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The ancient Greek aphorism “know thyself” engraved on the forecourt of the Temple of Apollo epitomizes the human desire for the exploration into the unknown. In fact, never has mankind dragged their feet in understanding themselves, as in the achievements scientists have made all these years in the studies of disease and pathology.

We describe a new species of forest bark beetle, Tomicus armandii Li & Zhang, collected from Pinus armandii in Yunnan, China. We used the D2 fragment of 28S rDNA to improve the taxonomy of Tomicus. The new species can easily be distinguished from the other Tomicus species using the following two morphological characters: punctures of interstria 2 on declivity appearing evenly biseriate or triseriate; erect interstrial setae on the declivity short, about 0.5× as long as distance between striae. The genetic distances of 28S rDNA measured between T. armandii and other species of Tomicus are similar to the distances between other Tomicus species, and these are much higher than intraspecific distances. The phylogenetic analysis of 28S rDNA agrees with the groupings obtained from morphological identification. DNA analysis has commonly been used in Tomicus taxonomy and is helpful for resolving taxon identification problems.

Growing evidence from animal and human studies show that opioids have a major impact on the composition and function of gut microbiota. This leads to disruption in gut permeability and altered microbial metabolites, driving both systemic and neuroinflammation, which in turn impacts central nervous system (CNS) homeostasis. Tolerance and dependence are the major comorbidities associated with prolonged opioid use. Inflammatory mediators and signaling pathways have been implicated in both opioid tolerance and dependence. We provide evidence that targeting the gut microbiome during opioid use through prebiotics, probiotics, antibiotics, and fecal microbial transplantation holds the greatest promise for novel treatments for opioid abuse. Basic research and clinical trials are required to examine what is more efficacious to yield new insights into the role of the gut-brain axis in opioid abuse.

Although liverworts are widely distributed around the world with a large number of extant species, reliable fossil records are relatively rare. Here, we report a new species, Ricciopsis baojishanensis Han and Yan, n. sp. (Ricciaceae) and an unnamed species, Hepaticites sp. from the Late Triassic Nanying’er Formation in Baojishan Basin, Baiyin City, Gansu Province, Northwest China. The generic designation is based on detailed comparison of the gross morphology with related fossil and extant species. The new species is characterized by its rosette-forming thallus, dichotomous branching, ribbon-like segments and entire margins. The current fossils represent the first record of liverwort from the Late Triassic in Baojishan Basin, Gansu Province. Based on the different fossil records of the Ricciaceae, we suggest that these taxa were widely distributed during Late Triassic to Oligocene worldwide, mainly in warm temperate and tropical environments, similar with their current distribution. The discovery of the present fossils indicates that the climate of Baojishan Basin in Late Triassic is warmer and more humid than that of today.

Emerging mutations in SARS-CoV-2 cause several waves of COVID-19 pandemic. Here we investigate the infectivity and antigenicity of ten emerging SARS-CoV-2 variants—B.1.1.298, B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), P.2(Zeta), B.1.429(Epsilon), B.1.525(Eta), B.1.526-1(Iota), B.1.526-2(Iota), B.1.1.318—and seven corresponding single amino acid mutations in the receptor-binding domain using SARS-CoV-2 pseudovirus. The results indicate that the pseudovirus of most of the SARS-CoV-2 variants (except B.1.1.298) display slightly increased infectivity in human and monkey cell lines, especially B.1.351, B.1.525 and B.1.526 in Calu-3 cells. The K417N/T, N501Y, or E484K-carrying variants exhibit significantly increased abilities to infect mouse ACE2-overexpressing cells. The activities of furin, TMPRSS2, and cathepsin L are increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y cause significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines elicited serum is mainly caused by the E484K mutation. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants. Our study provides insights regarding therapeutic antibodies and vaccines, and highlights the importance of E484K mutation., Li Zhang, Zhimin Cui, and Qianqian Li et al. compare the infectivity, host tropism, and antigenicity of 10 SARS-CoV-2 variants using a VSV-based pseudovirus system. Their results suggest that variants carrying E484K display the most significant reduction in sensitivity to neutralization, and may provide further insight into the development of relevant therapeutics for SARS-CoV-2 infection.

Maize (Zea mays L.) is a major economic crop worldwide. Maize can be infected by Alternaria species causing leaf blight that can result in significant economic losses. In this study, 168 Alternaria isolates recovered from symptomatic maize leaves were identified based on morphological characteristics, pathogenicity, and multilocus sequence analyses of the genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH), the internal transcribed spacer of ribosomal DNA (rDNA ITS), the RNA polymerase II second largest subunit (RPB2), and histone3 (HIS3). Maize isolates grouped to four Alternaria species including Alternaria tenuissima, A. alternata, A. burnsii, and Alternaria sp. Notably, A. tenuissima (71.4%) was the most prevalent of the four isolated species, followed by A. alternata (21.5%), Alternaria sp. (4.1%), and A. burnsii (3.0%). Pathogenicity tests showed that all four Alternaria species could produce elliptic to nearly round, or strip, lesions on leaves of maize, gray-white to dry white in the lesion centers and reddish-brown at the edges. The average disease incidence (58.47%) and average disease index (63.55) of maize leaves inoculated with A. alternata were significantly higher than levels resulting from A. tenuissima (55.28% and 58.49), Alternaria sp. (55.34% and 58.75), and A. burnsii (56% and 55). Haplotype analyses indicated that there were 14 haplotypes of A. tenuissima and five haplotypes of A. alternata in Heilongjiang Province and suggested the occurrence of a population expansion. Results of the study showed that Alternaria species associated with maize leaf blight in Heilongjiang Province are more diverse than those that have been previously reported. This is the first report globally of A. tenuissima, A. burnsii, and an unclassified Alternaria species as causal agents of leaf blight on maize.

Background & aims Hepatocellular carcinoma (HCC) is one of the main types of primary liver cancer with high morbidity and mortality, and poor treatment effect. Tripartite motif-containing protein 11 (TRIM11) has been shown to promote tumor formation in lung cancer, breast cancer, gastric cancer, and so on. However, the specific function and mechanism of TRIM11 in HCC have not been elucidated. Approach & results Through clinical analysis, we found that the expression of TRIM11 was upregulated in HCC tissues and was associated with high tumor node metastasis (TNM) stages, advanced histological grade and poor patient survival. Then, by gain- and loss-of-function investigations, we demonstrated that TRIM11 promoted cell proliferation, migration, and invasion in vitro and tumor growth in vivo. Mechanistically, RNA sequencing and mass spectrometry analysis showed that TRIM11 interacted with PH domain leucine rich repeats protein phosphatase 1 (PHLPP1) and promoted K48-linked ubiquitination degradation of PHLPP1, thus promoted activation of protein kinase B (AKT) signaling pathway. Moreover, overexpression of PHLPP1 blocked the promotional effect of TRIM11 on HCC function. Conclusions Our study confirmed that TRIM11 plays an oncogenic role in hepatocellular carcinoma through the PHLPP1/AKT signaling pathway, suggesting that targeting TRIM11 may be a promising target for the treatment of hepatocellular carcinoma.

The ubiquitously-expressed proteolytic enzyme furin is closely related to the pathogenesis of SARS-CoV-2 and therefore represents a key target for antiviral therapy. Based on bioinformatic analysis and pseudovirus tests, we discovered a second functional furin site located in the spike protein. Furin still increased the infectivity of mutated SARS-CoV-2 pseudovirus in 293T-ACE2 cells when the canonical polybasic cleavage site (682–686) was deleted. However, K814A mutation eliminated the enhancing effect of furin on virus infection. Furin inhibitor prevented infection by 682–686-deleted SARS-CoV-2 in 293T-ACE2-furin cells, but not the K814A mutant. K814A mutation did not affect the activity of TMPRSS2 and cathepsin L but did impact the cleavage of S2 into S2′ and cell–cell fusion. Additionally, we showed that this functional furin site exists in RaTG13 from bat and PCoV-GD/GX from pangolin. Therefore, we discovered a new functional furin site that is pivotal in promoting SARS-CoV-2 infection.

