Desulfovibrio vulgaris interacts with novel gut epithelial immune receptor LRRC19 and exacerbates colitis.

BACKGROUND: The overgrowth of Desulfovibrio, an inflammation promoting flagellated bacteria, has been found in ulcerative colitis (UC) patients. However, the molecular mechanism in promoting colitis remains unestablished. METHODS: The relative abundance Desulfovibrio vulgaris (D. vulgaris) in stool samples of UC patients was detected. Mice were treated with dextran sulfate sodium to induce colitis with or without administration of D. vulgaris or D. vulgaris flagellin (DVF), and the severity of colitis and the leucine-rich repeat containing 19 (LRRC19) signaling were assessed. The interaction between DVF and LRRC19 was identified by surface plasmon resonance and intestinal organoid culture. Lrrc19-/- and Tlr5-/- mice were used to investigate the indispensable role of LRRC19. Finally, the blockade of DVF-LRRC19 interaction was selected through virtual screening and the efficacy in colitis was assessed. RESULTS: D. vulgaris was enriched in fecal samples of UC patients and was correlated with the disease severity. D. vulgaris or DVF treatment significantly exacerbated colitis in germ-free mice and conventional mice. Mechanistically, DVF could interact with LRRC19 (rather than TLR5) in colitis mice and organoids, and then induce the production of pro-inflammatory cytokines. Lrrc19 knockdown blunted the severity of colitis. Furthermore, typhaneoside, a blockade of binding interfaces, blocked DVF-LRRC19 interaction and dramatically ameliorated DVF-induced colitis. CONCLUSIONS: D. vulgaris could promote colitis through DVF-LRRC19 interaction. Targeting DVF-LRRC19 interaction might be a new therapeutic strategy for UC therapy. Video Abstract.

Fecal microbiota transplantation: no longer cinderella in tumour immunotherapy.

The incidence of cancer has shown a great increase during the past decades and poses tough challenges to cancer treatment. Anti-tumour immunotherapy, represented by immune checkpoint inhibitors (ICIs), possesses favorable remission in unrestricted spectrum of cancer types. However, its efficacy seems to be heterogeneous among accumulating studies. Emerging evidences suggest that gut microbiota can modulate anti-tumour immuno-response and predict clinical prognosis. Therefore, remodeling microbiota characteristics with fecal microbiota transplantation (FMT) may be capable of reinforcing host ICIs performance by regulating immune-tumour cell interactions and altering microbial metabolites, thereby imperceptibly shifting the tumour microenvironment. However, the long-term safety of FMT is under concern, which calls for more rigorous screening. In this review, we examine current experimental and clinical evidences supporting the FMT efficacy in boosting anti-tumour immuno-response and lessening tumour-related complications. Moreover, we discuss the challenges in FMT and propose feasible resolutions, which may offer crucial guidance for future clinical operations.

Interface Engineering Modulated Valley Polarization in MoS2/hBN Heterostructure.

Layered transition metal dichalcogenides (TMDs) provide a favorable research platform for the advancement of spintronics and valleytronics because of their unique spin-valley coupling effect, which is attributed to the absence of inversion symmetry coupled with the presence of time-reversal symmetry. To maneuver the valley pseudospin efficiently is of great importance for the fabrication of conceptual devices in microelectronics. Here, we propose a straightforward way to modulate valley pseudospin with interface engineering. An underlying negative correlation between the quantum yield of photoluminescence and the degree of valley polarization was discovered. Enhanced luminous intensities were observed in the MoS2/hBN heterostructure but with a low value of valley polarization, which was in stark contrast to those observed in the MoS2/SiO2 heterostructure. Based on the steady-state and time-resolved optical measurements, we reveal the correlation between exciton lifetime, luminous efficiency, and valley polarization. Our results emphasize the significance of interface engineering for tailoring valley pseudospin in two-dimensional systems and probably advance the progression of the conceptual devices based on TMDs in spintronics and valleytronics.

Remnant Cholesterol as an Independent Predictor of Periodontitis: A Population-Based Study.

