Search

Seed dormancy is an adaptive strategy for environmental evolution. However, the molecular mechanism of the breaking of seed dormancy at cold temperatures is still unclear, and the genetic regulation of germination initiated by exposure to cold temperature requires further investigation. In the initial phase of the current study, the seed coat characteristics and embryo development of Fritillaria taipaiensis P.Y.Li at different temperatures (0°C, 4°C, 10°C & 25°C) was recorded. The results obtained demonstrated that embryo elongation and the dormancy-breaking was most significantly affected at 4°C. Subsequently, transcriptome analyses of seeds in different states of dormancy, at two stratification temperatures (4°C and 25°C) was performed, combined with weighted gene coexpression network analysis (WGCNA) and metabolomics, to explore the transcriptional regulation of seed germination in F. taipaiensis at the two selected stratification temperatures. The results showed that stratification at the colder temperature (4°C) induced an up-regulation of gene expression involved in gibberellic acid (GA) and auxin biosynthesis and the down-regulation of genes related to the abscisic acid (ABA) biosynthetic pathway. Thereby promoting embryo development and the stimulation of seed germination. Collectively, these data constitute a significant advance in our understanding of the role of cold temperatures in the regulation of seed germination in F. taipaiensis and also provide valuable transcriptomic data for seed dormancy for other non-model plant species.

Subarachnoid hemorrhage (SAH) is an important public health concern with high morbidity and mortality worldwide. SAH induces cell death, blood−brain barrier (BBB) damage, brain edema and oxidative stress. As the most abundant cell type in the central nervous system, astrocytes play an essential role in brain damage and recovery following SAH. This review describes astrocyte activation and polarization after SAH. Astrocytes mediate BBB disruption, glymphatic–lymphatic system dysfunction, oxidative stress, and cell death after SAH. Furthermore, astrocytes engage in abundant crosstalk with other brain cells, such as endothelial cells, neurons, pericytes, microglia and monocytes, after SAH. In addition, astrocytes also exert protective functions in SAH. Finally, we summarize evidence regarding therapeutic approaches aimed at modulating astrocyte function following SAH, which could provide some new leads for future translational therapy to alleviate damage after SAH.

Background: Behçet’s disease (BD) is a relapsing systemic immune disorder, and intestinal BD is a significant cause of mortality in patients with BD. Conventional therapeutic strategies for intestinal BD showed unsatisfactory outcomes, especially in those patients with refractory subtypes. In recent years, biologic agents have exhibited promising results in this field. While the sample sizes of existing studies were limited, the results were heterogeneous. Objectives: This study aimed to observe the efficacy of different biologics in clinical symptomatic improvement and intestinal mucosal healing. Design: This is a study including the report of case series and meta-analysis. Data sources and methods: This meta-analysis was conducted following the PRISMA guidelines. Free-text words and subject terms, including ‘Behcet’s Syndrome’, ‘Biologics’, ‘Tumor Necrosis Factor Antagonist’, were used to systematically research the relevant studies in the electronic databases (PubMed, Web of Science, Embase, and Cochrane Library). All retrieved articles were from inception to July 2021, and the data from our institution were also included in this meta-analysis. A double arcsine transformation was performed to stabilize the variance of the original ratio. Heterogeneity was evaluated via Q -test and I 2 statistics. Random-effects or fixed-effects model was used to calculate the pooled parameters, and the results were presented as forest plots with 95% confidence intervals. Results: Twelve studies were included, but only antitumor necrosis factor alpha (anti-TNF-α) agents were prescribed as biologicals for refractory intestinal BD. The symptom improvement rates at our institution ranged from 57.1 to 81.8%, and the mucosal healing rates were from 20 to 60% in different therapeutic periods. A total of 514 patients were enrolled in the meta-analysis, and the synthesized ratios showed that 59.8% ( n = 377) and 73.7% ( n = 317) of patients who received maintenance therapy with anti-TNF-α agents could achieve clinical symptomatic improvement during short-term (10–14 weeks) and long-term (48–54 weeks) periods, respectively. Furthermore, 77.8% ( n = 229) of patients with intestinal BD maintained therapeutic efficacy for a longer time (100 weeks). In addition, 60.9% ( n = 120) of the patients achieved sustained intestinal mucosal healing during a long-term follow-up (24–52 weeks). Conclusion: Anti-TNF-α treatment is effective in treating refractory intestinal BD but more studies are required to evaluate the effects of new biologics for intestinal BD in the near future. Registration: This study has been registered on PROSPERO, the ID is CRD42022329211. Plain language summary Anti-TNF-α agents are effective and safe in patients with intestinal Behçet’s disease Behçet’s disease (BD) is a disease affecting several organs including the gastrointestinal tract. Nowadays, the efficacy of existing therapy strategies is still unsatisfactory and some patients are suffering from repeated attacks of the disease. We noticed that a new kind of medicine, called antitumor necrosis factor alpha (anti-TNF-α) agents, was applied to these patients recently. The therapeutic efficacy is not convincing enough to evaluate since the number of patients receiving this new medicine was small in every individual study. Regarding this, we conducted a research to learn about the efficacy of this medicine at our own institution. Besides, we composed the results of other studies in an appropriate way. Then, we drew a conclusion on the exact efficacy of anti-TNF-α agents after the data analysis. We unveiled that the anti-TNF-α agents appeared both effective and safe in the management of intestinal BD patients when the classical therapy failed. More than half of the patients could achieve discomfort remission when they got the therapy of the new medicine at our institution. We also found that intestinal ulcers in most patients improved after they received the treatment. All in all, it offered another foothold for getting relief in these patients who were caught in this mire.

AimTo investigate the value of pretreatment blood biomarkers combined with magnetic resonance imaging (MRI) in predicting the efficacy of neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced rectal cancer (LARC).MethodsThis study involved patients with LARC who received NCRT and subsequently underwent total mesenteric excision from June 2015 to June 2021 at the First Affiliated Hospital of Soochow University. Patients with incomplete courses of neoadjuvant therapy, comorbidities with other malignancies or diseases that affect the study outcome, and those who underwent unplanned surgery were ultimately excluded. Laboratory data such as albumin, CEA, various blood cell levels, and MRI related data such as tumor regression grade assessed by magnetic resonance imaging (mrTRG) were collected from the included patients one week prior to NCRT. MrTRG is a common clinical imaging metric used to assess the degree of tumor regression in rectal cancer, primarily based on morphological assessment of residual tumor. Furthermore, pretreatment blood biomarkers such as neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), albumin to fibrinogen ratio (AFR), and prealbumin to fibrinogen ratio (PFR) were assessed. The independent variables for pathologic complete response (pCR) to NCRT were determined by univariate and multivariate logistic regression analyses. Receiver operating characteristic (ROC) curve analysis was used to examine the performance of MRI with or without pretreatment blood biomarkers in predicting pCR using DeLong’s method. A nomogram was created and confirmed internally.ResultsFifty-nine individuals with LARC satisfied the inclusion criteria, among which 23 showed pCR after NCRT. Logistic regression analysis demonstrated that pretreatment CEA (≤ 3 µg/L, OR = 0.151, P = 0.039), NLR (OR = 4.205, P = 0.027), LMR (OR = 0.447, P = 0.034), and PFR (OR = 0.940, P = 0.013) were independent predictors of pCR to NCRT. The AUCs of mrTRG alone and mrTRG plus the above four pretreatment blood biomarkers were 0.721 (P =0.0003) and 0.913 (P

Chemical liver injury is closely related to gut microbiota and its metabolites. In this study, we combined 16S rRNA gene sequencing, 1H NMR-based fecal metabolomics and GC-MS to evaluate the changes in gut microbiota, fecal metabolites and Short-chain fatty acids (SCFAs) in CCl4-induced liver injury in Sprague-Dawley rats, and the therapeutic effect of Shaoyao Gancao Decoction (SGD). The results showed that CCl4-induced liver injury overexpressed CYP2E1, enhanced oxidative stress, decreased antioxidant enzymes (SOD, GSH), increased peroxidative products MDA and inflammatory responses (IL-6, TNF-α), which were ameliorated by SGD treatment. H&E staining showed that SGD could alleviate liver tissue lesions, which was confirmed by the recovered liver index, ALT and AST. Correlation network analysis indicated that liver injury led to a decrease in microbiota correlation, while SGD helped restore it. In addition, fecal metabolomic confirmed the PICRUSt results that liver injury caused disturbances in amino acid metabolism, which were modulated by SGD. Spearman’s analysis showed that liver injury disrupted ammonia transport, urea cycle, intestinal barrier and energy metabolism. Moreover, the levels of SCFAs were also decreased, and the abundance of Lachnoclostridium, Blautia, Lachnospiraceae_NK4A136_group, UCG-005 and Turicibacter associated with SCFAs were altered. However, all this can be alleviated by SGD. More importantly, pseudo germ-free rats demonstrated that the absence of gut microbiota aggravated liver injury and affected the efficacy of SGD. Taken together, we speculate that the gut microbiota has a protective role in the pathogenesis of liver injury, and has a positive significance for the efficacy of SGD. Moreover, SGD can treat liver injury by modulating gut microbiota and its metabolites and SCFAs. This provides useful evidence for the study of the pathogenesis of liver injury and the clinical application of SGD.