Over-substitution of fishmeal with soybean meal (SBM) commonly leads to inferior growth performance and intestinal dysfunction in fish. This study aims to evaluate whether dietary gamma-aminobutyric acid (GABA) could ameliorate the adverse effects in turbot fed a high-SBM diet (HSD). Two hundred and seventy turbots were randomly divided into three treatments fed with a control diet (CNT, containing 60% fishmeal), an HSD (with 45% fishmeal protein replaced by SBM), and an HSD supplemented with GABA (160 mg kg-1) for 53 days. The results displayed that dietary GABA ameliorated HSD-induced growth impairment and enhanced the feed intake of turbot. GABA ameliorated HSD-induced oxidative stress and apoptosis in turbot intestine by restoring the antioxidant parameters (malondialdehyde level, antioxidant enzymes activity and antioxidant mechanism-related genes expression) and expression of apoptosis-related genes (Bcl2, Bax, Bid, and Caspase3) to similar levels to those in the CNT group. GABA alleviated HSD-induced intestinal pathological disruption and inflammatory alterations with significantly decreased mRNA expression of pro-inflammatory cytokines TNF-α and IL-1β and signal molecule NF-κB p65, and elevated mRNA expression of anti-inflammatory cytokine TGF-β1. Furthermore, GABA could act as an intestinal microbiota modulator, which reversed HSD-induced microbiota dysbiosis. Spearman’s correlation analysis indicated that the altered intestinal microbiota was closely associated with the growth performance and intestinal function of turbot. Taken together, GABA ameliorated HSD-induced intestine dysfunction via relieving oxidative stress, inflammation, apoptosis and microbiota dysbiosis, and the findings would contribute to a better understanding for the function of GABA in fish intestine.

As one of the major approaches in combating the COVID-19 pandemics, the availability of specific and reliable assays for the SARS-CoV-2 viral genome and its proteins is essential to identify the infection in suspected populations, make diagnoses in symptomatic or asymptomatic individuals, and determine clearance of the virus after the infection. For these purposes, use of the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) for detection of the viral nucleic acid remains the most valuable in terms of its specificity, fast turn-around, high-throughput capacity, and reliability. It is critical to update the sequences of primers and probes to ensure the detection of newly emerged variants. Various assays for increased levels of IgG or IgM antibodies are available for detecting ongoing or past infection, vaccination responses, and persistence and for identifying high titers of neutralizing antibodies in recovered individuals. Viral genome sequencing is increasingly used for tracing infectious sources, monitoring mutations, and subtype classification and is less valuable in diagnosis because of its capacity and high cost. Nanopore target sequencing with portable options is available for a quick process for sequencing data. Emerging CRISPR-Cas-based assays, such as SHERLOCK and AIOD-CRISPR, for viral genome detection may offer options for prompt and point-of-care detection. Moreover, aptamer-based probes may be multifaceted for developing portable and high-throughput assays with fluorescent or chemiluminescent probes for viral proteins. In conclusion, assays are available for viral genome and protein detection, and the selection of specific assays depends on the purposes of prevention, diagnosis and pandemic control, or monitoring of vaccination efficacy., During the COVID-19 pandemics, sensitive and reliable assays for SARS-CoV-2 detection are essential for screening the population, identifying asymptomatic individuals, making diagnoses, monitoring treatment responses, and determining viral clearance. This review summarizes the principles, advantages, disadvantages, and specific applications of currently available assays for detection of the viral nucleotide, genome or proteins, as well as host antibody responses, and provide overall guidelines for selection of optimal assays for specific usage.

Li Zhang, Xiaoping Li, Jiang Lu, Yi Qian, Tao Qian, Xing Wu, Qinghua Xu Department of Hepatobiliary and Pancreatic Surgery, LiYang People’s Hospital, LiYang, 213300, Jiangsu, People’s Republic of ChinaCorrespondence: Qinghua Xu; Xing WuDepartment of Hepatobiliary and Pancreatic Surgery, LiYang People’s Hospital, 70# JianShe West Road, LiYang, 213300, Jiangsu, People’s Republic of ChinaTel/Fax +86-519-68091108Email xqh7888882@163.com; sxj6628@126.comBackground: Previous studies have shown that epidermal growth factor receptor (EGFR) promotes cell proliferation through the PI3K-Akt-mTOR signaling pathway and participates in the occurrence and development of hepatocellular carcinoma (HCC). Here, we focused on the functional polymorphism of EGFR in the 3ʹ-untranslated region (UTR), aiming to reveal the potential mechanisms by which functional polymorphism is associated with the risk and development of HCC in the Han Chinese population.Methods: This study was a hospital-based case-control study. A total of 600 patients were enrolled, and another 600 healthy volunteers served as controls. The miR-associated SNPs in EGFR were screened, and genotyping was performed by TaqMan allele differential analysis. In this study, genotyping, real-time PCR, cell transfection and double luciferase reporter gene were used for subsequent analysis.Results: HBV/HCV infection instead of alcohol exposure, smoking exposure, hypertension or diabetes mellitus was associated with an increased risk of HCC. Compared with TT genotypes, TG and GG genotypes of EGFR rs884225 were significantly associated with reduced HCC risk. The stratified analysis of association between rs884225 and HCC subgroup feature reveal a highly correlation with tumor size. Furthermore, qRT-PCR confirmed that EGFR rs884225, TG and GG genotypes were more likely to bind to miR-3196 and down-regulate EGFR level in cells, thereby inhibiting cell proliferation.Conclusion: This study suggested that EGFR rs884225 is associated with a reduced risk of liver cancer and may be a developing biomarker.Keywords: miR-3196, polymorphism, proliferation, hepatocellular carcinoma, HCC, epidermal growth factor receptor, EGFR

Severe acute respiratory syndrome coronavirus 2 variants have continued to emerge in diverse geographic locations with a temporal distribution. The Lambda variant containing multiple mutations in the spike protein, has thus far appeared mainly in South America. The variant harbours two mutations in the receptor binding domain, L452Q and F490S, which may change its infectivity and antigenicity to neutralizing antibodies. In this study, we constructed 10 pseudoviruses to study the Lambda variant and each individual amino acid mutation's effect on viral function, and used eight cell lines to study variant infectivity. In total, 12 monoclonal antibodies, 14 convalescent sera, and 23 immunized sera induced by mRNA vaccines, inactivated vaccine, and adenovirus type 5 vector vaccine were used to study the antigenicity of the Lambda variant. We found that compared with the D614G reference strain, Lambda demonstrated enhanced infectivity of Calu-3 and LLC-MK2 cells by 3.3-fold and 1.6-fold, respectively. Notably, the sensitivity of the Lambda variant to 5 of 12 neutralizing monoclonal antibodies, 9G11, AM180, R126, X593, and AbG3, was substantially diminished. Furthermore, convalescent- and vaccine-immunized sera showed on average 1.3–2.5-fold lower neutralizing titres against the Lambda variant. Single mutation analysis revealed that this reduction in neutralization was caused by L452Q and F490S mutations. Collectively, the reduced neutralization ability of the Lambda variant suggests that the efficacy of monoclonal antibodies and vaccines may be compromised during the current pandemic.

Multiple myeloma, a plasma cell malignancy in the bone marrow, remains largely incurable with currently available therapeutics. In this study, we discovered that the activated leukocyte cell adhesion molecule (ALCAM) interacted with epidermal growth factor receptor (EGFR), and regulated myelomagenesis. ALCAM was a negative regulator of myeloma clonogenicity. ALCAM expression was positively correlated with patients’ survival. ALCAM-knockdown myeloma cells displayed enhanced colony formation in the presence of bone marrow stromal cells (BMSCs). BMSCs supported myeloma colony formation by secreted epidermal growth factor (EGF), which bound with its receptor (EGFR) on myeloma cells and activated Mek/Erk cell signaling, PI3K/Akt cell signaling, and hedgehog pathway. ALCAM could also bind with EGFR, block EGF from binding to EGFR, and abolish EGFR-initiated cell signaling. Hence, our study identifies ALCAM as a novel negative regulator of myeloma pathogenesis.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal gastrointestinal malignancies with high mortality. Recurrence develops within only a few years after curative resection and perioperative adjuvant therapy in 30–50% of these patients. Therefore, it is essential to identify postoperative recurrence biomarkers to facilitate selecting the following surveillance and therapeutic strategies. The general transcription factor IIE subunit beta (GTF2E2) is crucial for physiological and pathological functions, but its roles in the aggression and recurrence of ESCC remain ambiguous. In this study, we found that GTF2E2 was highly expressed in ESCC samples, and elevated GTF2E2 expression predicted early recurrence after surgery for ESCC patients. High expression of GTF2E2 associated with more aggressive clinic features and poor prognosis. GTF2E2 promoted the proliferation and mobility of ESCC cells in vitro and in vivo. We further revealed that miR-139-5p repressed GTF2E2 expression by downregulating its mRNA through binding with Argonaute 2 (Ago2). Rescue assays suggested that miR-139-5p affected GTF2E2-mediated ESCC progression. Moreover, GTF2E2 positively interacted with FUS promoter and regulated FUS expression, and the phenotype changes caused by GTF2E2 manipulation were recovered by rescuing FUS expression in ESCC cells. Additionally, we demonstrated that GTF2E2 promotes ESCC cells progression via activation of the AKT/ERK/mTOR pathway. In conclusion, GTF2E2 may serve as a novel biomarker for recurrence after surgery and a potential therapeutic target for ESCC patients, and it promotes ESCC progression via miR-139-5p/GTF2E2/FUS axis.

