancer progression and drug resistance.ConclusionsRAD21 can serve as a valuable prognostic marker for ovarian cancer and has the potential as a therapeutic target that can expand the utility of PARP inhibitors.

BackgroundFetal ductal constriction (DC) is associated with excessive polyphenol-rich food (PRF) consumption during pregnancy. However, the effect of this hemodynamic change on fetal cardiac function still needs to be elucidated. Therefore, this study aimed to evaluate the cardiac function of fetuses with PRF-related DC and to describe serial observations of cardiac function changes.MethodsWe compared the traditional echocardiographic indices, including morphological, hemodynamic, and functional parameters, between study fetuses and controls. For global and segmental deformation analysis of the left and right ventricles, fetalHQ with the speckle-tracking technique was used to calculate sphericity index (SI), global longitudinal strain (GLS), fractional shortening (FS), fractional area change (FAC), etc. In addition, follow-up data were compared with the generalized linear model.ResultsA total of 60 DC fetuses and 60 gestational-matched controls were enrolled in our study, with 20 DC fetuses undertaking a follow-up echocardiogram after 2–3 weeks. Compared with controls, there was a distinct decrease in right ventricular GLS (RVGLS) (−13.39 ± 3.77 vs. −21.59 ± 2.51, p < 0.001), RVFAC (22.20 ± 9.56 vs. 36.01 ± 4.84, p < 0.001), left ventricular GLS (LVGLS) (−19.52 ± 3.24 vs. −23.81 ± 2.01 p < 0.001), and LVFAC (39.64 ± 7.32 vs. 44.89 ± 4.91, p = 0.004). For 24-segment FS analysis, DC fetuses showed lower FS in left ventricular (LV) segments 18–24, with no difference in LV segments 1–17. Right ventricular (RV) FS in segments 4–23 was also reduced in the DC group. The 24-segment SI analysis indicated significantly lower SI in DC than those in controls for LV segments 1–14 and RV segments 19–24. We found that the pulsatility index (PI) of ductus arteriosus (DA) was an independent variable for RVGLS (β = −0.29, p = 0.04). In 20 DC fetuses with follow-up echocardiograms, no obvious difference in myocardial deformation was found between the initial examination and follow-up data.ConclusionLeft and right ventricular performances were both impaired in DC fetuses, along with a series of morphological and hemodynamic changes. Although the state of DA constriction improved on second examinations, cardiac function was not completely restored.

Abstract A four‐dimensional ensemble‐variational (4DEnVar) data assimilation (DA) system was developed based on the global forecast system of the Global/Regional Assimilation and Prediction System (GRAPES‐GFS). Instead of using the adjoint technique, this system utilizes a dimension‐reduced projection (DRP) technique to minimize the cost function of the standard four‐dimensional variational (4DVar) DA. It dynamically predicts ensemble background error covariance (BEC) and realizes the explicit flow‐dependence of BEC in the variational configuration. An inflation technique based on a linear combination of analysis increments and balanced random perturbations, is utilized to overcome the problem of underestimation of BEC matrix (B‐matrix) during the assimilation cycle. To mitigate the spurious correlations in the ensemble B‐matrix caused by the insufficient ensemble members, an ensemble‐sample‐based subspace localization method is utilized. In order to evaluate the new system, single‐point observation experiments (SOEs) and observing system simulation experiments (OSSEs) were conducted with sounding and cloud‐derived wind data based on GRAPES‐GFS. The explicit flow‐dependent characteristic of the 4DEnVar system using a localized ensemble covariance was verified in the SOEs. In the OSSEs, the ensemble mean analysis of 4DEnVar outperforms the analysis of 4DVar. The deterministic forecast initialized from the 4DEnVar ensemble mean analysis has better performance in the short‐range forecasts, better (worse) performance in the early (late) period of the medium‐range forecasts in the Northern Extratropics, and opposite performance in the Southern Extratropics, and exhibits slightly worse effects in the Tropics. Moreover, the ensemble mean forecast initialized by the 4DEnVar system has higher forecast skills.

The rational regulation of catalyst active sites at atomic scale is a key approach to unveil the relationship between structure and catalytic performance. Herein, we reported a strategy for the controllable deposition of Bi on Pd nanocubes (Pd NCs) in the priority order from corners to edges and then to facets (Pd NCs@Bi). The spherical aberration-corrected scanning transmission electron microscopy (ac-STEM) results indicated that Bi2O3 with an amorphous structure covers the specific sites of Pd NCs. When only the corners and edges of the Pd NCs were covered, the supported Pd NCs@Bi catalyst exhibited an optimal trade-off between high conversion and selectivity in the hydrogenation of acetylene to ethylene under ethylene-rich conditions (99.7% C2H2 conversion and 94.3% C2H4 selectivity at 170 °C) with remarkable long-term stability. According to the H2-TPR and C2H4-TPD measurements, the moderate hydrogen dissociation and the weak ethylene adsorption are responsible for this excellent catalytic performance. Following these results, the selectively Bi-deposited Pd nanoparticle catalysts showed incredible acetylene hydrogenation performance, which provides a feasible perspective to design and develop highly selective hydrogenation catalysts for industrial applications.

