Search

The drought-adapted shrub guayule (Parthenium argentatum) produces rubber, a natural product of major commercial importance, and two co-products with potential industrial use: terpene resin and the carbohydrate fructan. The rubber content of guayule plants subjected to water stress is higher compared to that of well-irrigated plants, a fact consistently reported in guayule field evaluations. To better understand how drought influences rubber biosynthesis at the molecular level, a comprehensive transcriptome database was built from drought-stressed guayule stem tissues using de novo RNA-seq and genome-guided assembly, followed by annotation and expression analysis. Despite having higher rubber content, most rubber biosynthesis related genes were down-regulated in drought-stressed guayule, compared to well-irrigated plants, suggesting post-transcriptional effects may regulate drought-induced rubber accumulation. On the other hand, terpene resin biosynthesis genes were unevenly affected by water stress, implying unique environmental influences over transcriptional control of different terpene compounds or classes. Finally, drought induced expression of fructan catabolism genes in guayule and significantly suppressed these fructan biosynthesis genes. It appears then, that in guayule cultivation, irrigation levels might be calibrated in such a regime to enable tunable accumulation of rubber, resin and fructan.

Alzheimer's disease (AD) is a destructive neurodegenerative disease that currently has no effective treatment option available. Ginkgolide B (GB) is a terpene lactone derivative of Ginkgo biloba that possesses neuroprotective effects in various diseases. The aim of the present study was to investigate whether GB protects against cognitive impairment in AD by mitigating oxidative stress, inflammation and ferroptosis using senescence-accelerated P8 (SAMP8) mice. The results showed that GB improved the cognitive dysfunction of SAMP8 mice in the Morris water maze and novel object recognition test, which was associated with the attenuation of oxidative stress, inflammation and nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4 (GPX4) pathway-mediated ferroptosis. Furthermore, Ras-selective lethal small molecule 3, a GPX4 inhibitor and ferroptosis inducer, compromised GB-induced cognitive performance in SAMP8 mice. These findings suggested that GB alleviated AD-induced cognitive defects by mitigating oxidative stress, neuroinflammation and ferroptosis, and that the inhibition of ferroptosis is required for GB to have beneficial effects in AD.

The elongation factor Tu GTP-binding domain-containing 2 gene (EFTUD2) participates in antiviral immune responses. However, the association between genetic polymorphisms of EFTUD2 and hepatitis B v...

CRISPR-Cas transcriptional programming in bacteria is an emerging tool to regulate gene expression for metabolic pathway engineering. Here we implement CRISPR-Cas transcriptional activation (CRISPRa) in P. putida using a system previously developed in E. coli. We provide a methodology to transfer CRISPRa to a new host by first optimizing expression levels for the CRISPRa system components, and then applying rules for effective CRISPRa based on a systematic characterization of promoter features. Using this optimized system, we regulate biosynthesis in the biopterin and mevalonate pathways. We demonstrate that multiple genes can be activated simultaneously by targeting multiple promoters or by targeting a single promoter in a multi-gene operon. This work will enable new metabolic engineering strategies in P. putida and pave the way for CRISPR-Cas transcriptional programming in other bacterial species.

Carbapenems, as the "last line of defense" against Gram-negative bacteria, are increasingly being challenged by drug-resistant bacteria, especially Enterobacteriaceae. In this study, a carbapenem-resistant Gram-negative bacterium, named AH001, was isolated from hospital sewage, and a modified Hodge test confirmed that this bacterium can produce carbapenemase. Further analysis revealed that this bacterium exhibits multidrug resistance against an additional seven antibiotics. Whole-genome sequencing and analysis showed that AH001 could not be classified by existing MLST, and its serotype could not be distinguished among O9, O89 or O168 according to O antigen prediction. More attention should be given to the role of environmental sources of Escherichia coli in the development and transfer of drug resistance in the hospital environment.

T lymphocytes, the major effector cells in cellular immunity, produce cytokines in immune responses to mediate inflammation and regulate other types of immune cells. Work in the last three decades has revealed significant heterogeneity in CD4+ T cells, in terms of their cytokine expression, leading to the discoveries of T helper 1 (Th1), Th2, Th17, and T follicular helper (Tfh) cell subsets. These cells possess unique developmental and regulatory pathways and play distinct roles in immunity and immune-mediated pathologies. Other types of T cells, including regulatory T cells and γδ T cells, as well as innate lymphocytes, display similar features of subpopulations, which may play differential roles in immunity. Mechanisms exist to prevent cytokine production by T cells to maintain immune tolerance to self-antigens, some of which may also underscore immune exhaustion in the context of tumors. Understanding cytokine regulation and function has offered innovative treatment of many human diseases.

The general public spends one-third of its time under artificial lighting, which lacks bands beneficial to human health, and long-term exposure will have a negative impact on bone health. Here, we report the effects of long-term, low-dose ultraviolet (UV) supplementation to white light-emitting diode (LED) light exposure on intestinal microorganisms and bone metabolism, as well as the correlations between the two. Normal and ovariectomized rats were irradiated with LED white light with or without supplementation with UV. The effects of UV supplementation on the intestinal flora and the relationship between the intestinal flora and bone were investigated by measuring the intestinal flora, bone metabolism markers, and bone histomorphology. UV supplementation affected the bone density and bone mass by changing the relative content of Firmicutes, Saccharibacteria, and Proteobacteria; however, the intestinal flora were not the only factors affecting bone. Ultraviolet supplementation changed the composition and function of the gut flora in the bone loss model. By increasing the synthesis of short-chain fatty acids and affecting immunomodulatory, intestinal flora directly or indirectly regulate the activity of osteoclasts and thus mediate UV-mediated improvements in bone metabolism. Our work shows that UV supplementation affects bone density by influencing the intestinal flora, introducing a novel strategy to develop healthier artificial light sources and prevent bone loss. KEY POINTS: • We measured the bone metabolism markers and bone histomorphometry of rats. • The diversity, composition, and function of intestinal flora were analyzed. • The relationship between gut microbiota and host bone physiology was analyzed.