As conventional treatments for diabetic wounds often fail to achieve rapid satisfactory healing, the development of effective strategies to accelerate diabetic wound repair is highly demanded. Herein, fibroblast growth factor 21 (FGF21) and metformin co-loaded multifunctional polyvinyl alcohol (PVA) hydrogel were fabricated for improved diabetic wound healing. The in vitro results proved that the hydrogel was adhesive and injectable, and that it could particularly scavenge reactive oxygen species (ROSs), while the in vivo data demonstrated that the hydrogel could promote angiogenesis by recruiting endothelial progenitor cells (EPCs) through upregulation of Ang-1. Both ROSs’ removal and EPCs’ recruitment finally resulted in enhanced diabetic wound healing. This work opens a strategy approach to diabetic wound management by combining biological macromolecules and small chemical molecules together using one promising environmental modulating drug delivery system.

ABSTRACT Tick infestations have been reported as one of the factors threatening the health of giant pandas, but studies of viral pathogens carried by ticks feeding on the blood of giant pandas are limited. To assess whether blood-sucking ticks of giant pandas can carry viral pathogens and if so, whether the viruses in ticks are associated with those previously detected in giant panda hosts, we determined the viromes of ticks detached from giant pandas in a field stocking area in Sichuan Province, southwest China. Using viral metagenomics we identified 32 viral species in ticks, half of which (including anellovirus [n = 9], circovirus [n = 3], and gemycircularvirus [n = 4]) showed homology to viruses carried by giant pandas and their associated host species (such as red pandas and mosquitoes) in the same living domain. Remarkably, several viruses in this study phylogenetically assigned as bunyavirus, hepe-like virus, and circovirus were detected with relatively high abundance, but whether these newly identified tick-associated viruses can replicate in ticks and then transmit to host animals during a blood meal will require further investigation. These findings further expand our understanding of the role of giant panda-infesting ticks in the local ecosystem, especially related to viral acquisition and transmission, and lay a foundation to assess the risk for giant panda exposure to tick-borne viruses. IMPORTANCE Ticks rank only second to mosquitoes as blood-feeding arthropods, capable of spreading pathogens (including viruses, bacteria, and parasites) to hosts during a blood meal. To better understand the relationship between viruses carried by ticks and viruses that have been reported in giant pandas, it is necessary to analyze the viromes of giant panda-parasitic blood-sucking ticks. This study collected 421 ticks on the body surface of giant pandas in Sichuan Province, China. We characterized the extensive genetic diversity of viruses harbored by these ticks and reported frequent communication of viruses between giant pandas and their ticks. While most of the virome discovered here are nonpathogenic viruses from giant pandas and potentially tick-specific viruses, we revealed some possible tick-borne viruses, represented by novel bunyaviruses. This research contributes to the literature because currently there are few studies on the virome of giant panda-infesting ticks.

Tarbinskiellus portentosus (Lichtenstein, 1796) is an agricultural and forestry pest, but people in some places use it as a delicacy. The complete mitogenome of T. portentosus (GenBank accession number MZ427921) is 15, 498 bp in size, including 13 protein-coding genes, 22 transfer RNAs, two ribosomal RNAs genes, and a noncoding A + T-rich region. The A + T-rich region is located between 12S rRNA and tRNAIle. The base composition of the whole T. portentosus mitogenome is 40.62% for A, 9.87% for G, 32.20% for T, and 17.31% for C, with a high AT content of 72.82%. The phylogeny analysis indicated that T. portentosus had a close relationship with Cardiodactylus muiri. The present data could contribute to further detailed diversity and phylogeographic analysis for this edible cricket.

Phase change materials (PCMs), which can absorb and release large amounts of latent heat during phase change, have been extensively studied for heat storage and thermal management. However, technical bottlenecks regarding low thermal conductivity and leakage have hindered practical applications of PCMs. In this paper, a simple, economical, and scalable absorption polymerization technique is proposed to prepare the polymethyl methacrylate/propyl palmitate/expanded graphite (MPCM/EG) phase change composites by constructing the microencapsulated phase change materials (polymethyl methacrylate/propyl palmitate, MPCM) with core-shell structures in the three-dimensional (3D) EG networks, taking propyl palmitate as the PCM core, polymethyl methacrylate (PMMA) as the shell, and long-chain “worm-like” EG as the thermally conductive networks. This technique proved to be a more appropriate combinatorial pathway than direct absorption of MPCM via EG. The MPCM/EG composites with high thermal conductivity, high enthalpy, excellent thermal stability, low leakage, and good thermal cycle reliability were prepared. The results showed that the MPCM-80/EG-10 composite demonstrated a high thermal conductivity of 3.38 W/(m·K), a phase change enthalpy up to 152.0 J/g, an encapsulation ratio of 90.3%, outstanding thermal stability performance, and long-term thermal cycle reliability when the EG loading is 10% and propyl palmitate is 80%. This research offers an easy and efficient approach for designing and fabricating phase change composites with promising applications in diverse energy-saving fields, such as renewable energy collection, building energy conservation, and microelectronic devices thermal protection.

Bridge cables are commonly used in bridge construction, and assessing their condition is crucial for ensuring bridge safety. However, current inspection methods often rely on large and heavy detection mechanical structures, which can be inconvenient during the inspection process. In light of these limitations, this paper proposes a portable non-destructive inspection method for bridge cables that detects the total magnetic flux variations utilizing an inductive search coil sensor. The occurrence of corrosion and cracks in bridge cables leads to changes in their original sectional area and permeability. These changes result in variations in the induced current that is excited by the coil, leading to distortions in both the magnetic field energy and the coil’s self-inductance. Thus, cable damage can be detected inversely by monitoring coil self-inductance variation. To assess the feasibility of this method, a numerical analysis is conducted, and an experimental structure is designed using a mock-up cable specimen with parallel steel wires that have varying degrees of damage. The experimental results demonstrate the effectiveness of the proposed method, which utilizes an inductive search coil sensor, intuitively identifies and quantifies internal flaws on the cable in real-time while maintaining a lightweight structure. The width and amplitude of the coil inductive response show a positive correlation with the flaw’s axial length and cross-sectional area, indicating that these parameters can be utilized to quantify the size of the flaw.

Intracranial aneurysms (IAs) are highly prevalent in the population, and their rupture poses a significant risk of death or disability. However, the treatment of aneurysms, whether through interventional embolization or craniotomy clipping surgery, is not always safe and carries a certain proportion of morbidity and mortality. Therefore, early detection and prompt intervention of IAs with a high risk of rupture is of notable clinical significance. Moreover, accurately predicting aneurysms that are likely to remain stable can help avoid the risks and costs of over-intervention, which also has considerable social significance. Recent advances in artificial intelligence (AI) technology offer promising strategies to assist clinical trials. This review will discuss the state-of-the-art AI applications for assessing the rupture risk of IAs, with a focus on achievements, challenges, and potential opportunities.