T follicular helper (TFH) cells are specialized effector CD4+ T cells that are critical in humoral immunity, but the function of post-transcriptional regulation is not clearly defined. Here, the authors demonstrate that RNA methylation is important for TFH effector differentiation and subsequent antibody formation through stabilization of Tcf7 transcripts.

Smoothened (SMO) protein is a member of the G protein-coupled receptor (GPCR) family that is involved in the Hedgehog (Hh) signaling pathway. It is a putative target for treating various cancers, including medulloblastoma and basal cell carcinoma (BCC). Characterizing membrane proteins such as SMO in their native state is highly beneficial for the development of effective pharmaceutical drugs, as their structures and functions are retained to the highest extent in this state. Therefore, although SMO protein is conventionally solubilized in detergent micelles, incorporating the protein in a lipid-based membrane mimic is still required. In this study, we used styrene maleic acid (SMA) copolymer that directly extracted membrane protein and surrounding lipids as well as formed the so-called polymer nanodiscs, to solubilize and purify the SMO transmembrane domain encapsulated by SMA-nanodiscs. The obtained SMA-nanodiscs showed high homogeneity and maintained the physiological activity of SMO protein, thereby enabling the measurement of the dissociation constant (Kd) for SMO ligands SMO-ligands Shh Signaling Antagonist V (SANT-1) and Smoothened Agonist (SAG) using ligand-based solution nuclear magnetic resonance spectroscopy. This work paves the way for investigating the structure, function, and drug development of SMO proteins in a native-like lipid environment.

Short-chain fatty acids (SCFA) are principal nutrient substrates of intestinal epithelial cells that regulate the epithelial barrier in yaks. Until now, metagenomics sequencing has not been reported in diarrheal yaks. Scarce information is available regarding the levels of fecal SCFA and diarrhea in yaks. So, our study aims to identify the potential pathogens that cause the emerging diarrhea and explore the potential relationship of short-chain fatty acids in this issue. We estimated diarrhea rate in yaks after collecting an equal number of fecal samples from affected animals. Metagenomics sequencing and quantitative analysis of SCFA were performed, which revealed 15%–25% and 5%–10% prevalence of diarrhea in yak’s calves and adults, respectively. Violin box plot also showed a higher degree of dispersion in gene abundance distribution of diarrheal yaks, as compared to normal yaks. We found 366,163 significant differential abundance genes in diarrheal yaks, with 141,305 upregulated and 224,858 downregulated genes compared with normal yaks via DESeq analysis. Metagenomics binning analysis indicated the higher significance of bin 33 (Bacteroidales) (p

Abstract Background It is known that the transcription factor zinc finger protein 703 (ZNF703) plays an important role in physiological functions and the occurrence and development of various tumors. However, the role and mechanism of ZNF703 in ovarian cancer are unclear. Materials and methods Immunohistochemistry was used to analyze the expression of ZNF703 in ovarian cancer patients and to assess the effect of ZNF703 expression on the survival and prognosis of ovarian cancer patients. ZNF703 overexpression and suppression expression experiments were used to evaluate the effect of ZNF703 on malignant biological behavior of ovarian cancer cells in vitro. Detecting the interaction between HE4 and ZNF703 by immunofluorescence colocalization and coprecipitation, and nuclear translocation. Chromatin immunoprecipitation-sequencing (ChIP-Seq), dual luciferase reporter assay, ChIP-PCR, in vivo model were applied to study the molecular mechanism of ZNF703 affecting the development of ovarian cancer. Results ZNF703 was highly expressed in ovarian cancer tissues, and its expression level is related to the prognosis of ovarian cancer patients. In vivo and in vitro experiments confirmed that ZNF703 overexpression/inhibition expression will promoted/inhibited the malignant biological behavior of ovarian cancer. Mechanically, ZNF703 interacted with HE4, and HE4 promoted nuclear translocation of ZNF703. ChIP-Seq identified multiple regulatory targets of ZNF703, of which ZNF703 directly binds to the enhancer region of PEA15 to promote the transcription of PEA15 and thereby promoted the proliferation of cancer cells. Conclusion The results showed that ZNF703 as an oncogene played an important role in the epigenetic modification of ovarian cancer proliferation, and suggested that ZNF703 as a transcription factor may become a prognostic factor and a potential therapeutic target for ovarian cancer.