Objective: Numerus studies present that remnant cholesterol (RC) as a risk factor participates in the progression of multiple diseases. The aim of this study was to assess the relationship between cholesterol and periodontitis in the US population to find a reliable lipid predictor for periodontitis. Materials and Methods: Clinical data was retrieved from the National Health and Nutrition Examination Survey (NHANES) database between 2009 and 2014. The logistic regression was conducted to examine the corelationship between RC and various clinical features. Meanwhile, the dose-response relationship was measured through restricted cubic spline analysis. And the propensity score matching (PSM) was established to further investigate the potential relationship between RC and periodontitis. Results: A number of 4,829 eligible participants were included in this study. It was found that the increased RC is associated with the higher risk of periodontitis after adjusting the potential confounding factors with the adjusted odds ratios (aOR) of 1.403 (95% confidence intervals (CI): 1.171-1.681, P < 0.001, univariate analysis) and 1.341 (95% CI: 1.105-1.629, P = 0.003, multivariate analysis) in the highest grade. There were significant differences in the relationship between RC and various clinical features including age, gender, body mass index (BMI), race, hypertension, and diabetes mellitus (all P < 0.001). Besides, the calculated thresholds for predicting periodontitis were 19.99 (before propensity score matching (PSM)) and 20.91 (after PSM) mg/dL. Conclusions: In this study, RC was identified to be positively associated with the occurrence of periodontitis, which suggests that RC can be considered as a predictor for periodontitis.

Prenatal Maternal Stress Exacerbates Experimental Colitis of Offspring in Adulthood.

The prevalence of inflammatory bowel disease (IBD) is increasing worldwide and correlates with dysregulated immune response because of gut microbiota dysbiosis. Some adverse early life events influence the establishment of the gut microbiota and act as risk factors for IBD. Prenatal maternal stress (PNMS) induces gut dysbiosis and perturbs the neuroimmune network of offspring. In this study, we aimed to investigate whether PNMS increases the susceptibility of offspring to colitis in adulthood. The related index was assessed during the weaning period and adulthood. We found that PNMS impaired the intestinal epithelial cell proliferation, goblet cell and Paneth cell differentiation, and mucosal barrier function in 3-week-old offspring. PNMS induced low-grade intestinal inflammation, but no signs of microscopic inflammatory changes were observed. Although there was no pronounced difference between the PNMS and control offspring in terms of their overall measures of alpha diversity for the gut microbiota, distinct microbial community changes characterized by increases in Desulfovibrio, Streptococcus, and Enterococcus and decreases in Bifidobacterium and Blautia were induced in the 3-week-old PNMS offspring. Notably, the overgrowth of Desulfovibrio persisted from the weaning period to adulthood, consistent with the results observed using fluorescence in situ hybridization in the colon mucosa. Mechanistically, the fecal microbiota transplantation experiment showed that the gut microbiota from the PNMS group impaired the intestinal barrier function and induced low-grade inflammation. The fecal bacterial solution from the PNMS group was more potent than that from the control group in inducing inflammation and gut barrier disruption in CaCo-2 cells. After treatment with a TNF-α inhibitor (adalimumab), no statistical difference in the indicators of inflammation and intestinal barrier function was observed between the two groups. Finally, exposure to PNMS remarkably increased the values of the histopathological parameters and the inflammatory cytokine production in a mouse model of experimental colitis in adulthood. These findings suggest that PNMS can inhibit intestinal development, impair the barrier function, and cause gut dysbiosis characterized by the persistent overgrowth of Desulfovibrio in the offspring, resulting in exacerbated experimental colitis in adulthood.

A spontaneous bilateral fallopian tube pregnancy with didelphic uterus: A case report.