For the aim of unveiling the molecular mechanism of flowering, the MADS-box genes of SUPPRESSOR of OVEREXPRESSION of CONSTANS 1 (NnSOC1) and NnSOC1-like were isolated in Nelumbo nucifera. Seven introns splicing of NnSOC1 and NnSOC1-like strictly followed the GT-AG rule, consisting of all the characteristic motifs of SOC1 family. NnSOC1 and NnSOC1-like were widely distributed in reproductive and vegetative tissues of N. nucifera, exhibiting the highest expression in leaves and the lowest level in embryo. Additionally, both genes were expressed in the whole flowering stage, with the highest mRNA level observed in the initiation stage of flowering and the lowest expression in fruit set. Ectopic expression of NnSOC1 and NnSOC1-like advanced the flowering time of transgenic Arabidopsis, and decreased the rosetta leaves production. These results suggested that NnSOC1 and NnSOC1-like were involved in initiation of flowering, which are likely to serve as fundamental research for studying molecular mechanism of flowering in aquatic plants. © 2021 Friends Science Publishers

Epidemiological evidences have indicated that fine particulate matter (PM2.5 ) exposure is associated with the occurrence and development of hypertension. The present study aims to explore the effects of parental PM2.5 exposure on blood pressure in offspring and elucidate the potential mechanism. The parental male and female C57BL/6 mice were exposed to concentrated PM2.5 or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) for 16 weeks. At week 12, the mice were assigned to breed offspring. The male offspring mice were further exposed to PM2.5 or FA as above method. During the parental exposure, the average PM2.5 concentration was 133.7 ± 53.32 μg/m3 in PM chamber, whereas the average concentration in FA chamber was 9.4 ± 0.23 μg/m3 . Similarly, during the offspring exposure, the average concentration in PM and FA chamber were 100.76 ± 26.97 μg/m3 and 9.15 ± 0.15 μg/m3 , respectively. The PM2.5 -exposed offspring mice displayed the elevation of blood pressure, the increase of angiotensin II (Ang II), the decrease of angiotensin converting enzyme 2 (ACE2) and Ang (1-7) in serum when compared with the FA-exposed offspring mice. The similar results displayed in the proteins expression of ACE2, AT1R, and Ang (1-7) in vessel and kidney. More importantly, parental PM exposure further induced the increase in serous Ang II and the protein expression of AT1R in vessel, but decrease in ACE2 and Ang (1-7). The serous Ang II was positively associated with splenic T helper type 17 (Th17) cell population and serous IL (interleukin)-17A, but negatively associated with T regular (Treg) cell population and serous IL-10. The results suggested that parental air pollution exposure might induce the elevation of offspring blood pressure via mediate Th17- and Treg-related immune microenvironment.

Commercial cultivars of kiwifruit (Actinidia spp.) can have green-fleshed or yellow-fleshed fruit depending on their chlorophyll degradation ability. In recent years, an increasing number of yellow...

Germinal center (GC) responses potentiate the generation of follicular regulatory T (TFR) cells. However, the molecular cues driving TFR cell formation remain unknown. Here, we show that sclerostin domain-containing protein 1 (SOSTDC1), secreted by a subpopulation of follicular helper T (TFH) cells and T-B cell border-enriched fibroblastic reticular cells, is developmentally required for TFR cell generation. Fate tracking and transcriptome assessment in reporter mice establishes SOSTDC1-expressing TFH cells as a distinct T cell population that develops after SOSTDC1- TFH cells and loses the ability to help B cells for antibody production. Notably, Sostdc1 ablation in TFH cells results in substantially reduced TFR cell numbers and consequently elevated GC responses. Mechanistically, SOSTDC1 blocks the WNT-β-catenin axis and facilitates TFR cell differentiation.

NADPH oxidase 2 (NOX2) is a major subtype of NOX and is responsible for the generation of reactive oxygen species (ROS) in brain tissues. MicroRNAs (miRNAs/miRs) are important epigenetic regulators of NOX2. The present study aimed to identify the role of NOX2 miRNA-targets in ischemic stroke (IS). A rat cerebral ischemia/reperfusion (CI/R) injury model and a SH-SY5Y cell hypoxia/reoxygenation (H/R) model were used to simulate IS. Gene expression levels, ROS production and apoptosis in tissue or cells were determined, and bioinformatic analysis was conducted for target prediction of miRNA. In vitro experiments, including function-gain and luciferase activity assays, were also performed to assess the roles of miRNAs. The results indicated that NOX2 was significantly increased in brain tissues subjected to I/R and in SH-SY5Y cells subjected to H/R, while the expression of miR-532-3p (putative target of NOX2) was significantly decreased in brain tissues and plasma. Overexpression of miR-532-3p significantly suppressed NOX2 expression and ROS generation in SH-SY5Y cells subjected to H/R, as well as reduced the relative luciferase activity of cells transfected with a reporter gene plasmid. Collectively, these data indicated that miR-532-3p may be a target of NOX2 and a biomarker for CI/R injury. Thus, the present study may provide a novel target for drug development and IS therapy.

Objective rheumatism refers to a large group of diseases with different etiology, mainly characterized by autoimmune disorder. Intestinal flora combines with the digestive organs of the human body to synthesize and secrete the key substances of growth. Several studies have reported abnormal intestinal flora in rheumatic diseases. The purposes of this research were to review the primary studies and figure out the relationship between intestinal flora and rheumatic disease activity. The article search was based on the database of PubMed (MEDLINE), EMBASE, Cochrane to collect English language studies that were published from 1985 to 2019. The articles concerning the intestinal flora and disease activities of rheumatic diseases were classified by disease types, and the relationship between disease activities and intestinal flora was summarized. Eight rheumatic diseases were included in the study. It was found that the changes of intestinal flora were significantly correlated with the activities of rheumatic diseases. There were significant differences in the classification of disease activity and the composition of intestinal flora. Interfering with the composition of intestinal flora can apparently modulate the development of disease. But how to apply such findings is rarely reported. The study finds out that intestinal flora disorder is linked to the activity of rheumatic diseases. But which specific gut flora is connected to the disease activity needs further researches. More discussion is needed on how to apply the results to clinical treatment.

Citrobacter rodentium colonizes at the colon and causes mucosal inflammation in mice. Previous studies have revealed the importance of the innate and adaptive immune response for controlling C. rodentium infection. In the present study, we examined the role of T follicular helper (Tfh) cells in intestinal C. rodentium infection using mice with Bcl6 deficiency in T cells. Tfh cells were absolutely required at the late, but not the early, phase to control infection. Compared with control mice, we observed systemic pathogen dissemination and more severe colitis in Tfh-deficient mice. Furthermore, the susceptibility of Tfh-deficient mice correlated with an impaired serum IgG1 response to infection, and serum Abs from infected wild-type mice protected Tfh-deficient mice from infection. The transfer of wild-type Tfh cells also restored the levels of IgG1 and led to effective clearance of the pathogens in Tfh-deficient mice. Moreover, during C. rodentium infection, IL-21– and IL-4–producing Tfh cells were increased obviously in wild-type mice, correlating with IgG1 as the major isotype in germinal center B cells. Taken together, our work highlights the requirement and the function of Tfh cells in regulating humoral response for the host protection against C. rodentium infection.