Early brain injury (EBI) subsequent to subarachnoid hemorrhage (SAH) is strongly associated with delayed cerebral ischemia and poor patient prognosis. Based on investigations into the molecular mechanisms underlying EBI, neurovascular dysfunction resulting from SAH can be attributed to a range of pathological processes, such as microvascular alterations in brain tissue, ionic imbalances, blood–brain barrier disruption, immune–inflammatory responses, oxidative stress, and activation of cell death pathways. Research progress presents a variety of promising therapeutic approaches for the preservation of neurological function following SAH, including calcium channel antagonists, endothelin-1 receptor blockers, antiplatelet agents, anti-inflammatory agents, and anti-oxidative stress agents. EBI can be mitigated following SAH through neuroprotective measures. To enhance our comprehension of the relevant molecular pathways involved in brain injury, including brain ischemia–hypoxic injury, neuroimmune inflammation activation, and the activation of various cell-signaling pathways, following SAH, it is essential to investigate the evolution of these multifaceted pathophysiological processes. Facilitating neural repair following a brain injury is critical for improving patient survival rates and quality of life.

The new power system is an energy interconnection network based on renewable energy generation. Information interconnection, data security, and reliability are the basis for the digital transformation of the power grid. Data sharing, lifecycle management, security, and user information privacy are issues that need to be addressed urgently. This paper analyzes the characteristics of the multi-combination of power grid data across services and introduces smart contract, cross-chain, and security encryption-related technologies. Based on the effective combination of smart contract and CP-ABE, data sharing schemes, including data sharing mechanism and data access control model are designed. Given this scheme, the blockchain system’s overall architecture is proposed, including the main chain, side chain, data sharing, and cross-chain information interaction. Finally, the underlying blockchain service platform is built using the Hyperledger open-source framework. We deploy the platform to verify the feasibility of the scheme according to the requirements of the data center, trust center, and blockchain-distributed nodes.

Blood-based detection of circulating cell-free DNA (cfDNA) is a non-invasive and easily accessible method for early cancer detection. Despite the extensive utility of cfDNA, there are still many challenges to developing clinical biomarkers. For example, cfDNA with genetic alterations often composes a small portion of the DNA circulating in plasma, which can be confounded by cfDNA contributed by normal cells. Therefore, filtering out the potential false-positive cfDNA mutations from healthy populations will be important for cancer-based biomarkers. Additionally, many low-frequency genetic alterations are easily overlooked in a small number of cfDNA-based cancer tests. We hypothesize that the combination of diverse types of cancer studies on cfDNA will provide us with a new perspective on the identification of low-frequency genetic variants across cancer types for promoting early diagnosis. By building a standardized computational pipeline for 1358 cfDNA samples across seven cancer types, we prioritized 129 shard genetic variants in the major cancer types. Further functional analysis of the 129 variants found that they are mainly enriched in ribosome pathways such as cotranslational protein targeting the membrane, some of which are tumour suppressors, oncogenes, and genes related to cancer initiation. In summary, our integrative analysis revealed the important roles of ribosome proteins as common biomarkers in early cancer diagnosis.

Graphene oxide aerogel (GOA) has wide application prospects due to its low density and high porosity. However, the poor mechanical properties and unstable structure of GOA have limited its practical applications. In this study, polyethyleneimide (PEI) was used to graft onto the surface of GO and carbon nanotubes (CNTs) to improve compatibility with polymers. Composite GOA was prepared by adding styrene-butadiene latex (SBL) to the modified GO and CNTs. The synergistic effect of PEI and SBL, resulted in an aerogel with excellent mechanical properties, compressive resistance, and structural stability. When the ratio of SBL to GO and GO to CNTs was 2:1 and 7:3, respectively, the obtained aerogel performance was the best, and the maximum compressive stress was 784.35% higher than that of GOA. The graft of PEI on the surface of GO and CNT could improve the mechanical properties of the aerogel, with greater improvements observed with grafting onto the surface of GO. Compared with GO/CNT/SBL aerogel without PEI grafting, the maximum stress of GO/CNT–PEI/SBL aerogel increased by 5.57%, that of GO–PEI/CNT/SBL aerogel increased by 20.25%, and that of GO–PEI/CNT–PEI/SBL aerogel increased by 28.99%. This work not only provided a possibility for the practical application of aerogel, but also steered the research of GOA in a new direction.

AIM: To explore the efficacy of Qiju Dihuang decoction combined with sodium hyaluronate eye drops in the treatment of xerophthalmia after cataract surgery.METHODS: A total of 120 patients with xerophthalmia after cataract surgery admitted to our hospital were selected between January 2018 and January 2020, and randomly divided into control group and observation group, with 60 cases in each group. The control group was treated with sodium hyaluronate eye drops alone, and the observation group was given Qiju Dihuang decoction combined with sodium hyaluronate eye drops, and they were treated for 1mo. The clinical efficacy, Traditional Chinese Medicine(TCM)syndromes scores, tear film break-up time(BUT), Schirmer Ⅰ test(SⅠt), corneal fluorescein staining(FL)and quality of life [25-item National Eye Institute Visual Function Questionnaire(NEI-VFQ-25)]were compared between the two groups.RESULTS:After treatment, the total effective rate of treatment was 93% in observation group and was 75% in control group(P

Abstract Background Cervical cancer (CC) is one of the most common gynaecological malignancies all around the world. The mechanisms of cervical carcinoma formation remain under close scrutiny. The long non-coding RNAs (lncRNA) and microRNAs (miRNAs) play important roles in controlling gene expression and promoting the development and progression of cervical cancer by acting as competitive endogenous RNA (ceRNA). However, the roles of lncRNA associated with ceRNAs in cervical carcinogenesis remains unknown. In this study, the expression of long non-coding RNA HOTAIR was investigated in HPV16 positive cervical cancer cells, the candidate miRNAs and target genes were identified to clarify putative ceRNAs of HOTAIR/miRNA in cervical cancer cells. Methods The proliferation ability of cells was measured by CCK8 and EdU incorporation assays and cell apoptosis was analyzed by flow cytometry. The expression of HOTAIR, miR-214-3p, HPV16 E7 mRNA were detected by qRT-PCR. As for searching for the interaction between miR-214-3p and HOTAIR, the binding sites for miR-214-3p on HOTAIR was predicted by starbase v2.0 database, then dual-luciferase assay was used to verify the binding sites. In addition, Gene Ontology (GO) and protein–protein interaction (PPI) network analysis of target genes of miR-214-3p were performed with bioinformatics analysis. The potential signal pathway regulated by HOTAIR/miR-214-3p was predicted by KEGG enrichment analysis and confirmed by qPCR and WB analysis in cervical cancer cells. Results Our results showed that expression of HOTAIR was up-regulated, while that of miR-214-3p was down-regulated in HPV16-positive cervical cancer cells. The expression status of HPV16 E7 played an important role in regulating expression of HOTAIR or miR-214-3p in cervical cancer cells. HOTAIR knockdown could significantly inhibited cell proliferate ability and promote cellular apoptosis, whereas the inhibition of miR-214-3p expression partially reversed such results. Bioinformatics analysis identified 1451 genes as target genes of miR-214-3p. The Gene ontology (GO) and KEGG Pathway enrichment analysis showed that these target genes were mainly related to regulation of cell communication, protein binding, enzyme binding and transferase activity, and Wnt ligand biogenesis. Pathway enrichment analysis results showed that the predicted target genes were significantly enriched in Wnt/β-catenin signaling pathway. Finally, our results confirmed that miR-214-3p could significantly inhibit β-catenin expression in HPV16 positive cancer cells by qPCR and WB analysis. Conclusion HOTAIR could act as a ceRNA through binding to miR-214-3p, promote cell proliferation and inhibit the apoptosis of HPV16 positive cervical cancer. HOTAIR/miR-214-3p/Wnt/β-catenin signal pathway might played important regulated roles in HPV16 positive cervical cancer. Our results provided new insight into defining novel biomarkers for cervical cancer.