Bacterial sample preparation is crucial for its observation by scanning electron microscopy (SEM). However, the current polylysine (PLL) method leads to bacterial morphological changes. To overcome this problem, we employed chitosan (CS) to coat coverslips to prepare bacteria for SEM and compared it with the PLL method. Coverslips coated with 0.025% (w/v) CS showed satisfactory bacterial binding ability. Within 30 min of binding time, the number of bacteria on CS-coated and PLL-coated coverslips exhibited no differences. Four bacteria strains were employed to compare the differences in SEM images between the two methods. Most of the bacteria showed irregular surface or sticky substances after settling on PLL-coated coverslips, while bacteria with clear surface texture were observed on CS-coated coverslips. Transmission electron microscopy (TEM) images showed deformed bacterial envelope on PLL-coated coverslips; meanwhile, similar intact envelope was observed from the bacteria on CS-coated coverslips and the bacteria without any treatment. The TEM results verified the morphological differences of SEM between the two methods. Except for morphology, the length of the rod-shaped bacteria was longer on CS-coated coverslips than that on PLL-coated coverslips, less shrinkage of the sample was observed, and CS could preserve the length of the rod-shaped bacteria better than PLL in its preparation for SEM. It is demonstrated that the low-cost CS could be utilized in bacterial preparation for SEM to acquire preferable images. Bacterial suspension with optical density at 600 nm of about 0.5, deposited on 0.025% CS-coated coverslips for 30 min, and followed by routine fixation, dehydration, and drying are optimal parameters.

Silver nanoparticles (AgNPs) are effective antimicrobial compounds that are used in a myriad of applications. Soil microorganisms play crucial roles in nitrogen cycling, but there is a lack of comprehensive understanding of the effects of AgNPs on enzymatic activity in the nitrogen cycle, nitrifying bacteria, and nitrogen transformation in soil. Herein, enzyme activities were determined following the addition of different forms of nitrogen, ammonium nitrogen ((NH4)2SO4), nitrate nitrogen (KNO3), and amide nitrogen (urea, CO(NH2)2) at 200 mg N kg–1, into the soil amended with AgNPs at 0, 10, 50, and 100 mg kg–1. After 7 d of incubation with 10 mg kg–1 AgNPs, the activities of urease, nitrite reductase (NiR), nitrate reductase (NaR), and hydroxylamine reductase (HyR) were reduced by 12.5%, 25.0%, 12.2%, and 24.2%, respectively. Of particular note, more than 53.5%, 61.7%, and 34.7% of NaR, NiR, and HyR activities, respectively, were inhibited at 100 mg kg–1 AgNPs. The abundance (most probable number) of ammonia- and nitrite-oxidizing bacteria (AOB and NOB, respectively) was measured using real-time quantitative polymerase chain reaction (qPCR) and the Cochran method. The abundance of AOB and NOB decreased when AgNPs were present in the soil. The NH4NO3 amendment increased copy numbers of bacterial and archaeal amoA nitrification functional genes, by 38.3% and 12.4%, respectively, but AgNPs at 50 mg kg–1 decreased these values by 70% and 56.4%, respectively. The results of 15N enrichment (atom% excess) of NH4+ and NO3– experiments illustrated the influence of AgNPs on soil nitrogen transformation. According to the 15N atom% excess detected, the conversion of 15N-labeled NH4+ to NO3– was significantly inhibited by the different levels of AgNPs in soil. The reduced gross nitrification rate further confirmed this finding. Overall, this study revealed considerable evidence that AgNPs inhibited nitrogen cycle enzyme activity, the number of nitrifying bacteria, the abundance of the amoA gene, and the gross nitrification rate. Silver nanoparticles inhibited nitrogen transformation, and the rate of nitrification was also negatively correlated with AgNP levels.

Wei-Wei Liu, Wei-Dong Li, Yan-Ju Zhang, Man-Li Zhang Breast Center, Cangzhou People’s Hospital, Cangzhou 061000, Hebei Province, People’s Republic of ChinaCorrespondence: Man-Li ZhangBreast Center, Cangzhou People’s Hospital, Intersection of Chongqing Road and Jilin North Road, Yunhe District, Cangzhou 061000, Hebei Province, People’s Republic of ChinaTel +86-135-6645-8334Email manko8866@126.comObjective: To explore the regulatory role of miR497-5p–CCNE1 axis in triple-negative breast cancer (TNBC) cells and its predictive value for early diagnosis.Methods: Cancer tissue and adjacent tissue samples were collected from 86 patients with TNBC.RT-PCR was used to detect the expression of miR497-5p and CCNE1 (target gene) mRNA, determined by biological prediction in tissue and TNBC cells. ROC was used to analyze the diagnostic value of miR497-5p in TNBC. MTT, invasion, and flow cytometry were used to detect the proliferation, invasion, cycle, apoptosis rate, and expression of related proteins of TNBC cells with overexpression of miR497-5p or knockdown of CCNE1.Results: RT-qPCR results showed that miR497-5p levels were significantly downregulated in TNBC tissue and cells, while CCNE1 expression was significantly upregulated, and miR497-5p expression was negatively correlated with that of CCNE1 (P< 0.001). ROC analysis showed that the AUC of miR497-5p for TNBC was > 0.9, which had better diagnostic value. The cell tests revealed that miR497-5p played a role in tumor inhibition, including inhibiting proliferation and invasion of TNBC cells, blocking the cell cycle, and promoting apoptosis. Bioinformatic prediction and subsequent experiments revealed that CCNE1 was the direct target of miR497-5p. Furthermore, after knocking down the expression of CCNE1 in TNBC cells, the proliferation and invasion of TNBC cells were significantly inhibited, the cell cycle blocked, and the apoptosis rate significantly increased (P< 0.001), and expression of the proapoptosis-related proteins Bax and caspase 3 (cleaved) were upregulated, while expression of the antiapoptosis-related protein BCL2 was downregulated (P< 0.001).Conclusion: miR497-5p inhibited the proliferation and invasion of TNBC cells by targeting CCNE1, blocked the cell cycle and promoted the apoptosis of TNBC cells, and had better diagnostic value for TNBC. miR497-5p can be used as a new potential target for the treatment of TNBC.Keywords: miR497-5p, TNBC, CCNE1, proliferation, invasion, apoptosis

To develop new antifungal agents against phytopathogenic fungi, a series of citral-thiazolyl hydrazine derivatives were designed, synthesized, and characterized by FT-IR, 1H NMR, 13C NMR, and HRMS. Antifungal activity results showed that most synthetic compounds exhibited broad-spectrum antifungal activities against six phytopathogenic fungi in vitro. Notably, compounds b and c15 exhibited remarkable antifungal activity against Colletotrichum gloeosprioides, Rhizoctonia solani, Phytophthora nicotianae var. nicotianae, Diplodia pinea, Colletotrichum acutatum, and Fusarium oxysporum f. sp. niveum, which were all superior to the positive control tricyclazole. Structure-activity relationship (SAR) studies demonstrated that introducing electron-withdrawing groups such as F on the benzene ring exhibited outstanding antifungal activities against all the tested fungi. Furthermore, compound b could effectively control rice sheath blight and showed higher curative activities against R. solani than validamycin·bacillus in vivo. In addition, the in vitro cytotoxicity results indicated that compound b possessed moderate cytotoxicity activity, and all citral-thiazolyl hydrazine derivatives exhibited lower or no cytotoxicity to the LO2 and HEK293 cell lines. In addition, the acute oral toxicity test showed that compound b had moderate toxicity (level II) with an LD50 value of 310 mg/kg bw (95% confidence limit: 175-550 mg/kg bw). Finally, a preliminary action mechanism study showed that causing obvious malformation of mycelium and increasing cell membrane permeability are two of the potential mechanisms by which compound b exerts antifungal activity. The present work indicates that some of these derivatives may serve as novel potential fungicides, and compound b is expected to be the leading structure for the development of new antifungal agents.