Direct seeded rice (DSR) has received much attention because of its time- and labour-saving and low-input demand. However, the long-term cultivation method of seedling-transplantation has led to loss of some low-temperature-tolerant genes expressed at the bud stage. It has made many currently popular rice varieties unsuitable for direct seeding production. Therefore, it is important to identify cold-tolerance genes at the bud stage and to provide genes for subsequent molecular marker assistant breeding. In this study, we used a recombinant inbred line population constructed by cross of Lijiangxintuanheigu (LTH) and Shennong 265 (SN265) and its linkage map containing 2818 markers to detect cold tolerance QTLs at the bud stage. A total of five QTLs were detected on rice chromosomes 1, 3, 9, and 11. All the cold tolerance alleles were from the cold-tolerant parent LTH. The LOD values of these QTLs ranged from 3.05 to 24.01, and the phenotypic variations ranged from 8.0% to 53.5%. Among them, the major QTL qCTB11b was located in a 790 kb interval of 21.24 Mb to 22.03 Mb on the long arm of chromosome 11. Subsequently, the “selective mapping” strategy was used for QTL verification and pyramiding effect analysis. Genetic improvement of cold tolerance at the bud stage would be achieved through pyramiding more QTLs. These results not only promote people’s understanding of the genetic basis for cold tolerance at the bud stage in rice but also provide theoretical basis and technical guidance for genetic improvement of DSR varieties.

Objective: To investigate the prevalence of Salmonella Typhi and Paratyphi resistance to quinolones and characterize the underlying mechanism in Jiangsu Province of China. Methods: Antimicrobial susceptibility testing was performed using Kirby-Bauer disc diffusion system. Quinolone resistance-determining region (QRDR), plasmid-mediated quinolone resistance (PMQR) determinant genes were detected by PCR and sequencing. Results: Out of 239 Salmonella isolates, 164 were S. Typhi and 75 were S. Paratyphi. 128 (53.6%) Salmonella isolates were resistant to nalidixic acid; 11 (4.6%) isolates to ciprofloxacin and 66 (27.6%) isolates were intermediate to ciprofloxacin. QRDR were present in 69 S. Typhi isolates, among which mutation at codon 83 (n = 45) and 133 (n = 61) predominated. In S. Paratyphi, the most common mutations were detected in gyrA at codon 83(n = 24) and parC: T57S (n = 8). Seven mutations were first reported in Salmonella isolates including gyrB: S426G, parC: D79G and parE: [S498T, E543K, V560G, I444S, Y434S]. PMQR genes including qnrD1, qnrA1, qnrB4, aac (6′)-Ib-cr4 and qnrS1 were detected in 1, 2, 3, 7 and 9 isolates, relatively. Conclusions: High resistance to quinolones in Salmonella remains a serious problem in Jiangsu, China. The presence of the novel mutations increases the complexity of quinolone-resistant genotypes and poses a threat to public health. Subject terms: Salmonella Typhi, Salmonella Paratyphi, antimicrobial resistance, QRDR, PMQR.

RNA secondary structure elements in the mRNA 3ʹ-untranslated regions (3ʹUTR) play important roles in post-transcriptional regulation. RNA structure elements in the viral RNA provide valuable model for studying diverse regulation mechanisms. Herpesvirus genomes are double-stranded DNA with GC-rich sequences, which can be transcribed into abundant GC-rich RNAs. It is valuable to explore the structures and function of those GC-rich RNAs. We identified a G2-quadruplex-forming sequence named PQS18-1 in the 3ʹUTR of the unique immediate early gene of Pseudorabies virus (PRV), an important member of alphaherpesvirus subfamily. The RNA PQS18-1 was folded into parallel G-quadruplex structure, enhancing gene expression. Both non-G-quadruplex mutant and G3-quadruplex mutant in the 3ʹUTR showed lower gene expression level than the wildtype G2-quadruplex. A chemical compound destroyed PQS18-1 G2-quadruplex and suppressed gene expression, accordingly reducing PRV replication by one titre in the PK15 cells at 24 hours post infection. Our findings indicated that the RNA G2-quadruplex in 3ʹUTR was essential for high expression of IE180 gene, and it could be a specific post-transcription regulation element in response to small molecules or other macromolecules. This study discovers a novel RNA G2-quadruplex in the 3ʹUTR of an immediate early gene of alphaherpesvirus, and provides a new nucleic acid target for anti-virus drug design.

Maintenance of regulatory T (Treg) cells is crucial for the regulatory function of Treg cells in immune homeostasis and self-tolerance; however, the detailed underlying mechanisms remain elusive. In the current study, we found that the cytokine suppressor CIS (cytokine induced SH-2 protein) is required for maintenance of Treg cell identity. Mice with Treg-specific Cis-deficiency displayed aggravated experimental allergic asthma, and in adulthood, developed splenomegaly, lymphadenopathy and spontaneous eosinophilic airway inflammation, accompanied by accumulation of effector memory helper T (TH) cells. Cis-deficiency led to the loss of Foxp3 expression and the decrease in suppressive function of Treg cells. Cis-deficient Treg cells expressed TH2 cell signature genes, Gata3, Irf4 and Il4, and excessive interleukin-4-signal transducer and activator of transcription 6 (IL-4-STAT6) signals resulted in repressive chromatin modification in the Foxp3 locus and permissive modification in the Il4 loci. In vitro, blockade of IL-4 restored the expression of Foxp3 and the suppressive function of inducible Treg (iTreg) cells. Thus, we identified a novel feedback loop in stabilization of Treg cells and suppression of TH2-type inflammation in a Treg-intrinsic manner.

As a native in Southeast Asia, Sagittaria trifolia L. var. sinensis (arrowhead) is an aquatic perennial herb of Alismataceae family. For the aim of discovering genes and development molecular markers, high-throughput transcriptome sequencing is applied to generate enormous transcript sequences from arrowhead leaf generate. Through trimmed and assembled, 51, 836 contigs were obtained with mean length of 680 bp. Sequence similarity analyses against four public databases (NR, GO, KEGG, KOG) found 23, 595 contigs that could be annotated with gene descriptions, conserved protein domains, or gene ontology terms. In this study, 3, 861 simple sequence repeat (SSR) markers of arrowhead were identified in 3, 174 contigs of transcriptome data,and 2, 476 primer pairs were designed for marker development. Of these, 100 primers were randomly selected, synthesized and used for validation of the amplification and assessment of polymorphisms in 79 arrowhead accessions. 78 loci reliably amplified a clear single band of expexted size, and 68 loci were scoreable and polymorphic with 2 to 11 alleles per locus. The polymorphism information content valued ranged from 0.01 to 0.84. The SSR markers developed from arrowhead, could be successfully applied to Sagittaria pygmaea, with a transferability rate of 91.14% (72/79). The phylogenetic tree was also constructed to analyse the genetic diversity in arrowhead accessions. The large number of SSR markers developed in this study will be useful in the researches of population genetics, genetic diversity, and germplasm characterization in arrowhead.