Abstract In order to explore the role of exosomal circRNAs in the occurrence and development of sepsis, we looked for potential diagnostic markers to accurately identify sepsis and to lay a molecular basis for precise treatment. Ultracentrifugation was used to extract exosomes from the serum of patients with sepsis and healthy individuals. Then, changes in circRNA expression in exosomes were studied by circRNA microarray analysis. Gene ontology (GO) analysis and Kyoto City Encyclopaedia of Genes and Genomes (KEGG) pathway analysis were used to annotate the biological functions and pathways of genes, and a circRNA-miRNA-mRNA regulatory network was constructed. In the microarray analysis, 132 circRNAs were significantly differentially expressed, including 80 and 52 that were upregulated and downregulated, respectively. RT-qPCR verified the results of microarray analysis: hsa_circRNA_104484 and hsa_circRNA_104670 were upregulated in sepsis serum exosomes. ROC analysis showed that hsa_circRNA_104484 and hsa_circRNA_104670 in serum exosomes have the potential to be used as diagnostic markers for sepsis. The circRNA-miRNA-mRNA network predicted the potential regulatory pathways of differentially expressed circRNAs. There are differences in the expression of circRNA in serum exosomes between patients with sepsis and healthy individuals, which may be involved in the occurrence and development of the disease. Among them, elevations in hsa_circRNA_104484 and hsa_circRNA_104670 could be used as novel diagnostic biomarkers and molecular therapeutic targets.

Abstract Background Brain cancer is one of the eight most common cancers occurring in people aged 40+ and is the fifth-leading cause of cancer-related deaths for males aged 40–59. Accurate subtype identification is crucial for precise therapeutic treatment, which largely depends on understanding the biological pathways and regulatory mechanisms associated with different brain cancer subtypes. Unfortunately, the subtype-implicated genes that have been identified are scattered in thousands of published studies. So, systematic literature curation and cross-validation could provide a solid base for comparative genetic studies about major subtypes. Results Here, we constructed a literature-based brain cancer gene database (BCGene). In the current release, we have a collection of 1421 unique human genes gathered through an extensive manual examination of over 6000 PubMed abstracts. We comprehensively annotated those curated genes to facilitate biological pathway identification, cancer genomic comparison, and differential expression analysis in various anatomical brain regions. By curating cancer subtypes from the literature, our database provides a basis for exploring the common and unique genetic mechanisms among 40 brain cancer subtypes. By further prioritizing the relative importance of those curated genes in the development of brain cancer, we identified 33 top-ranked genes with evidence mentioned only once in the literature, which were significantly associated with survival rates in a combined dataset of 2997 brain cancer cases. Conclusion BCGene provides a useful tool for exploring the genetic mechanisms of and gene priorities in brain cancer. BCGene is freely available to academic users at http://soft.bioinfo-minzhao.org/bcgene/ .

Abstract Background Cells show directed migration response to electric signals, namely electrotaxis or galvanotaxis. PI3K and PTEN jointly play counterbalancing roles in this event via a bilateral regulation of PIP3 signaling. PI3K has been proved essential in anterior signaling of electrotaxing cells, whilst the role of PTEN remains elusive. Methods Dictyostelium cells with different genetic backgrounds were treated with direct current electric signals to investigate the genetic regulation of electrotaxis. Results We demonstrated that electric signals promoted PTEN phosphatase activity and asymmetrical translocation to the posterior plasma membrane of the electrotaxing cells. Electric stimulation produced a similar but delayed rear redistribution of myosin II, immediately before electrotaxis started. Actin polymerization is required for the asymmetric membrane translocation of PTEN and myosin. PTEN signaling is also responsible for the asymmetric anterior redistribution of PIP3/F-actin, and a biased redistribution of pseudopod protrusion in the forwarding direction of electrotaxing cells. Conclusions PTEN controls electrotaxis by coordinately regulating asymmetric redistribution of myosin to the posterior, and PIP3/F-actin to the anterior region of the directed migration cells.

Abstract Background This study examines the socioeconomic differentials in trends in the prevalence of hypertension and pre-hypertension and hypertension awareness, treatment, and control in rural Southwestern China. Methods Two cross-sectional interviews and health examination surveys were administered in rural Yunnan Province, including 6,350 consenting participants in 2009 and 6,359 consenting participants in 2016 (aged ≥ 35 years). Participant demographics, socioeconomic status (SES), and ethnicity, along with information about hypertension awareness, treatment, and control, were collected using similar questionnaires in the two surveys. The participants’ blood pressure levels were also measured. Results From 2009 to 2016, the prevalence of hypertension substantially increased from 28.4% to 39.5% (P

Environmental stochasticity and toxin-producing phytoplankton (TPP) are the key factors that affect the aquatic ecosystems. To investigate the effects of environmental stochasticity and TPP on the dynamics of plankton populations, a stochastic phytoplankton-zooplankton system with two TPP is studied theoretically and numerically in this paper. Theoretically, we first prove that the system possesses a unique and global positive solution with positive initial values, and then derive some sufficient conditions guaranteeing the extinction and persistence in the mean of the system. Significantly, it is shown that the system has a stationary distribution when toxin liberation rate reaches some a critical value. Additionally, numerical analysis shows that the white noise can affect the survival of plankton populations directly. Furthermore, it has been observed that the increasing one toxin liberation rate can increase the survival chance of phytoplankton and reduce the biomass of zooplankton, but the combined effects of two liberation rates on the changes in plankton populations are stronger than that of controlling any one of the two TPP.

BackgroundNearly all anti-PD-1 antibodies are of the IgG4 isotype, and thus possess residual FcR effector functions. Such anti-PD-1 antibodies are also associated with immune tolerance and escape due to instability of the CH3 domain and Fc-Fc interaction. In this trial, we examined the efficacy and safety of penpulimab, a novel IgG1 anti-PD-1 antibody that does not bind to the Fc receptor, in patients with refractory or relapsed classical Hodgkin lymphoma (R/R cHL).MethodsAdult patients (≥18 years of age) with R/R cHL received 200 mg penpulimab once biweekly until disease progression or unacceptable toxicities for a maximum of 24 months. The primary endpoint was objective response rate (ORR) based on the Independent Radiology Review Committee per Lugano 2014 criteria. Secondary endpoints included progression-free survival (PFS), overall survival (OS), treatment-related adverse events (TRAEs) and immune-related adverse events (irAEs).ResultsA total of 94 patients were enrolled. The median follow-up was 15.8 months. The ORR was 89.4% (95% CI 80.8%, 95.0%) in the full analysis set (85 patients). Forty (47.1%) patients achieved complete remission, 36 (42.4%) patients achieved partial remission. The 12-month PFS rate was 72.1% (95% CI 60.5%, 80.8%) and the 18-month OS rate was 100%. Totally 97.9% (92/94) of patients experienced at least one TRAE. The rate of grade 3 and above TRAEs was 26.6% (25/94). In addition, 51 (54.3%) patients experienced an irAE, and 4 (4.3%) patients developed grade 3 or above irAEs. No irAE-related death occurred.ConclusionsPenpulimab was effective and safe in patients with R/R cHL.

Background & Aims: Hepatitis B virus (HBV) infection is a significant cause of liver function damage. However, previous studies on HBV mainly aimed at ordinary people, and there is a lack of consensus on the relationship between HBV infection and gestational diabetes mellitus (GDM) and whether HBV-infected pregnant women should undergo antiviral treatment. In addition, systematic studies on the impact of HBV infection on GDM have rarely been studied directly. Therefore, the overall goal of this study was to pursue the association between HBV infection, liver function, and GDM using Xiamen area gestational big data.Methods: Using the Xiamen Primary Health Information System-maternal and child health information system, the data on participants (138,867 in total) expected confinement between 2008 and 2018 were included. Using univariate and multivariate logistic regressions, we constructed models to determine the role of HBV infection and liver function status in GDM. In addition, an analysis of variance tests was performed to study whether the relationship between HBsAg and GDM differed in the normal liver function and the abnormal liver function subgroups.Results: HBsAg's positive status showed a substantial correlation with GDM onset in univariate and multivariate logistic regressions (p < 0.001). Subgroup analysis among HBsAg, liver function, and GDM suggests that both HBsAg and liver function affect the onset of GDM and have the highest prevalence of both abnormalities. Furthermore, ANOVA was used to investigate the association of HBsAg positive (p < 0.001), abnormal liver function (p < 0.001), and their interaction (p = 0.302) on the onset of GDM. This result showed that HBsAg is an independent factor of GDM pathogenesis, regardless of liver function status.Conclusion: HBsAg and liver function are independent factors in GDM. Therefore, regarding these results, while clinicians consider the traditional risk factors of GDM, it is necessary to consider the HBV infection status. Conducting a dietary intervention for HBsAg-positive pregnant women at the early stage of pregnancy is conducive to reducing the adverse effects.