RATIONALE: In this article, we report interesting clinical manifestation of spontaneous bilateral fallopian tube pregnancies in a patient with a didelphic uterus. PATIENT CONCERNS: A 26-year-old female patient, gravida 2, para 0 + 1, suffered from progressive abdominal pain and vaginal bleeding. A laboratory exam revealed a human chorionic gonadotropin level of 1091 IU/L. Transvaginal ultrasound detected no embryo sacs in the uterus but revealed a didelphic uterus, and a mass measuring 39 mm x 32 mm in the left adnexa region with another mass measuring 42 x 28 mm in the right adnexa region. DIAGNOSES: An ectopic pregnancy in the left adnexa region and a corpus hemorrhagicum in the right adnexa region were suspected. INTERVENTIONS: Laparoscopic exploration operation confirmed a didelphic uterus, and pathological biopsy revealed bilateral fallopian tube pregnancies. OUTCOMES: The patient made a good recovery and the human chorionic gonadotropin became normal within the following 2 months. LESSONS: To the best of our knowledge, clinical manifestation of spontaneous bilateral fallopian tube pregnancies in a patient with a didelphic uterus has never been reported before. Based on the experience with this case, we suggest that if a gestational sac is found in 1 fallopian tube, the contralateral fallopian tube needs to be examined for an ectopic pregnancy during surgery.

Mir-27a-3p attenuates bronchiolitis obliterans in vivo via the regulation of dendritic cells' maturation and the suppression of myofibroblasts' differentiation.

Bronchiolitis obliterans (BO), is a chronic rejection phenotype characterized by chronic small airway fibrous obliteration, hinders the patients who suffer from lung transplanting for surviving longer. Cell-based therapies using dendritic cells (DCs) and T regulatory cells (Tregs) have been developed to regulate allograft rejection, and to induce and maintain immune tolerance. In the present study, the effects of mir-27a-3p on regulating DCs as well as resulting effects on BO attenuation have been investigated. According to our reporter assays, the potential targets of mir-27a-3p were Smad2, sprouty2, and Smad4, respectively. Furthermore, sprouty2 inhibition by mir-27-3p indirectly activated extracellular regulated protein kinases (ERK) and increased IL-10 production in DCs. This led to a positive feedback loop that maintained the immature state of DCs via IL-10/JAK/STAT3 pathway, and caused an increase in Foxp3+ CD4+ T cells amount as well as TGF-ß level. Furthermore, mir-27a-3p regulated TGF-ß function, inhibited TGF-ß/Smad pathway, and suppressed myofibroblast differentiation through influencing the function of Smad2 and Smad4. In short, the study indicated the effect of mir-27a-3p on suppressing DC maturation, which implicated the potential clinical application in treating postlung transplant BO.

Construction of gene causal regulatory networks using microarray data with the coefficient of intrinsic dependence.

BACKGROUND: In the past two decades, biologists have been able to identify the gene signatures associated with various phenotypes through the monitoring of gene expressions with high-throughput biotechnologies. These gene signatures have in turn been successfully applied to drug development, disease prevention, crop improvement, etc. However, ignoring the interactions among genes has weakened the predictive power of gene signatures in practical applications. Gene regulatory networks, in which genes are represented by nodes and the associations between genes are represented by edges, are typically constructed to analyze and visualize such gene interactions. More specifically, the present study sought to measure gene-gene associations by using the coefficient of intrinsic dependence (CID) to capture more nonlinear as well as cause-effect gene relationships. RESULTS: A stepwise procedure using the CID along with the partial coefficient of intrinsic dependence (pCID) was demonstrated for the rebuilding of simulated networks and the well-known CBF-COR pathway under cold stress using Arabidopsis microarray data. The procedure was also applied to the construction of bHLH gene regulatory pathways under abiotic stresses using rice microarray data, in which OsbHLH104, a putative phytochrome-interacting factor (OsPIF14), and OsbHLH060, a positive regulator of iron homeostasis (OsPRI1) were inferred as the most affiliated genes. The inferred regulatory pathways were verified through literature reviews. CONCLUSIONS: The proposed method can efficiently decipher gene regulatory pathways and may assist in achieving higher predictive power in practical applications. The lack of any mention in the literature of some of the regulatory event may have been due to the high complexity of the regulatory systems in the plant transcription, a possibility which could potentially be confirmed in the near future given ongoing rapid developments in bio-technology.