Background Banana fruits are rich in various high-value metabolites and play a key role in the human diet. Of these components, carotenoids have attracted considerable attention due to their physiological role and human health care functions. However, the accumulation patterns of carotenoids and genome-wide analysis of gene expression during banana fruit development have not been comprehensively evaluated. Results In the present study, an integrative analysis of metabolites and transcriptome profiles in banana fruit with three different development stages was performed. A total of 11 carotenoid compounds were identified, and most of these compounds showed markedly higher abundances in mature green and/or mature fruit than in young fruit. Results were linked to the high expression of carotenoid synthesis and regulatory genes in the middle and late stages of fruit development. Co-expression network analysis revealed that 79 differentially expressed transcription factor genes may be responsible for the regulation of LCYB (lycopene β-cyclase), a key enzyme catalyzing the biosynthesis of α- and β-carotene. Conclusions Collectively, the study provided new insights into the understanding of dynamic changes in carotenoid content and gene expression level during banana fruit development.

Description, Inhibition of LPA1/ROCK enhances IFN-I/III production in multiple cell types against virus infection., Growing evidence indicates the vital role of lipid metabolites in innate immunity. The lipid lysophosphatidic acid (LPA) concentrations are enhanced in patients upon HCV or SARS-CoV-2 infection, but the function of LPA and its receptors in innate immunity is largely unknown. Here, we found that viral infection promoted the G protein–coupled receptor LPA1 expression, and LPA restrained type I/III interferon production through LPA1. Mechanistically, LPA1 signaling activated ROCK1/2, which phosphorylated IRF3 Ser97 to suppress IRF3 activation. Targeting LPA1 or ROCK in macrophages, fibroblasts, epithelial cells, and LPA1 conditional KO mice promoted interferon-induced clearance of multiple viruses. LPA1 was colocalized with the receptor ACE2 in lung and intestine. Together with previous findings that LPA1 and ROCK1/2 promoted vascular leaking or lung fibrosis, we propose that the current available preclinical drugs targeting the LPA1-ROCK module might protect from SARS-CoV-2 or various virus infections in the intestine or lung.

Background:Lycopene epsilon-cyclase (ε-LCY) is a key enzyme in the carotenoid biosynthetic pathway (CBP) of higher plants. In previous work, we cloned two Ntε-LCY genes from allotetraploid tobacco (Nicotiana tabacum), Ntε-LCY2 and Ntε-LCY1, and demonstrated the overall effect of Ntε-LCY genes on carotenoid biosynthesis and stress resistance. However, their genetic and functional characteristics require further research in polyploid plants.Results: Here, we used CRISPR/Cas9 to obtain Ntε-LCY2 and Ntε-LCY1 mutants in allotetraploid N.tabacum K326. Ntε-LCY2 and Ntε-LCY1 had similar promoter cis-acting elements, including light-responsive elements. The Ntε-LCY genes were expressed in roots, stems, leaves, flowers, and young fruit, and their highest expression levels were found in leaves. Ntε-LCY2 and Ntε-LCY1 genes responded differently to normal light and high light stress. Both the Ntε-LCY2 and the Ntε-LCY1 mutants had a more rapid leaf growth rate, especially ntε-lcy2-1. The expression levels of CBP genes were increased in the ntε-lcy mutants, and their total carotenoid content was higher. Under both normal light and high light stress, the ntε-lcy mutants had higher photosynthetic capacities and heat dissipation levels than the wild type, and this was especially true of ntε-lcy2-1. The reactive oxygen species content was lower in leaves of the ntε-lcy mutants.Conclusion: In summary, the expression patterns and biological functions of the Ntε-LCY genes Ntε-LCY1 and Ntε-LCY2 differed in several respects. The mutation of Ntε-LCY2 was associated with a greater increase in the content of chlorophyll and various carotenoid components, and it enhanced the stress resistance of tobacco plants under high light.

Background: Mechanical stretch is utilized to promote skin regeneration during tissue expansion for reconstructive surgery. Although mechanical stretch induces characteristic morphological changes in the skin, the biological processes and molecular mechanisms involved in mechanically induced skin regeneration are not well elucidated.Methods: A male rat scalp expansion model was established and the important biological processes related to mechanical stretch-induced skin regeneration were identified using Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and gene set enrichment analysis (GSEA). Analysis was also conducted by constructing a protein–protein interaction (PPI) network, identifying key modules and hub genes, determining transcription factor (TF)-mRNA regulatory relationships, and confirming the expression pattern of the TFs and hub genes.Results: We identified nine robust hub genes (CXCL1, NEB, ACTN3, MYOZ1, ACTA1, TNNT3, PYGM, AMPD1, and CKM) that may serve as key molecules in skin growth. These genes were determined to be involved in several important biological processes, including keratinocyte differentiation, cytoskeleton reorganization, chemokine signaling pathway, glycogen metabolism, and voltage-gated ion channel activity. The potentially significant pathways, including the glucagon signaling pathway, the Wnt signaling pathway, and cytokine–cytokine receptor interaction, were distinguished. In addition, we identified six TFs (LEF1, TCF7, HMGA1, TFAP2C, FOSL1, and ELF5) and constructed regulatory TF–mRNA interaction networks.Conclusion: This study generated a comprehensive overview of the gene networks underlying mechanically induced skin regeneration. The functions of these key genes and the pathways in which they participate may reveal new aspects of skin regeneration under mechanical strain. Furthermore, the identified TF regulators can be used as potential candidates for clinical therapeutics for skin pretreatment before reconstructive surgery.

Genetic variations in tumor necrosis factor receptor superfamily (TNFRSF) 13B have already proved to be associated with immune- related diseases. This study aimed to explore the relationship of tumor necrosis factor superfamily (TNFSF) 13, TNFRSF13B, and TNFRSF14 missense mutations with the susceptibility of HCV infection. SNPs in TNFSF13 (rs3803800, rs11552708), TNFRSF13B (rs34562254), and TNFRSF14 (rs4870) were genotyped in 469 intravenous drug users, 728 hemodialysis patients and 1636 paid blood donors by TaqMan real-time PCR assay. And the USCS Brower and RNAfold web servers were used to predict the potential biological functions of the positive SNPs. After adjustment for gender, age, ALT level, AST level and route of infection, the results of logistic regression analysis showed that the subjects carried rs34562254 TT mutant homozygous type in TNFRSF13B were more likely to be infected by HCV compared to those with rs34562254 CC wild homozygous type (co-dominant model: OR = 1.52, 95% CI: 1.17–1.98, P = 0.002; recession model: OR = 1.41, 95% CI: 1.10–1.81, P = 0.007; additive model: OR = 1.21, 95% CI: 1.07–1.37, P = 0.002). And the effect of the risk allele (rs34562254-T) is more evident in female, elder (≥ 50), paid blood donors, lower ALT level (≤ 40 U/L) and lower ALT level (≤ 40 U/L) subgroup. The result of bioinformatics analysis showed that rs34562254 was located at the highest peak of the H3K4Me1 histone marker with the UCSC genome browser. And the minimum free energy (MFE) of the centroid secondary structure for the mutant T allele (-38.90 kcal/mol) of rs34562254 was higher than that of the wild C allele (-45.60 kcal/mol) with the RNAfold web servers. In addition, the RegulomeDB score of rs34562254 was 3a with the RegulomeDB web servers. All the above results of bioinformatics analysis suggested that rs34562254 may affect the gene expression level by regulating the transcriptional activity of the corresponding gene region. The rs34562254 polymorphisms in TNFRSF13B were significantly associated with HCV infection among Chinese Han population.