BackgroundGenomic profiling of cerebrospinal fluid (CSF) can be used to detect actionable mutations and guide clinical treatment of non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastases. Examining the performance of CSF samples in real-world settings can confirm the potential of CSF genotyping for guiding therapy in clinical practice.Patients and MethodsWe included 1,396 samples from 970 NSCLC patients with CNS metastases in real-world settings. All samples underwent targeted next-generation sequencing of 1,021 cancer-relevant genes. In total, 100 CSF samples from 77 patients who had previously received targeted treatment were retrospectively analyzed to explore the mechanisms of TKI-resistance.ResultsFor NSCLC patients with CNS metastases, CSF samples were slightly more often used for genomic sequencing in treated patients with only distant CNS metastases compared to other patients (10.96% vs. 0.81–9.61%). Alteration rates in CSF samples were significantly higher than those in plasma, especially for copy number variants (CNV). The MSAFs of CSF samples were significantly higher than those of plasma and tumor tissues (all p

BackgroundEffective personal protective equipment (PPE) contribute to the prevention of COVID-19 infection. However, it is necessary to evaluate the potential risk of different medical protections in the isolation ward of COVID-19.ObjectivesWe aimed to explore the dynamics in physiological indexes of medical staff under primary and secondary PPE in the isolation ward of COVID-19 and provide the scientific basis for determining the safe work strategy.Materials and MethodsIn this study, 30 female nurses were selected to simulate medical work under the primary or secondary PPE, respectively. The oral temperature, axillary temperature, heart rate, respiratory rate, blood oxygen saturation, and blood pressure were measured and recorded every 20 min. The subjective adverse symptoms were recorded every 30 min. The blood glucose and weight of the individuals were measured and recorded before and after the trial.ResultsThe results indicated that the median trial persistence time in the participants with moderate-intensity work wearing the secondary PPE (70.0 min) was much lower than that with moderate-intensity work wearing the primary PPE (180 min) and with light-intensity work wearing the primary PPE (110 min; p < 0.05). Importantly, the heart rate, oral/axillary temperature, and respiratory rate of physiological indexes of the participants under moderate-intensity work wearing the secondary PPE increased significantly faster than the primary PPE (p < 0.001), while blood oxygen saturation decreased significantly faster than the primary PPE (p < 0.001). In addition, the proportions of subjective adverse symptoms (such as dry mouth, dizziness, palpitations, and anhelation) were much higher than primary PPE (p < 0.001). The average sweat volume and blood glucose consumption of participants under moderate-intensity work wearing primary PPE were higher than secondary PPE (p < 0.001).ConclusionThe combination of an exacerbated workload and secondary PPE worn by COVID-19 healthcare workers increases the change in physiological indicators, and in some cases the adverse symptoms, which can affect and even suspend their medical work. For any medical institution, there is room for improvement in terms of bioethics of a “Job Well Done” to reduce the risks of medical activities under secondary PPE.

Fibrosis can occur in many organs, and severe cases leading to organ failure and death. No specific treatment for fibrosis so far. In recent years, microRNA-34a (miR-34a) has been found to play a role in fibrotic diseases. MiR-34a is involved in the apoptosis, autophagy and cellular senescence, also regulates TGF-β1/Smad signal pathway, and negatively regulates the expression of multiple target genes to affect the deposition of extracellular matrix and regulate the process of fibrosis. Some studies have explored the efficacy of miR-34a-targeted therapies for fibrotic diseases. Therefore, miR-34a has specific potential for the treatment of fibrosis. This article reviews the important roles of miR-34a in fibrosis and provides the possibility for miR-34a as a novel therapeutic target in fibrosis.

Background Oncolytic viruses (OVs) are capable to inflame the tumor microenvironment (TME) and elicit infiltrating tumor-specific T cell responses. However, OV treatment negatively alters the cancer-immune set point in tumors to attenuate the antitumor immune response, which suggests the necessity of dissecting the immune landscape of the virus-treated tumors and developing novel strategies to maximize the potential of OVs. The aim of this study is to investigate the effect of the single-chain variable fragment (scFv)-armed OVs targeting PD-1 on the TME, and ultimately overcome localized immunosuppression to sensitize tumors to immunotherapies.Methods A tumor-selective oncolytic herpes simplex virus vector was engineered to encode a humanized scFv against human PD-1 (hPD-1scFv) (YST-OVH). The antitumor efficacy of YST-OVH was explored in multiple therapeutic mouse models. The neurotoxicity and safety of YST-OVH were evaluated in nonhuman primates. The precise dynamics in the TME involved in YST-OVH treatment were dissected using cytometry by time-of-flight (CyTOF).Results The identified hPD-1scFv showed superior T-cell activating activity. Localized delivery of hPD-1scFv by YST-OVH promotes systemic antitumor immunity in humanized PD-1 mouse models of established cancer. Immune profiling of tumors using CyTOF revealed the enhanced antitumor effect of YST-OVH, which largely relied on CD8+ T cell activity by augmenting the tumor infiltration of effector CD8+ T cells and establishment of memory CD8+ T cells and reducing associated CD8+ T cell exhaustion. Furthermore, YST-OVH treatment modified the cancer-immune set point of tumors coupled to coexpression of CTLA-4 and TIM-3 on exhausted CD8+ T cells and high levels of CTLA-4+ Treg cells. A combination approach incorporating anti-CTLA-4 or anti-TIM-3 further improved efficacy by increasing tumor immunogenicity and activating antitumor adaptive immune responses. Moreover, this therapeutic strategy showed no neurotoxicity and was well tolerated in nonhuman primates. The benefit of intratumoral hPD-1scFv expression was also observed in humanized mice bearing human cancer cells.Conclusion Localized delivery of PD-1 inhibitors by engineered YST-OVH was a highly effective and safe strategy for cancer immunotherapy. YST-OVH also synergized with CTLA-4 or TIM-3 blockade to enhance the immune response to cancer. These data provide a strong rationale for further clinical evaluation of this novel therapeutic approach.

BackgroundLocal governments in China took restrictive measures after the outbreak of COVID-19 to control its spread, which unintentionally resulted in reduced anthropogenic emission sources of air pollutants. In this study, we intended to examine the effects of the COVID-19 lockdown policy on the concentration levels of particulate matter with aerodynamic diameters of ≤1 μm (PM1), ≤2.5 μm (PM2.5), and ≤10 μm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), ozone (O3), and carbon monoxide (CO) and the potential subsequent reductions in the incidence of ischemic and hemorrhagic stroke in Shandong Province, China.MethodsA difference-in-difference model combining the daily incidence data for ischemic and hemorrhagic stroke and air pollutant data in 126 counties was used to estimate the effect of the COVID-19 lockdown on the air pollutant levels and ischemic and hemorrhagic stroke incident counts. The avoided ischemic stroke cases related to the changes in air pollutant exposure levels were further estimated using concentration-response functions from previous studies.ResultsThe PM1, PM2.5, PM10, NO2, and CO levels significantly decreased by −30.2, −20.9, −13.5, −46.3, and −13.1%, respectively. The O3 level increased by 11.5% during the lockdown compared with that in the counterfactual lockdown phase of the past 2 years. There was a significant reduction in population-weighted ischemic stroke cases (−15,315, 95% confidence interval [CI]: −27,689, −2,942), representing a reduction of 27.6% (95% CI: −49.9%, −5.3%). The change in the number of hemorrhagic stroke cases was not statistically significant. The total avoided PM1-, PM2.5-, PM10-, NO2-, and CO–related ischemic stroke cases were 739 (95% CI: 641, 833), 509 (95% CI: 440, 575), 355 (95% CI: 304, 405), 1,132 (95% CI: 1,024, 1,240), and 289 (95% CI: 236, 340), respectively.ConclusionThe COVID-19 lockdown indirectly reduced the concentration levels of PM1, PM2.5, PM10, NO2, and CO and subsequently reduced the associated ischemic stroke incidence. The health benefits due to the lockdown are temporary, and long-term measures should be implemented to increase air quality and related health benefits in the post-COVID-19 period.