During a screening for novel and useful actinobacteria in desert animal, a new actinomycete was isolated and designated strain TRM63209T. The strain was isolated from in vivo of a Blattella germanica in Tarim University in Alar City, Xinjiang, north-west China. The strain was found to exhibit an inhibitory effect on biofilm formation by Candida albicans ATCC 18,804. The strain was observed to form abundant aerial mycelium, occasionally twisted and which differentiated into spiral spore chains. Spores of TRM63209T were observed to be oval-shaped, with a smooth surface. Strain TRM63209T was found to grow optimally at 28 °C, pH 8 and in the presence of 1% (w/v) NaCl. The whole-cell sugars of strain TRM63209T were rhamnose ribose, xylose, mannose, galactose and glucose, and the principal polarlipids were found to be diphosphatidylglycerol, phos-phatidylethanolamine, phosphatidylcholine, phosphatidylinositol mannoside, phosphatidylinositol and an unknown phospholipid(L). The diagnostic cell wall amino acid was identified as LL-diaminopimelic acid. The predominant menaquinone was found to be MK-9(H6) (14.64%), MK-9(H2) (19.65%), MK-9(H8) (22.34%), MK-10(H2) (25.37%). The major cellular fatty acids were identified as iso-C16:0, 16:0, anteiso-C15:0, anteiso-C17:0, iso-C15:0 and Sum in Feature 3. Analysis of the 16S rRNA sequence showed that strain TRM63209T exhibits high sequence similarity to Streptomyces bungoensis strain DSM 41781T 98.20%. A multi-locus sequence analysis of five house-keeping genes (atpD, gyrB, rpoB, recA and trpB) and phylogenomic analysis also illustrated that strain TRM63209T should be assigned to the genus Streptomyces. The DNA G + C content of the strain was determined to be 70.2 mol%. Average nucleotide identity (ANI) between strain TRM63209T and S. bungoensis DSM 41781T, Streptomyces phyllanthi PA1-07T, Streptomyces longwoodensis DSM 41677T and Streptomyces caeruleatus NRRL B-24802T were 82.76%, 82.54%, 82.65%, 84.02%, respectively. Digtal DNA-DNA (dDDH) hybridization were 26.30%, 25.10%, 26.20%, 29.50%, respectively. Therefore, it is concluded that strain TRM63209T represents a novel species of the genus Streptomyces, for which the name Streptomyces blattelae is proposed. The type strain is TRM63209T (CCTCC AA 2018093T = LMG 31,403 = TRM63209T).

BACKGROUND AND PURPOSE In chronic kidney disease (CKD), patients inevitably reach end-stage renal disease and require renal transplant. Evidence suggests that CKD is associated with metabolite disorders. However, the molecular pathways targeted by metabolites remain enigmatic. Here, we describe roles of 1-hydroxypyrene in mediating renal fibrosis. EXPERIMENTAL APPROACH We analysed 5406 urine and serum samples from patients with Stage 1-5 CKD using metabolomics, and 1-hydroxypyrene was identified and validated using longitudinal and drug intervention cohorts as well as 5/6 nephrectomised and adenine-induced rats. KEY RESULTS We identified correlations between the urine and serum levels of 1-hydroxypyrene and the estimated GFR in patients with CKD onset and progression. Moreover, increased 1-hydroxypyrene levels in serum and kidney tissues correlated with decreased renal function in two rat models. Up-regulated mRNA expression of aryl hydrocarbon receptor and its target genes, including CYP1A1, CYP1A2 and CYP1B1, were observed in patients and rats with progressive CKD. Further we showed up-regulated mRNA expression of aryl hydrocarbon receptor and its three target genes, plus up-regulated nuclear aryl hydrocarbon receptor protein levels in mice and HK-2 cells treated with 1-hydroxypyrene, which caused accumulation of extracellular matrix components. Treatment with aryl hydrocarbon receptor short hairpin RNA or flavonoids inhibited mRNA expression of aryl hydrocarbon receptor and its target genes in 1-hydroxypyrene-induced HK-2 cells and mice. CONCLUSION AND IMPLICATIONS Metabolite 1-hydroxypyrene was demonstrated to mediate renal fibrosis through activation of the aryl hydrocarbon receptor signalling pathway. Targeting aryl hydrocarbon receptor may be an alternative therapeutic strategy for CKD progression.

The aim of this study was to compare the differences of dietary tea leaves (TL) and tea residue (TR) inclusion on rumen fermentation characteristics and to explore whether TR could be an alternative feedstuff of ruminants. For these purposes, seven treatments consisted of two inclusion types (TL vs. TR) and three inclusion levels (g/g of dry matter basis) of 10% (TL10/TR10), 20% (TL20/TR20), and 30% (TL30/TR30) in each inclusion type, plus control group with inclusion of 0% (CON) were designed, with four replicates in each group, to conduct an in vitro ruminal fermentation test. Results showed that the contents of crude protein, neutral detergent fiber, and acid detergent fiber were higher in TR than TL, while TL contained more ether extract and crude ash than TR. Interaction effects between inclusion type and inclusion level were observed in concentrations of isobutyrate and microbial crude protein (MCP), as well as in gas production and digestibility of organic matter. Fermentation characteristics were significantly influenced by TL and TR depending on the inclusion level, except for the concentration of total branched-chain volatile fatty acid. These significant differences of fermentation characteristics due to inclusion level mainly focused on CON and tea inclusion, with higher values in CON than TR or TL groups. The total gas production during the 48-h incubation showed no differences among CON, TL10, and TR10. The inclusion of TR and TL decreased the production of methane. The concentration of MCP in CON, TR10 and TR30 was lower than TR20 and all TL groups. In conclusion, dietary inclusion of TR and TL possessed equivalent effect on rumen fermentation characteristics and methane production, substituting diet with TR or TL for over 10% would inhibit rumen fermentation despite positive effects in TR20 and all TL groups regarding more MCP and less methane production. This study indicates that special attention should be paid to the inclusion level of TR and TL when considering them as alternative feedstuffs of ruminants. Further in vivo study is needed to evaluate the applicability of tea residue as a feedstuff for production of ruminants.

Background Esophageal cancer is the fifth most common cancer affecting men in China. The primary treatment options are surgery and traditional radio-chemotherapy; no effective targeted therapy exists yet. Self-assembled RNA nanocarriers are highly stable, easily functionally modified, and have weak off-tumor targeting effects. Thus, they are among the most preferred carriers for mediating the targeted delivery of anti-tumor drugs. miR-375 was found to be significantly down-regulated in esophageal squamous cell carcinoma (ESCC) tissues and its overexpression effectively inhibits the proliferation, migration, and invasion of ESCC cells. Moreover, epidermal growth factor receptor (EGFR) was overexpressed in ESCC cells, and accumulation of RNA nanoparticles in ESCC tumors was enhanced by EGFR-specific aptamer (EGFRapt) modification. Results Herein, a novel four-way junction RNA nanocarrier, 4WJ-EGFRapt-miR-375-PTX simultaneously loaded with miR-375, PTX and decorated with EGFRapt, was developed. In vitro analysis demonstrated that 4WJ-EGFRapt-miR-375-PTX possesses strong thermal and pH stabilities. EGFRapt decoration facilitated tumor cell endocytosis and promoted deep penetration into 3D-ESCC spheroids. Xenograft mouse model for ESCC confirmed that 4WJ-EGFRapt-miR-375-PTX was selectively distributed in tumor sites via EGFRapt-mediating active targeting and targeted co-delivery of miR-375 and PTX exhibited more effective therapeutic efficacy with low systemic toxicity. Conclusion This strategy may provide a practical approach for targeted therapy of ESCC. Graphical Abstract

Polybrominated diphenyl ethers (PBDEs) are persistent organic pollutants. They are constantly detected in terrestrial, ocean, and atmospheric systems, and it is of particular concern that these fat-soluble xenobiotics may have a negative impact on human health. This study aimed to evaluate the toxic effect and underlying mechanism of decabromodiphenyl ether (BDE-209) on human liver in a HepG2 cell model. The results showed that BDE-209 significantly induced HepG2 cells apoptosis, increased intracellular reactive oxygen species (ROS), disturbed [Ca 2+] homeostasis and mitochondrial membrane potential (MMP), and caused nuclear shrinkage and DNA double-strand breaks. BDE-209 also significantly decreased the activities of antioxidant parameters, superoxide dismutase (SOD), total antioxygenic capacity (T-AOC), glutathione (GSH), and total glutathione (T-GSH). The up-regulation of the Aryl hydrocarbon receptor (AhR)/cytochrome P4501A1 (CYP1A1) signaling pathway indicates that after long-term and high-dose exposure, BDE-209 may be a liver carcinogen. Interestingly, HepG2 cells attempt to metabolize BDE-209 through the Nrf2-mediated antioxidant pathway. These findings help elucidate the mechanisms of BDE-209-induced hepatotoxicity in humans.