Muscle atrophy usually occurs under mechanical unloading, which increases the risk of injury to reduce the functionality of the moving system, while there is still no effective therapy until now. It was found that miR-194 was significantly downregulated in a muscle atrophy model, and its target protein was the myocyte enhancer factor 2C (MEF2C). miR-194 could promote muscle differentiation and also inhibit ubiquitin ligases, thus miR-194 could be used as a nucleic acid drug to treat muscle atrophy, whereas miRNA was unstable in vivo, limiting its application as a therapeutic drug. A gelatin nanosphere (GN) delivery system was applied for the first time to load exogenous miRNA here. Exogenous miR-194 was loaded in GNs and injected into the muscle atrophy model. It demonstrated that the muscle fiber cross-sectional area, in situ muscle contractile properties, and myogenic markers were increased significantly after treatment. It proposed miR-194 loaded in GNs as an effective treatment for muscle atrophy by promoting muscle differentiation and inhibiting ubiquitin ligase activity. Moreover, the developed miRNA delivery system, taking advantage of its tunable composition, degradation rate, and capacity to load various drug molecules with high dosage, is considered a promising platform to achieve precise treatment of muscle atrophy-related diseases.

Objective This study aims to explore a three-dimensional planting mode in orchards and provide theoretical basis for the efficient peach-Morchella planting and soil management after Morchella cultivation. Methods Next-generation sequencing was performed to investigate the variations in soil physicochemical properties, enzyme activities and fungal composition under peach-Morchella intercropping for one year and two years, by using the soil without peach-Morchella intercropping as the control group. Results Peach-Morchella intercropping decreased the soil bulk density, and significantly increased the maximum field capacity, non-capillary porosity and total porosity, organic matter, available potassium and available zinc, which together improved soil structure and soil fertility. Besides, the intercropping mode obviously enhanced soil enzyme activities and mineral absorption and transformation in peach orchard soils. The intercropping also resulted in a decline of soil fungal diversity, and the 2-year soil samples were of higher abundance of Zygomycota. More importantly, peach-Morchella intercropping elevated the yields of both peach and Morchella, bringing about obviously higher economic benefits. Conclusion Continuous peach-Morchella intercropping improves the soil structure and fertility while decreases soil fungal diversity, which can contribute to greater economic benefits of the peach orchard. Our findings shed new light on the intercropping-fungus-soil relationship, and may facilitate the further development of peach-Morchella intercropping.

BackgroundKIR/HLA-C signaling pathway influences the innate immune response which is the first defense to hepatitis C virus (HCV) infection. The aim of this study was to determine the association between the genetic polymorphisms of KIR/HLA-C genes and the outcomes of HCV infection in a high-risk Chinese population.MethodsIn this case-control study, four single nucleotide polymorphisms (SNPs) of KIR/HLA-C genes (KIR2DS4/KIR2DS1/KIR2DL1 rs35440472, HLA-C rs2308557, HLA-C rs1130838, and HLA-C rs2524094) were genotyped by TaqMan assay among drug users and hemodialysis (HD) patients including 1,378 uninfected control cases, 307 subjects with spontaneous viral clearance, and 217 patients with persistent HCV infection. Bioinformatics analysis was used to functionally annotate the SNPs.ResultsAfter logistic regression analysis, the rs35440472-A and rs1130838-A alleles were found to be associated with a significantly elevated risk of HCV infection (OR = 1.562, 95% CI: 1.229–1.987, P < 0.001; OR = 2.134, 95% CI: 1.180–3.858, P = 0.012, respectively), which remained significant after Bonferroni correction (0.05/4). The combined effect of their risk alleles and risk genotypes (rs35440472-AA and rs1130838-AA) were linked to the increased risk of HCV infection in a locus-dosage manner (all Ptrend < 0.001). Based on the SNPinfo web server, rs35440472 was predicted to be a transcription factor binding site (TFBS) while rs1130838 was predicted to have a splicing (ESE or ESS) function.ConclusionKIR2DS4/KIR2DS1/KIR2DL1 rs35440472-A and HLA-C rs1130838-A variants are associated with increased susceptibility to HCV infection in a high-risk Chinese population.

BackgroundCoronavirus disease 2019 (COVID-19) has brought major harm and challenges to the world. Although many studies have suggested that IFN-I could affect the life cycle of the virus by regulating the expression level of microRNAs, the expression characteristics of plasma IFN-I signaling-related miRNAs at the acute and recovery phase of COVID-19 remain unclear.MethodsDemographic characteristics and fasting blood samples were collected from the acute and recovery phases of 29 COVID-19 patients and 29 healthy controls matched by age (± 5years) and gender (1:1). Expression levels of 12 IFN signaling-related miRNAs were analyzed using RT-qPCR. The receptor-binding domain (RBD) IgG antibody in the convalescent plasma samples was detected using competitive ELISA.ResultsCompared with healthy controls, patients with COVID-19 presented increased levels of miR-29b-3p (~ 5.91-fold), miR-497-5p (~ 2.28-fold), and miR-1246 (~ 7.97-fold), and decreased expression levels of miR-186-5p (~ 6.39-fold) and miR-15a-5p (~ 3.26-fold) at the acute phase of infection. However, the expression levels of miR-29b-3p and miR-1246, which significantly elevated at the acute phase, were not different between individuals at the recovery phase and healthy controls. The expression levels of miR-30b-5p, miR-497-5p, miR-409-3p and miR-548c-5p in convalescent plasma samples were significantly lower than those in healthy controls. However, the concentration of miR-186-5p in the convalescent plasma samples was significantly higher than that in healthy controls and patients with acute infection. Furthermore, competitive ELISA results showed that the plasma level of miR-497-5p at the acute phase positively correlated with RBD-IgG antibody response (r=0.48, P=0.038).ConclusionsThe present study firstly reported that timely and appropriate regulation of IFN signaling-related miRNA expression plays a critical role during both acute and recovery phase of SARS-CoV-2 infection. Furthermore, the circulating miR-497-5p level was positively correlated to RBD-IgG antibody response in COVID-19 patients.