BackgroundCardiovascular comorbidities (CVCs) affect the overall survival (OS) of patients with colorectal cancer (CRC). However, a prognostic evaluation system for these patients is currently lacking.ObjectivesThis study aimed to develop and validate a nomogram, which takes CVCs into account, for predicting the survival of patients with CRC.MethodsIn total, 21,432 patients with CRC were recruited from four centers in China between January 2011 and December 2017. The nomogram was constructed, based on Cox regression, using a training cohort (19,102 patients), and validated using a validation cohort (2,330 patients). The discrimination and calibration of the model were assessed by the concordance index and calibration curve. The clinical utility of the model was measured by decision curve analysis (DCA). Based on the nomogram, we divided patients into three groups: low, middle, and high risk.ResultsIndependent risk factors selected into our nomogram for OS included age, metastasis, malignant ascites, heart failure, and venous thromboembolism, whereas dyslipidemia was found to be a protective factor. The c-index of our nomogram was 0.714 (95% CI: 0.708–0.720) in the training cohort and 0.742 (95% CI: 0.725–0.759) in the validation cohort. The calibration curve and DCA showed the reliability of the model. The cutoff values of the three groups were 68.19 and 145.44, which were also significant in the validation cohort (p < 0.001).ConclusionTaking CVCs into account, an easy-to-use nomogram was provided to estimate OS for patients with CRC, improving the prognostic evaluation ability.

Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leads to the dysregulation of the immune system, exacerbates inflammatory responses, and even causes multiple organ dysfunction syndrome in patients with severe disease. Sarcoidosis is an idiopathic granulomatous multisystem disease characterized by dense epithelioid non-necrotizing lesions with varying degrees of lymphocytic inflammation. These two diseases have similar clinical manifestations and may also influence each other and affect their clinical courses. In this study, we analyzed some possible connections between sarcoidosis and COVID-19, including the role of the renin–angiotensin system in the respiratory system, immune response, and cell death pathways, to understand the underlying mechanisms of SARS-CoV-2 infection, predisposing patients to severe forms of COVID-19. This review will provide a new prospect for the treatment of COVID-19 and an opportunity to explore the pathogenesis and development of sarcoidosis.

Plant-associated microbes play important roles in plant health and disease. Mortierella is often found in the plant rhizosphere, and its possible functions are not well known, especially in medical plants. Mortierella alpina isolated from ginseng soil was used to investigate its effects on plant disease. The promoting properties and interactions with rhizospheric microorganisms were investigated in a medium. Further, a pot experiment was conducted to explore its effects on ginseng root rot disease. Physicochemical properties, high-throughput sequencing, network co-occurrence, distance-based redundancy analysis (db-RDA), and correlation analysis were used to evaluate their effects on the root rot pathogen. The results showed that Mortierella alpina YW25 had a high indoleacetic acid production capacity, and the maximum yield was 141.37 mg/L at 4 days. The growth of M. alpina YW25 was inhibited by some probiotics (Bacillus, Streptomyces, Brevibacterium, Trichoderma, etc.) and potential pathogens (Cladosporium, Aspergillus, etc.), but it did not show sensitivity to the soil-borne pathogen Fusarium oxysporum. Pot experiments showed that M. alpina could significantly alleviate the diseases caused by F. oxysporum, and increased the available nitrogen and phosphorus content in rhizosphere soil. In addition, it enhanced the activities of soil sucrase and acid phosphatase. High-throughput results showed that the inoculation of M. alpina with F. oxysporum changed the microbial community structure of ginseng, stimulated the plant to recruit more plant growth-promoting bacteria, and constructed a more stable microbial network of ginseng root. In this study, we found and proved the potential of M. alpina as a biocontrol agent against F. oxysporum, providing a new idea for controlling soil-borne diseases of ginseng by regulating rhizosphere microorganisms.

Abstract The performance of different BP readings and their combinations at a visit to identify children and adolescents with pediatric hypertension remains controversial. We aimed to assess the utility of different blood pressure (BP) readings and their combinations obtained at the initial screening visit for identifying Chinese children and adolescents with hypertension. Participants were 7831 children and adolescents aged 6‐17 years measured as part of a cross‐sectional survey conducted in Jinan, China between September 2012 and November 2014. BP was measured three times at up to three visits. Elevated BP at the initial visit was defined as systolic BP and/or diastolic BP ≥ age‐ and sex‐specific 95th percentiles using the Chinese BP references for children and adolescents based on different BP readings and their combinations. Participants with elevated BP using (BP2+BP3)/2 across three visits were defined as having hypertension. Of the different readings or combinations examined, the mean of the last two readings at the initial visit had the best predictive utility for children and adolescents with hypertension (sensitivity: 100.0%; specificity: 86.9%; positive predictive value: 27.6%; negative predictive value: 100.0%). This was also reflected in the area under the curve being highest for the mean of the last two readings (0.93, 95% confidence interval: 0.93‐0.94) compared with any of the other readings or combinations (BP1, BP2, BP3, [BP1+BP2]/2, [BP1+BP3]/2, and [BP1+BP2+BP3]/3; all p

In this paper, we propose a prey-predator model with age structure which is described by the mature period. The aim of this paper is to study how mature period affect the dynamics of interaction between prey and predator. The sufficient condition of the existence of non-negative steady state is derived. By using integrated semigroup theory, we obtain the characteristic equation, by which we find that the non-negative steady state will lose its stability via Hopf bifurcation induced by mature period, and the corresponding periodic solutions emerge. Additionally, some numerical simulations are provided to illustrate the results predicted by linear analysis. Especially, the numerical results indicate that both mature period and age can affect the amplitude and period of periodic solutions.

Abstract Background The aim of the study was to conduct a meta-analysis to evaluate the accuracy of neutrophil CD64, procalcitonin (PCT), and interleukin-6 (IL-6) as markers for the diagnosis of sepsis in adult patients. Methods Various databases were searched to collect published studies on the diagnosis of sepsis in adult patients using neutrophil CD64, PCT, and IL-6 levels. Utilizing the Stata SE 15.0 software, forest plots and the area under the summary receiver operating characteristic curves were drawn. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the curve (AUC) were calculated. Results Fifty-four articles were included in the study. The pooled sensitivity, specificity, and AUC of neutrophil CD64 for the diagnosis of sepsis were 0.88 (95% confidence interval [CI], 0.81–0.92), 0.88 (95% CI, 0.83–0.91), and 0.94 (95% CI, 0.91–0.96), respectively. The pooled sensitivity, specificity, and AUC of PCT for the diagnosis of sepsis were 0.82 (95% CI, 0.78–0.85), 0.78 (95% CI, 0.74–0.82), and 0.87 (95% CI, 0.83–0.89), respectively. Subgroup analysis showed that the AUC for PCT diagnosis of intensive care unit (ICU) sepsis was 0.86 (95% CI, 0.83–0.89) and the AUC for PCT diagnosis of non-ICU sepsis was 0.82 (95% CI, 0.78–0.85). The pooled sensitivity, specificity, and AUC of IL-6 for the diagnosis of sepsis were 0.72 (95% CI, 0.65–0.78), 0.70 (95% CI, 0.62–0.76), and 0.77 (95% CI, 0.73–0.80), respectively. Conclusions Of the three biomarkers studied, neutrophil CD64 showed the highest diagnostic value for sepsis, followed by PCT, and IL-6. On the other hand, PCT showed a better diagnostic potential for the diagnosis of sepsis in patients with severe conditions compared with that in patients with non-severe conditions.