Abstract Background Plakophilins (PKPs) are widely involved in gene transcription, translation, and signal transduction, playing a crucial role in tumorigenesis and progression. However, the function and potential mechanism of PKP1/2/3 in ovarian cancer (OC) remains unclear. It’s of great value to explore the expression and prognostic values of PKP1/2/3 and their potential mechanisms, immune infiltration in OC. Methods The expression levels, prognostic values and genetic variations of PKP1/2/3 in OC were explored by various bioinformatics tools and databases, and PKP2/3 were selected for further analyzing their regulation network and immune infiltration. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathways (KEGG) enrichment were also conducted. Finally, the expression and prognosis of PKP2 were validated by immunohistochemistry. Results The expression level and prognosis of PKP1 showed little significance in ovarian cancer, and the expression of PKP2/3 mRNA and protein were upregulated in OC, showing significant correlations with poor prognosis of OC. Functional enrichment analysis showed that PKP2/3 and their correlated genes were significantly enriched in adaptive immune response, cytokine receptor activity, organization of cell–cell junction and extracellular matrix; KEGG analysis showed that PKP2/3 and their significantly correlated genes were involved in signaling pathways including cytokine-mediated signaling pathway, receptor signaling pathway and pathways in cancer. Moreover, PKP2/3 were correlated with lymphocytes and immunomodulators. We confirmed that high expression of PKP2 was significantly associated with advanced stage, poor differentiation and poor prognosis of OC patients. Conclusion Members of plakophilins family showed various degrees of abnormal expressions and prognostic values in ovarian cancer. PKP2/3 played crucial roles in tumorigenesis, aggressiveness, malignant biological behavior and immune infiltration of OC, and can be regarded as potential biomarker for early diagnosis and prognosis evaluation in OC.

Abstract Background Cotton (Gossypium spp.) fiber yield is one of the key target traits, and improved fiber yield has always been thought of as an important objective in the breeding programs and production. Although some studies had been reported for the understanding of genetic bases for cotton yield-related traits, the detected quantitative trait loci (QTL) for the traits is still very limited. To uncover the whole-genome QTL controlling three yield-related traits in upland cotton (Gossypium hirsutum L.), phenotypic traits were investigated under four planting environments and 9244 single-nucleotide polymorphism linkage disequilibrium block (SNPLDB) markers were developed in an association panel consisting of 315 accessions. Results A total of 53, 70 and 68 significant SNPLDB loci associated with boll number (BN), boll weight (BW) and lint percentage (LP), were respectively detected through a restricted two-stage multi-locus multi-allele genome-wide association study (RTM-GWAS) procedure in multiple environments. The haplotype/allele effects of the significant SNPLDB loci were estimated and the QTL-allele matrices were organized for offering the abbreviated genetic composition of the population. Among the significant SNPLDB loci, six of them were simultaneously identified in two or more single planting environments and were thought of as the stable SNPLDB loci. Additionally, a total of 115 genes were annotated in the nearby regions of the six stable SNPLDB loci, and 16 common potential candidate genes controlling target traits of them were predicted by two RNA-seq data. One of 16 genes (GH_D06G2161) was mainly expressed in the early ovule-development stages, and the stable SNPLDB locus (LDB_19_62926589) was mapped in its promoter region. Conclusion This study identified the QTL alleles and candidate genes that could provide important insights into the genetic basis of yield-related traits in upland cotton and might facilitate breeding cotton varieties with high yield.

Abstract Background Tribbles pseudokinase 3 (TRIB3) protein is a pseudokinase which plays an important role in cellular stress, metabolism, and tumor progression. However, the expression and function of TRIB3 in ovarian cancer is unknown. Methods TRIB3 expression was detected by immunohistochemistry in the ovarian tissue samples. Following down-regulation of TRIB3 by siRNA, multiple aspects of ovarian cancer cells were detected by the MTT assay, flow cytometry, scratch test and Transwell. Additionally, changes in related molecules and the MEK/ERK pathway were detected by western blotting. Finally, many bioinformatic methods, websites and databases, such as gene set enrichment analysis (GSEA), DVAID, Genemania, TISIDB and cBioPortal were used to study the TRIB3. Results The expression level of TRIB3 was higher in ovarian epithelial malignant tumors as compared to other groups. Patients with a high expression level of TRIB3 had significantly shorter survival times,which was consistent with the results of analysis of the KM-plot database. Down-regulation of TRIB3 expression significantly inhibited the proliferation, invasion, and migration capabilities of ovarian cancer cells, and induced apoptosis and cell cycle arrest. Following TRIB3 siRNA transfection, expression levels of relative proteins were found to be decreased. Additionally, analysis in DAVID website and GSEA revealed that TRIB3 expression was associated with multiple biological processes. Protein phosphorylation levels of MEK and ERK also decreased following TRIB3-siRNA transfection. The Genemania website was used to analyze the proteins that interact with TRIB3. Analysis of TRIB3 in the TISIDB database and cBioPortal website showed that ovarian cancer patients with high levels of mutation in TRIB3 had poor prognosis, and that the expression of TRIB3 was related to immunomodulation. Conclusions The TRIB3 was highly expressed and promoting the malignant behavior of ovarian cancer cells by activating the MEK-ERK signaling pathway. It was also found to be associated with genetic variations and immune modulators.