SUMMARY Naive human embryonic stem cells (hESCs) have been isolated that more closely resemble the pre-implantation epiblast compared to conventional “primed” hESCs, but the signaling principles underlying these discrete stem cell states remain incompletely understood. Here, we describe the results from a high-throughput screen using ~3,000 well-annotated compounds to identify essential signaling requirements for naive human pluripotency. We report that MEK1/2 inhibitors can be replaced during maintenance of naive human pluripotency by inhibitors targeting either upstream (FGFR, RAF) or downstream (ERK1/2) kinases. Naive hESCs maintained under these alternative conditions display elevated levels of ERK phosphorylation but retain genome-wide DNA hypomethylation and a transcriptional identity of the pre-implantation epiblast. In contrast, dual inhibition of MEK and ERK promotes efficient primed-to-naive resetting in combination with PKC, ROCK, and TNKS inhibitors and activin A. This work demonstrates that induction and maintenance of naive human pluripotency are governed by distinct signaling requirements., Graphical abstract, In brief Khan et al. describe a high-throughput chemical screen to identify essential signaling requirements for naive human pluripotency in minimal conditions. They report that naive hESCs can be maintained by blocking distinct nodes in the FGF signaling pathway and that dual MEK/ERK inhibition promotes efficient primed-to-naive resetting in combination with activin A.

An increase in liver gluconeogenesis is an important pathological phenomenon in type 2 diabetes mellitus (T2DM) and oxymatrine is an effective natural drug used for T2DM treatment. The present study aimed to explore the effect of oxymatrine on gluconeogenesis and elucidate the underlying mechanism. Male Sprague-Dawley rats were treated with a high-fat diet and streptozotocin for 4 weeks to induce T2DM, and HepG2 cells were treated with 55 mM glucose to simulate T2DM in vitro. T2DM rats were treated with oxymatrine (10 or 20 mg/kg weight) or metformin for 4 weeks, and HepG2 cells were treated with oxymatrine (0.1 or 1 µM), metformin (0.1 µM), or oxymatrine combined with MK-2206 (AKT inhibitor) for 24 h. Fasting blood glucose and insulin sensitivity of rats were measured to evaluate insulin resistance. Glucose production and uptake ability were measured to evaluate gluconeogenesis in HepG2 cells, and the expression of related genes was detected to explore the molecular mechanism. Additionally, the body weight, liver weight and liver index were measured and hematoxylin and eosin staining was performed to evaluate the effects of the disease. The fasting glucose levels of T2DM rats was 16.5 mmol/l, whereas in the control rats, it was 6.1 mmol/l. Decreased insulin sensitivity (K-value, 0.2), body weight loss (weight, 300 g), liver weight gain, liver index increase (value, 48) and morphological changes were observed in T2DM rats, accompanied by reduced AKT phosphorylation, and upregulated expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). High-glucose treatment significantly increased glucose production and decreased glucose uptake in HepG2 cells, concomitant with a decrease in AKT phosphorylation and increase of PEPCK and G6Pase expression. In vivo, oxymatrine dose-dependently increased the sensitivity of T2DM rats to insulin, increased AKT phosphorylation and decreased PEPCK and G6Pase expression in the liver, and reversed the liver morphological changes. In vitro, oxymatrine dose-dependently increased AKT phosphorylation and glucose uptake of HepG2 cells subjected to high-glucose treatment, which was accompanied by inhibition of the expression of the gluconeogenesis-related genes, PEPCK and G6Pase. MK-2206 significantly inhibited the protective effects of oxymatrine in high-glucose-treated cells. These data indicated that oxymatrine can effectively prevent insulin resistance and gluconeogenesis, and its mechanism may be at least partly associated with the regulation of PEPCK and G6Pase expression and AKT phosphorylation in the liver.

Carbapenems, as the “last line of defense” against gram-negative bacteria, are increasingly being challenged by drug-resistant bacteria, especially in Enterobacteriaceae. In this study, a carbapenems resistant gram-negative bacterium, named AH001, was isolated from hospital sewage, and modified Hoge test confirmed this bacterium can produce carbapenemase. Further analysis revealed that this bacterium is multi-drug resistance, which against additional seven antibiotics. Whole-genome sequencing and analysis showed that AH001 could not be classified by existing MLST, and its serotype couldn’t be distinguished among O9, O89 or O168 in O antigen prediction. More attention should be paid to the role of environmental source Escherichia coli in the development and transfer of drug resistance in the hospital environment.

MYC-driven medulloblastomas are highly aggressive childhood brain tumors, however, the genetic events triggering MYC amplification and malignant transformation remain elusive. Here we report that mutations in CTDNEP1, a CTD nuclear-envelope-phosphatase, are the most significantly enriched recurrent alterations in MYC-driven medulloblastomas, and define high-risk subsets with poorer prognosis. CTDNEP1 ablation transforms murine cerebellar progenitors into MYC-amplified medulloblastomas, resembling their human counterparts. CTDNEP1 deficiency stabilizes MYC protein by elevating MYC serine-62 phosphorylation, and triggers genomic instability with eventual MYC amplification and p53 loss. Further, phosphoproteomics reveals that CTDNEP1 post-translationally modulates the activities of key regulators for proper chromosome segregation and mitotic checkpoints including topoisomerase TOP2A and checkpoint kinase CHEK1. Co-targeting CHEK1 and MYC activities synergistically inhibits CTDNEP1-deficient MYC-amplified tumor growth and prolongs animal survival. Together, our studies identify CTDNEP1 acting as a tumor suppressor in highly aggressive medulloblastomas by maintaining homeostatic MYC levels and genomic stability, highlighting a CTDNEP1-dependent therapeutic vulnerability.

Understanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application of embryonic stem cells (ESCs). While the protein-protein interactions of core pluripotency factors have been identified in mouse ESCs, their interactome in human ESCs (hESCs) has not to date been explored. Here we mapped the OCT4 interactomes in naïve and primed hESCs, revealing extensive connections to mammalian ATP-dependent nucleosome remodeling complexes. In naïve hESCs, OCT4 is associated with both BRG1 and BRM, the two paralog ATPases of the BAF complex. Genome-wide location analyses and genetic studies reveal that these two enzymes cooperate in a functionally redundant manner in the transcriptional regulation of blastocyst-specific genes. In contrast, in primed hESCs, OCT4 cooperates with BRG1 and SOX2 to promote chromatin accessibility at ectodermal genes. This work reveals how a common transcription factor utilizes differential BAF complexes to control distinct transcriptional programs in naïve and primed hESCs., Although the interactors of pluripotency factors have been identified in mouse embryonic stem cells (ESCs), their interactors in human ESCs remain unexplored. Here the authors map OCT4 protein interactions in naïve and primed human ESCs to find specific interactions with BAF subunits that promote an open chromatin architecture at blastocyst-associated genes and ectodermal genes, respectively.