Abstract Gestational diabetes mellitus (GDM) has aroused wide public concern, as it affects approximately 1.8–25.1% of pregnancies worldwide. This study aimed to examine the association of pre-pregnancy demographic parameters and early-pregnancy laboratory biomarkers with later GDM risk, and further to establish a nomogram prediction model. This study is based on the big obstetric data from 10 “AAA” hospitals in Xiamen. GDM was diagnosed according to the International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria. Data are analyzed using Stata (v14.1) and R (v3.5.2). Total 187,432 gestational women free of pre-pregnancy diabetes mellitus were eligible for analysis, including 49,611 women with GDM and 137,821 women without GDM. Irrespective of confounding adjustment, eight independent factors were consistently and significantly associated with GDM, including pre-pregnancy body mass index (BMI), pre-pregnancy intake of folic acid, white cell count, platelet count, alanine transaminase, albumin, direct bilirubin, and creatinine (p

The protein tyrosine phosphatase Src homology phosphotyrosyl phosphatase 2 (SHP2) is implicated in various cancers, and targeting SHP2 has become a promising therapeutic approach. We herein described a robust cross-validation high-throughput screening protocol that combined the fluorescence-based enzyme assay and the conformation-dependent thermal shift assay for the discovery of SHP2 inhibitors. The established method can effectively exclude the false positive SHP2 inhibitors with fluorescence interference and was also successfully employed to identify new protein tyrosine phosphatase domain of SHP2 (SHP2-PTP) and allosteric inhibitors. Of note, this protocol showed potential for identifying SHP2 inhibitors against cancer-associated SHP2 mutation SHP2-E76A. After initial screening of our in-house compound library (∼2300 compounds), we identified 4 new SHP2-PTP inhibitors (0.17% hit rate) and 28 novel allosteric SHP2 inhibitors (1.22% hit rate), of which SYK-85 and WS-635 effectively inhibited SHP2-PTP (SYK-85: IC50 = 0.32 μmol/L; WS-635: IC50 = 4.13 μmol/L) and thus represent novel scaffolds for designing new SHP2-PTP inhibitors. TK-147, an allosteric inhibitor, inhibited SHP2 potently (IC50 = 0.25 μmol/L). In structure, TK-147 could be regarded as a bioisostere of the well characterized SHP2 inhibitor SHP-099, highlighting the essential structural elements for allosteric inhibition of SHP2. The principle underlying the cross-validation protocol is potentially feasible to identify allosteric inhibitors or those inactivating mutants of other proteins.

Abstract Background Due to the hypoxia and nutrient deficiency microenvironment, glioblastoma (GBM) exhibits high autophagy activity and autophagy plays an important role in the progression of GBM. However, the molecular mechanism of autophagy in GBM progression remains unclear. The aim of this study is to delve out the role and mechanism of yes-associated protein (YAP) in GBM autophagy and progression. Methods The level of autophagy or autophagy flux were assessed by using western blotting, GFP-LC3 puncta (Live) imaging, transmission electron microscopy and GFP-RFP-LC3 assay. The GBM progression was detected by using CCK8, EdU, nude mouse xenograft and Ki67 staining. Isobaric tags for relative and absolute quantification (iTraq) quantitative proteomics was used to find out the mediator of YAP in autophagy. Expression levels of YAP and HMGB1 in tissue samples from GBM patients were examined by Western blotting, tissue microarray and immunohistochemistry. Results YAP over-expression enhanced glioma cell autophagy under basal and induced conditions. In addition, blocking autophagy by chloroquine abolished the promoting effect of YAP on glioma growth. Mechanistically, YAP over-expression promoted the transcription and translocation of high mobility group box 1(HMGB1), a well-known regulator of autophagy, from nucleus to cytoplasm. Down-regulation of HMGB1 abolished the promoting effect of YAP on autophagy and glioma growth. Furthermore, the expression of YAP and HMGB1 were positively associated with each other and suggested poor prognosis for clinical GBM. Conclusion YAP promoted glioma progression by enhancing HMGB1-mediated autophagy, indicating that YAP-HMGB1 axis was a feasible therapeutic target for GBM. Our study revealed a clinical opportunity involving the combination of chemo-radiotherapy with pharmacological autophagy inhibition for treating GBM patients with YAP high expression.

Background: Podocyte injury contributes to progressive glomerulosclerosis. Previously, we demonstrated the important role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in mediating the podocyte injury induced by aldosterone. Silent mating type information regulation 2 homolog 1 (SIRT1) is an NAD+-dependent deacetylase that is associated with the regulation of cellular inflammation. However, whether the activation of the NLRP3 inflammasome in podocytes is regulated by SIRT1, and the mechanism involved, remains unknown. Methods: In this study, we detected SIRT1 expression in patients with podocyte disease and performed an aldosterone infusion model in podocyte-specific Sirt1 knockout mice. In cultured podocytes, we used plasmids to overexpress SIRT1 and treated the podocyte with aldosterone. Results: SIRT1 was significantly decreased in the glomeruli of patients with podocyte disease. Sirt1-deficient mice showed significant urinary albumin excretion after aldosterone infusion, and the severity of the glomerular injury was significantly greater in podocyte-specific Sirt1 knockout mice than in the wild-type mice. Moreover, podocyte conditional Sirt1 knockout aggravated NLRP3 inflammasome activation and mitochondrial dysfunction (MtD). In vitro, overexpression of SIRT1 inhibited NLRP3 activation, protected against MtD and podocyte injury. Conclusion: Taken together, these findings revealed a novel regulatory mechanism of the NLRP3 inflammasome by SIRT1 by promoting mitochondrial function, which provides some potential targets for the treatment of glomerular diseases.

Analyzing the ecological stoichiometric characteristics and soil enzyme activity of litter and soil in different vegetation types within karst areas can help to clarify the nutrient cycles and element abundance in those areas, in addition to providing basic data for vegetation restoration and reconstruction. In this study, the carbon (C), nitrogen (N), and phosphorus (P) contents of litter and soil and the alkaline phosphatase (ALP), sucrase (Suc), urease (Ure), and catalase (CAT) activity of soil were measured in grassland (GR), shrubland (SR), arbor and shrub compound forest (AS), and arbor forest (AR). The correlation between litter and soil stoichiometry and soil enzyme activity was analyzed to reveal the effects of different vegetation types on the C, N, and P stoichiometric characteristics of litter and soil, soil enzyme activity, and their driving mechanisms. The results showed that the C, N, and P contents of litter in the study area were 366.2–404.48 g/kg, 12.37–15.26 g/kg, and 0.76–1.05 g/kg, respectively. The C, N, and P contents of soil in the study area were 27.69–42.4 g/kg, 2.38–4.25 g/kg, and 0.56–0.68 g/kg, respectively. The litter N content and soil C and N contents were highest in the arbor forest (p < 0.05), while those in the grassland were the lowest (p < 0.05). The C:P and N:P ratios of the litter and soil in the arbor forest and arbor and shrub compound forest were higher than those in the other two vegetation types; however, the C:N ratio of the litter and soil in the arbor forest was lower than that in the other three vegetation types. The N element had a strong coupling relationship between litter and soil, while the P element had a weak relationship. The activity of the four soil enzymes in the four vegetation types were ranked as follows: arbor forest > arbor and shrub compound forest > shrubland > grassland. In general, the arbor forest communities were more conducive to nutrient cycling and accumulation. This information could help to guide the restoration and management of vegetation in karst areas.

In the present work, the two-phase mixture (HTLc) of hydrotalcite and its oxide were used to improve the barrier properties, UV resistance and antimicrobial activity of Poly(ethylene terephthalate) (PET) for their application in liquid milk packaging. Firstly, CaZnAl-CO3-LDHs with a two-dimensional layered structure were synthesized by hydrothermal method. CaZnAl-CO3-LDHs precursors were characterized by XRD, TEM, ICP and dynamic light scattering. A series of PET/HTLc composite films were then prepared, characterized by XRD, FTIR and SEM, and a possible mechanism of the composite films with hydrotalcite was proposed. Barrier properties to water vapor and oxygen have been studied in PET nanocomposites, as well as their antibacterial efficacy by the colony technique and their mechanical properties after exposure to UV irradiation for 24 h. By the presence of 1.5 wt% HTLc in the PET composite film, the oxygen transmission rate (OTR) was reduced by 95.27%, the water vapor transmission rate was reduced by 72.58% and the inhibition against Staphylococcus aureus and Escherichia coli was 83.19% and 52.75%. Moreover, a simulation of the migration process in dairy products was used to prove the relative safety. This research first proposes a safe technique for fabricating hydrotalcite-based polymer composites with a high gas barrier, UV resistance and effective antibacterial activity.