Sepsis has become a major public health problem worldwide. Methylprednisolone sodium succinate (MP) is a commonly used drug to prevent inflammation. However, the role and underlying mechanism of MP in sepsis remain vague. MP inhibited the lipopolysaccharide (LPS)-induced production of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-17 and suppressed cell growth in alveolar type II epithelial cells (ATII cells). Small nucleolar RNA host gene 5 (SNHG5) expression was inhibited by LPS and restored by MP. Upregulation of SNHG5 inhibited the cellular role of LPS in ATII cells, and further, downregulation of SNHG5 inhibited the cellular role of MP in ATII cells under LPS conditions. SNHG5 elevated the expression of Copine 1 (CPNE1) by enhancing the mRNA stability of CPNE1. Increasing CPNE1 expression restored the silenced SNHG5-induced inhibitor role of MP in ATII cells under LPS conditions. Finally, MP attenuated lung injury and TNF-α and IL-17 secretion in an LPS-induced sepsis mouse model. Overall, this study investigated the mechanism underlying the effect of MP treatment in sepsis and, for the first time, revealed the important role of the SNHG5/CPNE1 pathway in the development and treatment of sepsis and the potential to serve as a diagnostic and therapeutic target for sepsis.

Summary Mouse embryonic stem cells (ESCs) show cell-to-cell heterogeneity. A small number of two-cell-like cells (2CLCs) marked by endogenous retrovirus activation emerge spontaneously. The 2CLCs are unstable and they are prone to transiting back to the pluripotent state without extrinsic stimulus. To understand how this bidirectional transition takes place, we performed single-cell RNA sequencing on isolated 2CLCs that underwent 2C-like state exit and re-entry, and revealed a step-by-step transitional process between 2C-like and pluripotent states. Mechanistically, we found that cell cycle played an important role in mediating these transitions by regulating assembly of the nucleolus and peri-nucleolar heterochromatin to influence 2C gene Dux expression. Collectively, our findings provide a roadmap of the 2C-like state entry and exit in ESCs and also a causal role of the cell cycle in promoting these transitions., Highlights • The entry to and exit from the 2C-like state showed a step-by-step roadmap • Cell cycle participates in mediating dynamic transitions between ESCs and 2CLCs • G1/S phase arrest facilitates the Dux locus escape from heterochromatin • Nucleolus-heterochromatin remodeling is involved in 2C activation, In this article, Jin Zhang and colleagues show that cell-cycle variations distinguish 2CLCs, ESCs, and the intermediate states using single-cell RNA-seq. They found that cell-cycle-associated remodeling of nucleoli and peri-nucleolar heterochromatin was involved in the regulation of the 2C program. They provide novel advances in the fundamental field of 2C activation and stem cell fate decision.

Genes related to human longevity have not been studied so far, and need to be investigated thoroughly. This study aims to explore the relationship among ABO gene variants, lipid levels, and longevity phenotype in individuals (≥90yrs old) without adverse outcomes. A genotype-phenotype study was performed based on 5803 longevity subjects and 7026 younger controls from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Four ABO gene variants associated with healthy longevity (rs8176719 C, rs687621 G, rs643434 A, and rs505922 C) were identified and replicated in the CLHLS GWAS data analysis and found significantly higher in longevity individuals than controls. The Bonferroni adjusted p-value and OR range were 0.013-0.020 and 1.126-1.151, respectively. According to the results of linkage disequilibrium (LD) analysis, the above four variants formed a block on the ABO gene (D'=1, r2range = 0.585-0.995). The carriers with genotypes rs687621 GG, rs643434 AX, or rs505922 CX (prange = 2.728 x 10-107-5.940 x 10-14; ORrange = 1.004-4.354) and haplotype CGAC/XGXX (p = 2.557 x 10-27; OR = 2.255) had a substantial connection with longevity, according to the results of genetic model analysis. Following the genotype and metabolic phenotype analysis, it has been shown that the longevity individuals with rs687621 GG, rs643434 AX, and rs505922 CX had a positive association with HDL-c, LDL-c, TC, TG (prange = 2.200 x 10-5-0.036, ORrange = 1.546-1.709), and BMI normal level (prange = 2.690 x 10-4-0.026, ORrange = 1.530-1.997). Finally, two pathways involving vWF/ADAMTS13 and the inflammatory markers (sE-selectin/ICAM1) that co-regulated lipid levels by glycosylation and effects on each other were speculated. In conclusion, the association between the identified longevity-associated ABO variants and better health lipid profile was elucidated, thus the findings can help in maintaining normal lipid metabolic phenotypes in the longevity population.

Anaplastic thyroid cancer (ATC) is a rare but highly lethal disease. ATCs are resistant to standard therapies and are extremely difficult to manage. The stepwise cell dedifferentiation results in the impairment of the iodine-metabolizing machinery and the infeasibility of radioiodine treatment in ATC. Hence, reinducing iodine-metabolizing gene expression to restore radioiodine avidity is considered as a promising strategy to fight against ATC. In the present study, capsaicin (CAP), a natural potent transient receptor potential vanilloid type 1 (TRPV1) agonist, was discovered to reinduce ATC cell differentiation and to increase the expression of thyroid transcription factors (TTFs including TTF-1, TTF-2, and PAX8) and iodine-metabolizing proteins, including thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase, and sodium iodine symporter (NIS), in two ATC cell lines, 8505C and FRO. Strikingly, CAP treatment promoted NIS glycosylation and its membrane trafficking, resulting in a significant enhancement of radioiodine uptake of ATC cells in vitro. Mechanistically, CAP-activated TRPV1 channel and subsequently triggered Ca2+ influx, cyclic adenosine monophosphate (cAMP) generation, and cAMP-responsive element-binding protein (CREB) signal activation. Next, CREB recognized and bound to the promoter of SLC5A5 to facilitate its transcription. Moreover, the TRPV1 antagonist CPZ, the calcium chelator BAPTA, and the PKA inhibitor H-89 effectively alleviated the redifferentiation exerted by CAP, demonstrating that CAP might improve radioiodine avidity through the activation of the TRPV1‒Ca2+/cAMP/PKA/CREB signaling pathway. In addition, our study indicated that CAP might trigger a novel cascade to redifferentiate ATC cells and provide unprecedented opportunities for radioiodine therapy in ATC, bypassing canonical TSH‒TSHR pathway.

BACKGROUND: Inappropriate macrophages phenotype transition contributes to the development of ulcerative colitis, and the poly (ethylene glycol)-block-poly (d, l-lactic acid) (PEG-PLA) nanoparticles delivery system can be utilized to improve the cryptotanshinone (CTS)-based therapy. METHODS: We used a single emulsification method to prepare CTS-encapsulated nanoparticles (NP(CTS)). The therapeutic efficacy of NP(CTS) was evaluated in dextran sulfate sodium (DSS)-induced colitis mice. Then the proportion of total macrophages and M2-like macrophages were assayed with flow cytometry, and the relative content of pro-inflammatory cytokines in the colon was detected with Western blot. Bone-marrow-derived macrophages (BMDMs) were induced into M1-like macrophages, which were further incubated with NP(CTS) to repolarize into M2 subtype(.) RESULTS: Cryptotanshinone could induce the transition of M1 subtype to M2 subtype as indicated by up-regulated expression of arginase 1 (ARG1), interleukin (IL)-10, and CD206. In vivo, orally administrated NP(CTS) accumulated in the colon-infiltrated macrophages in colitis mice. It further revealed that NP(CTS) significantly alleviated colitis symptoms as indicated by increased body weight and colon length, decreased tumor necrosis factor (TNF)-α, IL-1β, and IL-6 content in the colon, and diminished total macrophage proportion (CD45(+)CD11b(+)F4/80(+)) and up-regulated M2 proportion (CD45(+)CD11b(+)F4/80(+)CD206(hi)). CONCLUSION: Oral administration of NP(CTS) could ameliorate ulcerative colitis with the conversion of M1-like macrophages to M2-like macrophages.