Light quality is an important environmental factor that drives photosynthesis and regulates plant growth and development. The purpose of this study was to investigate effects of light quality on sugar metabolism of tomato fruit. Tomato variety ‘Micro-Tom’ was used as the test material. After a 30-day cultivation period, seedlings were moved to an artificial climate chamber and grown under different light conditions: ratio of red and blue light, 1:1 (RB11), ratio of red and blue light, 3:1 (RB31), ratio of red and blue light, 5:1 (RB51), ratio of red and blue light, 7:1 (RB71), and white light as the control (CK). Fruit were harvested at the mature green, breaker, and ripe stages. The soluble sugar, total soluble solids, glucose, fructose, and sucrose contents in developing tomato fruit were highest under the RB31 condition. To further investigate effects of light quality on tomato fruit sugar metabolism, proteomic analysis using total proteins extracted from the CK and RB31-treated tomato fruit revealed that nine, three, and two proteins related to sugar metabolism were differentially accumulated between the CK and RB31-treated fruit at mature green, breaker, and ripe stages, respectively. Seven of them were up-regulated and the rest were down-regulated. The transcript abundances of these corresponding genes were analyzed by qRT-PCR. The expression levels of 12 genes were consistent with the protein abundances, but expression levels of xylose isomerase and l-iditol 2-dehydrogenase did not correlate with their protein abundances.

T cells become dysfunctional when they encounter self antigens or are exposed to chronic infection or to the tumour microenvironment1. The function of T cells is tightly regulated by a combinational co-stimulatory signal, and dominance of negative co-stimulation results in T cell dysfunction2. However, the molecular mechanisms that underlie this dysfunction remain unclear. Here, using an in vitro T cell tolerance induction system in mice, we characterize genome-wide epigenetic and gene expression features in tolerant T cells, and show that they are distinct from effector and regulatory T cells. Notably, the transcription factor NR4A1 is stably expressed at high levels in tolerant T cells. Overexpression of NR4A1 inhibits effector T cell differentiation, whereas deletion of NR4A1 overcomes T cell tolerance and exaggerates effector function, as well as enhancing immunity against tumour and chronic virus. Mechanistically, NR4A1 is preferentially recruited to binding sites of the transcription factor AP-1, where it represses effector-gene expression by inhibiting AP-1 function. NR4A1 binding also promotes acetylation of histone 3 at lysine 27 (H3K27ac), leading to activation of tolerance-related genes. This study thus identifies NR4A1 as a key general regulator in the induction of T cell dysfunction, and a potential target for tumour immunotherapy.

Background While emerging evidence indicates that circHIPK3 is critically involved in tumorigenesis and the development of several cancers, its role in prostate cancer (PCa) is not clearly understood. Materials and methods Human PCa samples and their matched normal adjacent tissues were obtained from 26 patients to assess the expression of circHIPK3 and its relationship with PCa prognosis. A series of in vitro and in vivo functional experiments were carried out to elucidate the role of circHIPK3 in PCa progression and its underlying molecular mechanisms. Results In this study, we found that circHIPK3 was overexpressed in PCa tissues and that higher circHIPK3 expression was associated with tumor stage. Moreover, circHIPK3 knockdown markedly inhibited the proliferation, migration, and invasion of PCa cells in vitro and impaired tumor growth in vivo. Bioinformatics analysis and luciferase reporter assays demonstrated that circHIPK3 could promote MCL1 expression by interacting with miR-193a-3p in PCa. Finally, rescue assays illustrated that circHIPK3 knockdown could partially reverse the effects of MCL1 overexpression. Conclusion In summary, our study illustrated, for the first time, that circHIPK3-mediated miR-193a-3p-MCL1 signaling promotes PCa development and progression, providing a novel therapeutic target for PCa.

Summary: Emphysema results in destruction of alveolar walls and enlargement of lung airspaces and has been shown to develop during helminth infections through IL-4R-independent mechanisms. We examined whether interleukin 17A (IL-17A) may instead modulate development of emphysematous pathology in mice infected with the helminth parasite Nippostrongylus brasiliensis. We found that transient elevations in IL-17A shortly after helminth infection triggered subsequent emphysema that destroyed alveolar structures. Furthermore, lung B cells, activated through IL-4R signaling, inhibited early onset of emphysematous pathology. IL-10 and other regulatory cytokines typically associated with B regulatory cell function did not play a major role in this response. Instead, at early stages of the response, B cells produced high levels of the tissue-protective protein, Resistin-like molecule α (RELMα), which then downregulated IL-17A expression. These studies show that transient elevations in IL-17A trigger emphysema and reveal a helminth-induced immune regulatory mechanism that controls IL-17A and the severity of emphysema. : Emphysema causes pathology that can compromise lung function, and mechanisms for reducing disease severity remain unclear. Using a helminth model, Chen et al. show that type 2 immune response triggers lung B cells to produce RELMα, which then downregulates IL-17 production in the lung to limit emphysema. Keywords: emphysema, IL-17, B lymphocytes, RELMα, helminth

BackgroundThe tumor necrosis factor superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) play important roles in the immune responses to infections. The aim of this study was to determine the impact of single nucleotide polymorphisms (SNPs) of several TNFSF/TNFRSF genes on the risk of hepatitis C virus (HCV) infection in the Chinese high-risk population.MethodsThe TNFSF4-rs1234313, TNFSF4-rs7514229, TNFSF8-rs3181366, TNFSF8-rs2295800, TNFRSF8-rs2298209, and TNFRSF8-rs2230625 SNPs were genotyped in 2309 uninfected controls, 597 subjects with spontaneous HCV clearance and 784 patients with persistent HCV infection using the TaqMan-MGB assay. The putative functions of the positive SNPs were determined using online bioinformatics tools.ResultsAfter adjusting for gender, age, high-risk population, alanine transaminase (ALT), aspartate aminotransferase (AST), IL28B-rs12979860 and rs8099917 genotypes, the non-conditional logistic regression showed that rs7514229-T, rs3181366-T, and rs2295800-C were associated with an increased risk of HCV infection (all PFDR < 0.05). Combined analysis of rs7514229-T and rs3181366-T risk alleles showed that the subjects carrying 2–4 risk alleles were more susceptible to HCV infection compared with those lacking any risk allele (all P < 0.001). Furthermore, the risk of HCV infection increased with the number of risk alleles (Ptrend < 0.001). In silico analysis showed that rs7514229, rs3181366, and rs2295800 polymorphisms may affect the transcription of mRNA by regulating miRNA binding, TF binding, and promoter activation, respectively, which may have biological consequences.ConclusionTNFSF4-rs7514229, TNFSF8-rs3181366, and TNFSF8-rs2295800 are associated with increased risk of HCV infection in the Chinese high-risk population.