The molecular subtype is critical for accurate treatment and follow-up in patients with lung cancer; however, information regarding subtype-associated genes is dispersed among thousands of published studies. Systematic curation and cross-validation of the scientific literature would provide a solid foundation for comparative genetic studies of the major molecular subtypes of lung cancer. Here, we constructed a literature-based lung cancer gene database (LCGene). In the current release, we collected and curated 2507 unique human genes, including 2267 protein-coding and 240 non-coding genes from comprehensive manual examination of 10,960 PubMed article abstracts. Extensive annotations were added to aid identification of differentially expressed genes, potential gene editing sites, and non-coding gene regulation. For instance, we prepared 607 curated genes with CRISPR knockout information in 43 lung cancer cell lines. Further comparison of these implicated genes among different subtypes identified several subtype-specific genes with high mutational frequencies. Common tumor suppressors and oncogenes shared by lung adenocarcinoma and lung squamous cell carcinoma, for example, exhibited different mutational frequencies and prognostic features, suggesting the presence of subtype-specific biomarkers. Our retrospective analysis revealed 43 small cell lung cancer-specific genes. Moreover, 52 tumor suppressors and oncogenes shared by lung adenocarcinoma and squamous cell carcinoma confirmed the different molecular mechanisms of these two cancer subtypes. The subtype-based genetic differences, when combined, may provide insight into subtype-specific biomarkers for genetic testing.

Oxygen (O2) uptake by cells and tissues is a critical indicator of metabolic demand, changes in microenvironment, and pathophysiology. O2 uptake from the atmosphere accounts for virtually all the O2 consumption in the avascular cornea; however, a detailed spatiotemporal profile of corneal O2 uptake (COU) remains undetermined. Here, we used a non-invasive self-referencing optical fiber O2 sensor—the scanning micro-optrode technique (SMOT)—to report the O2 partial pressure and flux variations at the ocular surface of rodents and non-human primates. In vivo spatial mapping in mice revealed a distinct COU, characterized by a centripetal gradient with a significantly higher O2 influx at the limbus and conjunctiva regions than at the center of the cornea. This regional COU profile was reproduced ex vivo in freshly enucleated eyes. The centripetal gradient was conserved across the following species analyzed: mice, rats, and rhesus monkeys. In vivo temporal mapping in mice showed a significant increase in the O2 flux in the limbus in the evening compared to other times. Altogether, the data unveiled a conserved centripetal COU profile, which may be associated with the limbal epithelial stem cells residing at the intersection of the limbus and conjunctiva. These physiological observations will serve as a useful baseline for comparative studies with contact lens wear, ocular disease, diabetes, etc. Moreover, the sensor may be applied to understand the responses of the cornea and other tissues to various insults, drugs, or changes in the environment.

The traditional aqueous flame-retardant coating faces the problem of slow solvent evaporation rate in the preparation process. It is an urgent problem to ensure that the function of the membrane is not destroyed while accelerating the solvent volatilization. Herein, we fabricated films on the metal substrate surface by a totally novel method: demulsification-induced fast solidification to rapidly obtain the flame-retardant coating. The environmentally friendly flame retardants aluminum hydroxide and red phosphorus were mixed with the commercial water-based polyurethane 906 emulsion to explore the optimal mixing ratio, where the adhesion of the flame-retardant reached the Grade 3 standard, the sample remained intact after the 100 cm drop hammer test and the limiting oxygen index value reached 30.4%. In addition, compared with the traditional process, this method, with the advantages of rapidly drying, environmentally friendly, uniformly prepared coatings on the surface of any shape substrates, as well as accurate and controllable coating thickness, can be widely applied in the flame-retardant field.

Abstract Video‐assisted thoracoscopic surgery (VATS) subsegmentectomy has been widely used to resect small‐sized lung lesions in clinical practice. Precise identification of the subsegmental bronchus is one of the essential steps in performing thoracoscopic anatomic subsegmentectomy. Here, we report a thoracoscopic right S2a segmentectomy with preoperative electromagnetic navigational bronchoscopy (ENB)‐guided injection of methylene blue to identify the subsegmental bronchus in a 51‐year‐old male. We successfully performed complicated surgery using this method. This ENB‐guided dye marking method may accurately distinguish the subsegmental bronchus to effectively guide surgery.

As a nondestructive testing technology, $\gamma $ -photon imaging shows immense potential in the industrial field. However, the limitations of $\gamma $ -photon imaging theory and detection technology result in various problems, such as low image resolution and edge blur. The technology is particularly difficult to apply to industrial detection that requires high imaging speed and high resolution. Therefore, this study proposes a reconstruction algorithm for regions of interest (ROI) in $\gamma $ -photon images. The proposed algorithm is suitable for fast industrial detection and is based on the reconstruction algorithm for sinusoidal graph data, that is, the ordered subset expectation maximization (OSEM) image reconstruction algorithm. It is an improvement of the traditional point-and-line system matrix (SM) model. In the application of the proposed algorithm, the probability weight of a pixel is determined by the solid angle of the crystal bar at both ends of the line of response (LOR) to the pixel it passes through. In this work, the known contour parameters of industrial parts are used to describe the area of nuclide distribution as the ROI. Only the pixels through which the LOR passed in the ROI are counted, and the probability weights of these pixels are calculated to construct the SM. Gaussian filters are added in each iteration to suppress the clutter of scattered noise inside the image. The effectiveness of the algorithm was verified in two model experiments. A closed cavity detection experiment on industrial hydraulic parts was also conducted to compare the image reconstruction effects before and after the improvement. Results showed that the proposed algorithm can effectively improve image resolution and image edge contours. In the tee pipe model experiment and cavity detection experiment on hydraulic parts, the image reconstruction speed increased by more than 6 and 10 times, respectively. Hence, the proposed algorithm provided a feasible solution for quickly obtaining images with clear edges and high resolution under a large aperture detector ring.

With more renewables integrated into power grids, the systems are being transformed into low inertia power electronic dominated systems. In this situation, the virtual synchronous generator (VSG) control strategy was proposed to deal with insufficient inertia challenge caused by the reduction of synchronous generation. However, as the VSG control method emulates the dynamic behavior of traditional synchronous machines, the interaction between multiple VSG controllers and synchronous generators (SGs) may cause low-frequency oscillation similar to that caused by the interaction between multiple SGs. This paper reveals that the system low-frequency oscillatory modes are affected by multiple VSGs. Then Prony analysis is utilized to extract the system mode information which will be subsequently used for VSG controller design, and a decentralized sequential coordinated method is proposed to design the supplementary damping controller (SDC) for multiple VSGs. The system low-frequency oscillation is first analyzed based on a modified two-area system with a linearized state-space model, and a further case study based on a revised New England 10-machine 39-bus system is used to demonstrate the effectiveness of the proposed coordinated method for multiple VSGs.

Positron images generated by positron non-destructive testing technology under rapid detection scenes such as low concentration dose, low exposure time and short imaging time, which have some problems like low-resolution and poor definition. These issues cannot be solved for the being time. To solves these problems, this research super-resolves the low-resolution positron images to generate images with high-resolution and clear details. To make the generated super-resolution images more capable of restoring the features of low- resolution images, this research proposed a positron image super-resolution reconstruction method based on generative adversarial networks. In order to improve the input information utilization rate, long skip connections were added into the generator. In addition, the discriminant model, where composed of an image discriminator and a feature discriminator, can stimulate the generator to generate clearer super-resolution images which contain more details. In attempting to solve the problem of dataset matching, a special positron image super-resolution dataset is constructed for network application scenarios. In the adversarial training stage, perceptual similarity loss and adversarial loss are used to replace the traditional mean squared error loss to improve the images perception quality. Experimental results show that the proposed model can reconstruct low-resolution images by four times super-resolution in 0.16 seconds. The super-resolution images obtained are superior to other algorithms in visual effect, which have clearer detail structure and higher objective performance values. Hence this model can meet the requirements of rapid non-destructive testing of industrial parts.