Under the variant climate conditions in the transitional regions between tropics and subtropics, the impacts of climate factors on influenza subtypes have rarely been evaluated. With the available influenza A (Flu-A) and influenza B (Flu-B) outbreak data in Shenzhen, China, which is an excellent example of a transitional marine climate, the associations of multiple climate variables with these outbreaks were explored in this study. Daily laboratory-confirmed influenza virus and climate data were collected from 2009 to 2015. Potential impacts of daily mean/maximum/minimum temperatures (T/Tmax/Tmin), relative humidity (RH), wind velocity (V), and diurnal temperature range (DTR) were analyzed using the distributed lag nonlinear model (DLNM) and generalized additive model (GAM). Under its local climate partitions, Flu-A mainly prevailed in summer months (May to June), and a second peak appeared in early winter (December to January). Flu-B outbreaks usually occurred in transitional seasons, especially in autumn. Although low temperature caused an instant increase in both Flu-A and Flu-B risks, its effect could persist for up to 10 days for Flu-B and peak at 17 C (relative risk (RR) = 14.16, 95% CI: 7.46–26.88). For both subtypes, moderate–high temperature (28 C) had a significant but delayed effect on influenza, especially for Flu-A (RR = 26.20, 95% CI: 13.22–51.20). The Flu-A virus was sensitive to RH higher than 76%, while higher Flu-B risks were observed at both low ( 83%) humidity. Flu-A was active for a short term after exposure to large DTR (e.g., DTR = 10 C, RR = 12.45, 95% CI: 6.50–23.87), whereas Flu-B mainly circulated under stable temperatures. Although the overall wind speed in Shenzhen was low, moderate wind (2–3 m/s) was found to favor the outbreaks of both subtypes. This study revealed the thresholds of various climatic variables promoting influenza outbreaks, as well as the distinctions between the flu subtypes. These data can be helpful in predicting seasonal influenza outbreaks and minimizing the impacts, based on integrated forecast systems coupled with short-term climate models. Supplementary Information The online version contains supplementary material available at 10.1007/s00484-021-02204-y.

Previous studies showed that ORANGE (OR) plays a key role in carotenoid biosynthesis and response to various stress. In this study, we present our discovery of the role of Arabidopsis ORANGE (AtOR) in regulating the ABA-dependent adaptive response to drought stress. For drought tolerance treatment, two weeks old seedlings were transplanted to pots filled with compost soil and subjected to progressive drought treatment for 20 days and re-watered for 2 days. The growth conditions of Arabidopsis were recorded after drought treatment and survival rates were analyzed after re-watering. Quantitative RT-PCR was used to investigate the transcripts levels of AtOR gene under different treatment conditions. Subcellular localization results were obtained by laser scanning confocal microscopy. Overexpression of AtOR significantly enhanced the tolerance to drought stress in Arabidopsis and AtOR was induced by drought and mannitol stresses. Compared with the Col-0 plants, overexpression lines showed slower water loss and smaller stomatal pore size after ABA treatment. Subcellular localization imaging showed that AtOR protein was localized in the chloroplasts. AtOR regulates the expression of ABA- and stress-responsive genes (RAB18, RD29B, RD26, ADH1, ABI2, ABF2) to enhance the tolerance to drought stress.

The use of anti-programmed cell death-1 (PD-1) antibodies in treating malignancies is increasing; however, most registered clinical trials on anti-PD-1 antibodies exclude patients infected with hepatitis B virus (HBV). This retrospective study aimed to assess hepatotoxicity in cancer patients infected with HBV undergoing anti-PD1 antibody therapy and identify the associated risk factors. A total of 301 cancer patients positive for hepatitis B core antibodies (HbcAb) (negative or positive hepatitis B surface antigen [HBsAg]) who received PD-1 inhibitors were enrolled. The primary and secondary endpoints were the incidence rate of hepatotoxicity related to PD-1 inhibitor treatment, and risk factors associated with hepatic toxicity, respectively. Of the enrolled analyzed, 16.9% (n = 51) developed any grade and 4.7% (n = 14) developed grade 3-4 hepatotoxicity, respectively. Higher risk for any-grade hepatotoxicity development was associated with sero-positive HBsAg (OR = 6.30; P = 0.020), existence of liver involvement (OR = 2.10; P = 0.030), and detectable baseline HBV DNA levels (OR = 2.39; P = 0.012). Patients with prophylactic antiviral therapy decreased hazard for the incidence of grade 3-4 hepatotoxicity (OR = 0.10; P = 0.016). Our results suggested chronic (HBsAg-positive)/resolved (HBsAg-negative and HBcAb-positive) HBV-infected cancer patients are at an increased risk of hepatotoxicity following PD-1 inhibitor therapy. Cancer patients should be tested for HBsAg/HBcAb prior to the commencement of immune checkpoint inhibitor therapy. For patients with chronic/resolved HBV infection, ALT/AST and HBV DNA should be closely monitored during the whole immunotherapy period.

In response to brain injury, resident astrocytes become reactive and play dynamic roles in neural repair and regeneration. The signaling pathways underlying such reactive astrogliosis remain largely unclear. We here show that NEK6, a NIMA-related serine/threonine protein kinase, is rapidly induced following pathological stimulations and plays critical roles in reactive astrogliosis. Enhanced NEK6 expression promotes reactive astrogliosis and exacerbates brain lesions; and conversely, NEK6 downregulation dampens injury-induced astrocyte reactivity and reduces lesion size. Mechanistically, NEK6 associates with and phosphorylates STAT3. Kinase activity of NEK6 is required for induction of GFAP and PCNA, markers of reactive astrogliosis. Interestingly, NEK6 is also localized in the nucleus and binds to STAT3-responsive genomic elements in astrocytes. These results indicate that NEK6 constitutes a molecular target for the regulation of reactive astrogliosis.

Cancer metastasis accounts for nearly 90% of all cancer deaths. Metastatic cancer progression requires both cancer cell migration to the site of the metastasis and subsequent proliferation after colonization. However, it has long been recognized that cancer cell migration and proliferation can be uncoupled; but the mechanism underlying this paradox is not well understood. Here we report that TNFAIP8 (tumor necrosis factor-α-induced protein 8), a “professional” transfer protein of phosphoinositide second messengers, promotes cancer cell migration or metastasis but inhibits its proliferation or cancer growth. TNFAIP8-deficient mice developed larger tumors, but TNFAIP8-deficient tumor cells completely lost their ability to migrate toward chemoattractants and were defective in colonizing lung tissues as compared to wild-type counterparts. Mechanistically, TNFAIP8 served as a cellular “pilot” of tumor cell migration by locally amplifying PI3K–AKT and Rac signals on the cell membrane facing chemoattractant; at the same time, TNFAIP8 also acted as a global inhibitor of tumor cell growth and proliferation by regulating Hippo signaling pathway. These findings help explain the migration–proliferation paradox of cancer cells that characterizes many cancers.

Purpose: Incidence of contrast induced nephropathy (CIN) and related risk factors in patients with liver cancer and chronic kidney disease after trans-catheter arterial chemoembolization (TACE) is higher. The purpose of this study was to investigate the feasibility and safety of TACE therapy in such patients. Methods: A retrospective analysis was performed on 103 patients with liver cancer and chronic kidney disease who underwent TACE treatments. TACE was performed according to Seldinger’s technique of arterial embolization with minor modifications. Based on CIN diagnostic criteria, patients were divided into non-CIN (n=89) and CIN (n=14) groups. Multiple clinical parameters were assessed for the two groups after TACE. Serum creatinine levels were measured 48-72 h after TACE. Results: Tumor size (>5 cm), TACE frequency, contrast agent dosage, solitary kidney, volume of iodized oil used in the TACE (ml) and urea levels were significantly higher in CIN group in comparison with the non-CIN group, while serum albumin and haemoglobin levels were significantly lower. Multivariate logistic regression analysis confirmed that the volume of iodized oil and TACE frequency were significantly positively correlated, and serum albumin level was negatively correlated in the CIN group. Conclusion: Volume of iodized oil, TACE frequency and low serum albumin levels were found to be independent risk factors for CIN after TACE. Thus, it is safe and feasible for hepatocellular carcinoma patients with chronic kidney disease to receive TACE treatment, but adverse events management after TACE needs to be addressed.