Oral microbial diversity plays an important role on oral health maintenance. However, there are only few kinds of substrates available for the microbial flora in oral cavity, and it still remains unclear why oral microbial diversity can be formed and sustained without obvious competitive exclusion. Based on experimental phenomena and data, a new hypothesis was proposed, namely, the decomposition product negative feedback regulation on microbial population size and microbial delay responses including reproductive, reaction, interspecific competition, and substrate decomposition delay responses induced by oral immunity. According to hypothesis and its cellular automata (CA) model, the CA simulation results sufficiently proved that the decomposition product negative feedback regulation and four microbial delay responses could significantly alleviate the interspecific competitions and inhibit the emergence of dominant species, causing the formation and sustenance of oral microbial diversity. This study could also offer effective guidance of prevention and treatment of oral cavity diseases.

The study was conducted to evaluate the effect of water temperatures and intraperitoneal administration of microcystins (MCs) on the pharmacokinetics characteristics of epigallocatechin gallate (EGCG) in snakehead fish (Ophiocephalus argus Cantor) by RP-HPLC method. The results showed that EGCG was absorbed and eliminated more faster at 20ºC than at 10ºC. Then the detected results also showed that EGCG was significantly absorbed fast in MCs-treated group than in control group. However, EGCG elimination became very lowly in MCs-treated group. Therefore, the pharmacokinetic characteristics of EGCG were significantly affected by water temperature and MCs toxin.

Trisomy 21 induces microglial dysregulation in the Alzheimer’s brain through the perturbation of the ubiquitin-proteasome system., Down syndrome (DS), caused by trisomy of chromosome 21, is the most significant risk factor for early-onset Alzheimer’s disease (AD); however, underlying mechanisms linking DS and AD remain unclear. Here, we show that triplication of homologous chromosome 21 genes aggravates neuroinflammation in combined murine DS-AD models. Overexpression of USP25, a deubiquitinating enzyme encoded by chromosome 21, results in microglial activation and induces synaptic and cognitive deficits, whereas genetic ablation of Usp25 reduces neuroinflammation and rescues synaptic and cognitive function in 5×FAD mice. Mechanistically, USP25 deficiency attenuates microglia-mediated proinflammatory cytokine overproduction and synapse elimination. Inhibition of USP25 reestablishes homeostatic microglial signatures and restores synaptic and cognitive function in 5×FAD mice. In summary, we demonstrate an unprecedented role for trisomy 21 and pathogenic effects associated with microgliosis as a result of the increased USP25 dosage, implicating USP25 as a therapeutic target for neuroinflammation in DS and AD.

Background Although previous studies have reported the gut microbiome is closely related to hypertension development, whether the change in blood microbiome is associated with the risk of hypertension remains unclear. Methods One hundred and fifty incident hypertension cases and 150 age (± 2 years) and gender (1:1) matched nonhypertension controls included in this nested case–control study were recruited from a prospective cohort study of “135.” The composition of the blood microbiome was characterized using bacterial 16S ribosomal RNA gene sequencing. The relative abundance of detected bacteria was converted to a negative logarithm of 10 for the statistical analysis. Results Totally, 10,689,961 high-quality sequences were acquired. The Chao1 index of the blood microbiome in nonhypertension controls was significantly higher than in hypertensive group (2,302.08 ± 752.78 vs. 1,598.21 ± 500.88, P < 0.001). Compared with the nonhypertension controls, the relative abundance of Proteobacteria phylum was significantly increased (P < 0.001), whereas the relative abundance of phyla Firmicutes and Bacteroidetes were significantly reduced in the hypertensive cases (P < 0.001 and P = 0.039, respectively). At genus level, the risk of hypertension was directly associated with the relative abundance of Acinetobacter (odds ratio [OR]: 1.43, 95% confidence interval [CI]: 1.01–2.03), Sphingomonas (OR: 1.84, 95% CI: 1.32–2.56), and Staphylococcus (OR: 0.51, 95% CI: 0.36–0.73), respectively. In addition, the relative abundance of Pseudomonas was minor positively correlated with the total cholesterol level. However, the relative Staphylococcus level was minor positively correlated with high-density lipoprotein cholesterol level. Conclusions The composition of the blood microbiome is significantly associated with the development of hypertension.

Programmed death ligand 1 (PD-L1, CD274) is an essential immune checkpoint protein that binds to programmed death 1 (PD-1) on T-lymphocytes. T cell plays a critical role in killing cancer cells while the cancer cell exhibits immune escape by the expression of PD-L1. The binding of PD-L1 to PD-1 inhibits T cell proliferation and activity, leading to tumor immunosuppression. Increasing evidence shows that PD-L1 protein undergoes degradation in proteasomes or lysosomes by multiple pathways, leading to enhanced immunotherapy for cancer. Although some specific drugs induce PD-L1 degradation and increase antitumor activity, the combination of these drugs with PD-L1/PD-1 blockade significantly enhances cancer immunotherapy. In this review, we have discussed the interaction of PD-L1 degradation with cancer immunotherapy.

Compared with the normal environment, the microbiota in controlled closed cabins such as space capsules, Lunar/Mars bases have changed. To ensure the health of crewmembers, it’s necessary to understand the effects of these changes on human symbiotic microorganisms and immunity. In this study, the experimental platform “Lunar Palace 1” with a similar closed and controlled environment was used to research the effects of changed microbial exposure on human saliva microbiota and salivary cytokines. This paper studied on four crewmembers who participated in the third phase of the “Lunar Palace 365” experiment, analyzing the dynamic changes of saliva microbiota and salivary cytokines, and further studying the correlation between salivary cytokines and highly abundant genera. According to our data, the crewmembers’ saliva microbiota and salivary cytokines fluctuated smoothly throughout the whole experiment. Although a part of microbes increased or decreased some times, they recovered quickly after leaving the controlled environment. The level of IL-6, IL-10 and TNF-α in crewmembers’ saliva decreased from normal environment to the controlled environment, showing reduced levels of oral inflammatory response in crewmembers. In addition, although there were significant individual differences in crewmembers’ saliva microbiota, sharing living space reduced the difference. Furthermore, the level of TNF-α showed a consistent positive correlation with the abundance of Actinomyces and Rothia in the controlled environment, indicating healthy individuals’ oral mucosal barrier may be sensitive to changes in saliva microbiota. According to the result, semi-sterile environments in controlled closed cabins didn’t cause persistent changes in human saliva microbiota and oral immunity. Besides, it provides a new idea for future research on the impact of the controlled environment on crewmembers health, and provides guidance for studying the effect of semi-sterile environments on human immunity based on saliva microbiota.Key pointsSaliva microbes kept stable for individual but got convergent when sharing space;The level of salivary cytokines reduced after entering the controlled environment;There were complex correlations between salivary cytokines and saliva microbes;The crewmembers adapt well to the controlled environment.