The combination of photodynamic therapy (PDT) and chemodynamic therapy (CDT) have attracted a great deal of interest, but tumor hypoxia and glutathione (GSH) overproduction still limit their further applications. Herein, an intelligent reactive oxygen species (ROS) nanogenerator Ce6/GOx@ZIF-8/PDA@MnO2 (denoted as CGZPM; Ce6, GOx, ZIF-8, PDA, MnO2 are chlorin e6, glucose oxidase, zeolitic imidazolate framework-8, polydopamine and manganese dioxide respectively) with O2-generating and GSH-/glucose-depleting abilities was constructed by a facile and green one-pot method. After intake by tumor cells, the outer MnO2 was rapidly degraded by the acidic pH, and the overexpression of hydrogen peroxide (H2O2) and GSH with abundant Mn2+ and O2 produced would eventually achieve multifunctionality. The Mn2+ acted as an ideal Fenton-like agent and magnetic resonance (MR) imaging contrast agent, while the O2 promoted the PDT via hypoxia relief and facilitated the intratumoral glucose oxidation by GOx for starvation therapy (ST). Benefiting from the GOx-based glycolysis process, sufficient H2O2 was generated to improve the CDT efficacy through Mn2+-mediated Fenton-like reaction. Notably, MnO2 and PDA could decrease the tumor antioxidant activity by consuming GSH, resulting in remarkably enhanced PDT/CDT. Such a novel cascade bioreactor with tumor microenvironment (TME)-modulating capability opens new opportunities for ROS-based and combinational treatment paradigms.

microRNAs act as fine-tuners in the regulation of plant growth and resistance against biotic and abiotic stress. Here we demonstrate that rice miR1432 fine-tunes yield and blast disease resistance via different modules. Overexpression of miR1432 leads to compromised resistance and decreased yield, whereas blocking miR1432 using a target mimic of miR1432 results in enhanced resistance and yield. miR1432 suppresses the expression ofLOC_Os03g59790, which encodes an EF-hand family protein 1 (OsEFH1). Overexpression ofOsEFH1leads to enhanced rice resistance but decreased grain yield. Further study revealed that miR1432 andOsEFH1are differentially responsive to chitin, a fungus-derived pathogen/microbe-associated molecular pattern (PAMP/MAMP). Consistently, blocking miR1432 or overexpression ofOsEFH1improves chitin-triggered immunity responses. In contrast, overexpression ofACOT, another target gene regulating rice yield traits, has no significant effects on rice blast disease resistance. Altogether, these results indicate that miR1432 balances yield and resistance via different target genes, and blocking miR1432 can simultaneously improve yield and resistance.

The development of an effective vaccine to control the global coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2) is of utmost importance. In this study, a synthetic DNA-based vaccine candidate, known as pSV10-SARS-CoV-2, expressing the SARS-CoV-2 spike protein was designed and tested in 39 BALB/c mice with BC01, an adjuvant derived from unmethylated CpG motif-containing DNA fragments from the Bacillus Calmette-Guerin genome. Mice vaccinated with pSV10-SARS-CoV-2 with BC01 produced early neutralizing antibodies and developed stronger humoral and cellular immune responses compared to mice that received the DNA vaccine only. Moreover, sera from mice vaccinated with pSV10-SARS-CoV-2 with BC01 can neutralize certain variants, including 614G, 614G + 472 V, 452R, 483A, 501Y.V2, and B.1.1.7. The results of this study demonstrate that the addition of BC01 to a DNA-vaccine for COVID-19 could elicit more effective neutralizing antibody titers for disease prevention.

Purpose The application of fungicides is one of the main strategies to prevent clubroot disease. Currently, numerous studies focus on changes in the soil microbial community at different levels of clubroot disease severity. However, the effects of fungicides on the soil microbial community and causative pathogen, Plasmodiophora brassicae, while preventing clubroot disease remain unclear. Methods In this study, we evaluated the control efficacy of three fungicides (fluazinam, metalaxyl-mancozeb, and carbendazim) on clubroot disease of tumorous stem mustard in greenhouse experiment. Uninoculated and Water treatments after inoculation were performed as controls. At three (3 W) and six weeks (6 W) post-inoculation of P. brassicae, soil properties, bacterial composition (sequencing of 16S rRNA genes), and effector gene expression of the pathogen were analyzed. The correlation of these factors with disease index (DI) was explored. Results Fluazinam was the most effective in controlling clubroot disease of tumorous stem mustard with a controlled efficacy of 59.81%, and the abundance of P. brassicae in the soil decreased 21.29% after 3 weeks of treatment. Compared with other treatments, twelve out of twenty effector genes showed higher expression in fluazinam 3 W samples. Different fungicides had different effects on soil properties. EC (electrical conductivity), the main factor that positively associated with DI, was significantly lower in fluazinam treatment than the other two fungicide treatments. The application of fungicides, especially carbendazim, significantly reduced bacterial α-diversity and the composition of soil bacteria. Pseudomonas, Microbacterium, and Sphingobacterium (positively correlated with DI) were enriched in Water, metalaxyl-mancozeb, and carbendazim treatments, but were less abundant in fluazinam treatment. Among the three fungicide treatments, DI was significantly negatively correlated with Shannon and Chao 1 indices. Soil properties and the top bacterial genera that positively correlated with DI were influenced to a lesser degree in the fluazinam treatment. Conclusion Among three fungicides, fluazinam was the most effective agent with the highest control effects against clubroot disease. The strong virulence of fluazinam against P. brassicae was one of the main reasons for the prevention of clubroot disease, and in addition the alteration of rhizosphere bacterial community by fluazinam to the detriment of P. brassicae infection. Based on our results, EC could be an indicator of the severity of clubroot disease.

Pseudomonas aeruginosa rugose small-colony variants (RSCVs) are frequently isolated from chronic infections, yet they are rarely reported in environmental isolates. Here, during comparative genomic analysis of two P. aeruginosa strains isolated from crude oil, we discovered a spontaneous in-frame deletion, wspAΔ280-307 , which led to hyper-biofilm and RSCV phenotypes. WspA is a homolog of methyl-accepting chemotaxis proteins (MCPs) that senses surfaces to regulate biofilm formation by stimulating cyclic-di-guanosine monophosphate (c-di-GMP) synthesis through the Wsp system. However, the methylation sites of WspA have never been identified. In this study, we identified E280 and E294 of WspA as methylation sites. The wspAΔ280-307 mutation enabled the Wsp system to lock into a constitutively active state that is independent of regulation by methylation. The result is an enhanced production of c-di-GMP. Sequence alignment revealed three conserved repeat sequences within the amino acid residues 280 to 313 (aa280-313) region of WspA homologues, suggesting that a spontaneous deletion within this DNA encoding region was likely a result of intragenic recombination and that similar mutations might occur in several related bacterial genera. Our results provide a plausible explanation for the selection of RSCVs and a mechanism to confer a competitive advantage for P. aeruginosa in a crude-oil environment. This article is protected by copyright. All rights reserved.

Background Tick-borne encephalitis virus (TBEV) is an important causative agent that causes neurological infections in humans and animals. In recent years, only few epidemiological surveys on TBEV have been conducted in China. The purpose of this study was to determine the prevalence and subtype of TBEV in ticks in northeastern (NE) China. Methods A total of 3799 questing ticks were collected in NE China between April 2015 and June 2016. Ticks were pooled and tested for TBEV RNA using semi-nested reverse transcriptase polymerase chain reaction. Positive pools were used to isolate the virus and amplify complete sequences, followed by sequence identity and phylogenetic analysis. Results TBEV RNA was detected in Ixodes persulcatus ticks at a total prevalence of 2.9% (6/143; 95% confidence interval: 1.2-5.9%). Three TBEV strains were isolated (JL-T75, HLB-T74, and DXAL-T83) and showed 93.9-99.1% nucleotide identities and 97.1-99.5% amino acid identities in Far Eastern (FE) TBEV subtypes, and 82.9-87.6% nucleotide identities and 92.9-96.4% amino acid identities in other subtypes. For polyprotein, the JL-T75, HLB-T74, and DXAL-T83 strains showed 29, 50, and 55 amino acid residues, respectively, different from those in the TBEV vaccine (Senzhang) strain in China. Phylogenetic analysis revealed that these viruses were clustered in the FE-TBEV branch but formed distinct clades depending on the natural foci. Conclusions The results of this study suggest that the FE-TBEV subtype is still endemic in I. persulcatus ticks in NE China, and the viruses in different natural foci in NE China are more likely to have genetic differences. This article is protected by copyright. All rights reserved.

Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

Introduction Blocking vascular endothelial growth factor pathway can enhance the efficacy of EGFR tyrosine kinase inhibitors in EGFR-mutant NSCLC. ACTIVE is the first phase 3 study conducted in the People's Republic of China evaluating apatinib, a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, plus gefitinib as first-line therapy in EGFR-mutant NSCLC. Methods Treatment-naive patients with stage IIIB or IV nonsquamous NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and EGFR exon 19 deletion or exon 21 L858R mutation were randomized 1:1 to receive oral gefitinib (250 mg/d), plus apatinib (500 mg/d; apatinib [A] + gefitinib [G] group), or placebo (placebo [P] + gefitinib [G] group). Stratification factors were mutation type, sex, and performance status. The primary end point was progression-free survival (PFS) by blinded independent radiology review committee (IRRC). Secondary end points were investigator-assessed PFS, overall survival, quality of life (QoL), safety, etc. Next-generation sequencing was used to explore efficacy predictors and acquired resistance. Results A total of 313 patients were assigned to the A + G (n = 157) or P + G group (n = 156). Median IRRC PFS in the A + G group was 13.7 months versus 10.2 months in the P + G group (hazard ratio 0.71, p = 0.0189). Investigator- and IRRC-assessed PFS were similar. Overall survival was immature. The most common treatment-emergent adverse events greater than or equal to grade 3 were hypertension (46.5%) and proteinuria (17.8%) in the A + G group and increased alanine aminotransferase (10.4%) and aspartate aminotransferase (3.2%) in the P + G group. QoL in the two groups had no statistical differences. Post hoc analysis revealed PFS benefits tended to favor the A + G group in patients with TP53 exon 8 mutation. Conclusions Apatinib + gefitinib as first-line therapy had superior PFS in advanced EGFR-mutant NSCLC versus placebo + gefitinib. Combination therapy brought more adverse events but did not interfere QoL. Trial Registration NCT02824458.

Plants must maintain a balance between their carbon (C) supply and utilization during the day–night cycle for continuous growth since C starvation often causes irreversible damage to crop production. It is not well known how C fixation and allocation in the leaves of crops such as maize adapt to sudden environmental changes. Here, to quantify primary C fixation and partitioning in photosynthetic maize leaves under extended darkness and to relate these factors to plant growth, maize seedlings were subjected to extended darkness (ED) for three successive days at the 6th leaf fully expanded stage (V6). ED reduced plant growth and leaf chlorophyll levels but not the rate of net CO2 exchange. As a result of the reduction in photoassimilates, the accumulation of starch and total soluble carbohydrates (TSC) in mature leaves also decreased under ED. However, the percentage of the daily C fixation reserved in mature leaves increased. These transient C pools were largely composed of TSC and were mainly used for consumption by increased nocturnal respiration rather than for transport. As the days went on, both the amount of C accumulated and the percentage of the daily fixed C that was reserved in leaves decreased, which could be largely accounted for by the attenuated starch synthesis in all treatments. The activities of ADP-glucose pyrophosphorylase and soluble starch synthase decreased significantly over time. Therefore, this study concluded that both starch and TSC are involved in the coordination of the C supply and plant growth under a sudden C shortage but that they may be involved in different ways. While the ratio of reserved C to daily fixed C increased to maintain blade function under acute C starvation, both the amount and the proportion of C reserved in mature leaves decreased as plant growth continued in order to meet the growth demands of the plant.

Objectives The hospital environment has been implicated in the enrichment and exchange of pathogens and antibiotic resistance, but its potential in shaping the symbiotic microbial community of hospital staff is unclear. This study was designed to evaluate the alteration of the gut microbiome in medical workers compared to non-medical controls. Methods A prospective cross-sectional cohort study was conducted in the intensive care unit (ICU) and other departments of a centre in north-eastern China. Faecal samples of 175 healthy medical workers—short-term (1–3 months) workers (n = 80) and long-term (>1 year) workers (n = 95)—and 80 healthy non-medical controls were analysed using 16S rRNA amplicon sequencing. The hospital environmental samples (n = 9) were also analysed. Results The gut microbiomes of medical workers exhibited marked deviations in diversity and alteration in microbial composition and function. Short-term workers showed significantly higher abundances of taxa such as Lactobacillus, Butyrivibrio, Clostridiaceae, Clostridium, Ruminococcus, Dialister, Bifidobacterium, Odoribacter, and Desulfovibrio and lower abundances of Bacteroides and Blautia than the controls. Long-term workers showed higher abundances of taxa such as Dialister, Veillonella, Clostridiaceae, Clostridium, Bilophila, Desulfovibrio, Pseudomonas, and Akkermansia and lower abundances of Bacteroides and Coprococcus than the controls. The medical workers' department (ICU versus non-ICU) and position (resident doctor versus nursing staff) also impacted their gut microbiome. Compared with the non-ICU workers, workers in the ICU showed a significant increase in the abundances of Dialister, Enterobacteriaceae, Phascolarctobacterium, Pseudomonas, Veillonella, and Streptococcus and a marked depletion of Faecalibacterium, Blautia, and Coprococcus. In contrast with the nursing staff, the resident doctors showed a significant increase in Erysipelotrichaceae and Clostridium and a decrease in Bacteroides, Blautia, and Ruminococcus in the gut microbiome. Moreover, we found that the microbiota of hospital environments potentially correlated with the workers' gut microbiota. Conclusions Our findings demonstrated structural changes in the gut microbial community of medical workers.

Background Gasdermins (GSDMs) are a class of proteins related to pyrolysis and in humans, consist of GSDMA, GSDMB, GSDMC, GSDMD, DFNA5, and DFNB59. The inflammatory factors and cell contents released during pyrolysis can recruit immune cells and change the microenvironment. However, to date, there is a paucity of studies examining the relationship between GSDMs and the immune microenvironment in tumors. Therefore, this current report analyzed the expression of GSDM genes in tumors and their relationship with the immune microenvironment. Methods Apply GSCALite and GEPIA2 online analysis tools to analyze the gene expression levels and the Single nucleotide variant (SNV), copy number variation (CNV), and methylation characteristics of GSDM genes respectively. Use R software or TISIDB online analysis tool to carry out the correlation analysis required in the article. Furthermore, Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to examine the role of these GSDM genes in various cancers. Results The results demonstrated that CNV can cause an increase in GSDM gene expression, and methylation can inhibit GSDM gene expression. The elevated expression of GSDMA, GSDMB, GSDMC, GSDMD, and DFNA5 in some or most tumors was often accompanied by elevated immune scores, increased immune cell infiltration, and high expression of major histocompatibility complex (MHC) molecules, chemokines and their receptors, and immune checkpoint-related genes. However, DFNB59 was often negatively correlated with these indicators in tumors. GSDMD was the most highly expressed GSDM protein in various normal tissues and tumors, and showed the strongest correlation with immune microenvironment-related genes. Moreover, the methylation of GSDMD was accompanied by low immune cell infiltration, low expression of MHC molecule-related genes, low expression of chemokines and receptor-related genes, and low expression of immune checkpoint-related genes. Conclusions Therefore, the expression of GSDM-related genes is associated with the tumor immune microenvironment. The GSDM genes, especially GSDMD, may be used as therapeutic targets to predict or change the tumor microenvironment and as biomarkers to predict the therapeutic efficacy of immune checkpoint inhibitors.

Viruses can be transmitted from animals to humans (and vice versa) and across animal species. As such, host-virus interactions and transmission have attracted considerable attention. Non-human primates (NHPs), our closest evolutionary relatives, are susceptible to human viruses and certain pathogens are known to circulate between humans and NHPs. Here, we generated global statistics on virus infections in NHPs (VI-NHPs) based on a literature search and public data mining. In total, 140 NHP species from 12 families are reported to be infected by 186 DNA and RNA virus species, 68.8% of which are also found in humans, indicating high potential for crossing species boundaries. The top 10 NHP species with high centrality in the NHP-virus network include two great apes (Pan troglodytes, Pongo pygmaeus) and eight Old World monkeys (Macaca mulatta, M. fascicularis, M. leonina, Papio cynocephalus, Cercopithecus ascanius, C. erythrotis, Chlorocebus aethiops, and Allochrocebus lhoesti). Given the wide distribution of Old World monkeys and their frequent contact with humans, there is a high risk of virus circulation between humans and such species. Thus, we suggest recurring epidemiological surveillance of NHPs, specifically Old World monkeys that are in frequent contact with humans, and other effective measures to prevent potential circulation and transmission of viruses. Avoidance of false positives and sampling bias should also be a focus in future work.

While recent studies have shown the importance of intraspecific trait variation in the processes of community assembly, we still know little about the contributions of intraspecific trait variability to ecosystem functions. Here, we conducted a functional group removal experiment in an alpine meadow in Qinghai-Tibetan Plateau over 4 years to investigate the relative importance of inter- and intraspecific variability in plant height for productivity. We split total variability in plant height within each of 75 manipulated communities into interspecific variability (TVinter) and intraspecific variability within a community (ITVwithin). Community-weighted mean height among communities was decomposed into fixed community-weighted mean (CWMfixed) and intraspecific variability among communities (ITVamong). We constructed a series of generalized additive mixed models and piecewise structural equation modeling to determine how trait variability (i.e. TVinter, ITVwithin, CWMfixed and ITVamong) indirectly mediated the changes in productivity in response to functional group removal. Community productivity was not only affected directly by treatment manipulations, but also increased with both inter- and intraspecific variability (i.e. CWMfixed and ITVamong) in plant height indirectly. This suggests that both the ‘selection effect’ and a ‘shade-avoidance syndrome’ can incur higher CWMfixed and ITVamong, and may simultaneously operate to regulate productivity. Our findings provide new evidence that, besides interspecific variability, intraspecific trait variability in plant height also plays a role in maintaining net primary productivity.