The correlation between growth hormone receptor (GHR) polymorphism and obstructive sleep apnea syndrome among the Han and Hani population in China.

Obstructive sleep apnea syndrome (OSAS) is a common health problem that is associated with abnormality in craniofacial morphology. The growth hormone receptor (GHR) belongs to the cytokine receptor superfamily and mediates the majority of growth hormone signaling, which, among other functions, determines mandibular growth and development. The aim of this study was to determine if correlations exist between single nucleotide polymorphisms (SNPs) in the GHR gene and OSAS in the Han or Hani ethnic groups in China. A total of 274 Han subjects (106 with OSAS and 168 without OSAS) and a total of 270 Hani subjects (64 with OSAS and 206 without OSAS) were enrolled in our study. Genomic DNA was extracted from peripheral blood obtained from all subjects. Genotyping was undertaken for eight SNPs in the GHR gene (rs3756416, rs7727047, rs2910875, rs12153009, rs2972781, rs12518414, rs4410646, and rs6451620) using PCR amplification and Sanger sequencing. The genotype frequency of rs12518414 was associated with OSAS in both the Han and Hani groups, and the A allele frequency was remarkably lower in Hani OSAS patients compared with Hani controls (16.7 vs 29.9%). In addition, the G allele frequency of the rs3756416 SNP was significantly lower in OSAS patients compared with normal controls in the Hani ethnic group (12.5 vs 24.6%). In a comparison between ethnic groups, genotype frequencies of four SNPs (rs2972781, rs6451620, rs12518414, and rs7727047) differed between Han and Hani OSAS patients, with the A allele frequency of the rs12518414 and G allele frequency of the rs7727047 were significantly higher in the Han OSAS patients. In conclusion, significant associations were detected between some SNPs in the GHR gene and OSAS occurrence while others appeared to be ethnicity-dependent.

The function of OsbHLH068 is partially redundant with its homolog, AtbHLH112, in the regulation of the salt stress response but has opposite functions to control flowering in Arabidopsis.

KEY MESSAGE: The homologous genes OsbHLH068 and AtbHLH112 have partially redundant functions in the regulation of the salt stress response but opposite functions to control flowering in Arabidopsis. The transcription factor (TF) basic/Helix-Loop-Helix (bHLH) is important for plant growth, development, and stress responses. OsbHLH068, which is a homologous gene of AtbHLH112 that is up-regulated under drought and salt stresses, as indicated by previous microarray data analysis. However, the intrinsic function of OsbHLH068 remains unknown. In the present study, we characterized the function and compared the role of OsbHLH068 with that of its homolog, AtbHLH112. Histochemical GUS staining indicated that OsbHLH068 and AtbHLH112 share a similar expression pattern in transgenic Arabidopsis during the juvenile-to-adult phase transition. Heterologous overexpression of OsbHLH068 in Arabidopsis delays seed germination, decreases salt-induced H2O2 accumulation, and promotes root elongation, whereas AtbHLH112 knock-out mutant displays an opposite phenotype. Both OsbHLH068-overexpressing transgenic Arabidopsis seedlings and the Atbhlh112 mutant display a late-flowering phenotype. Moreover, the expression of OsbHLH068-GFP driven by an AtbHLH112 promoter can compensate for the germination deficiency in the Atbhlh112 mutant, but the delayed-flowering phenotype tends to be more severe. Further analysis by microarray and qPCR indicated that the expression of FT is down-regulated in both OsbHLH068-overexpressing Arabidopsis plants and Atbhlh112 mutant plants, whereas SOC1 but not FT is highly expressed in AtbHLH112-overexpressing Arabidopsis plants. A comparative transcriptomic analysis also showed that several stress-responsive genes, such as AtERF15 and AtPUB23, were affected in both OsbHLH068- and AtbHLH112-overexpressing transgenic Arabidopsis plants. Thus, we propose that OsbHLH068 and AtbHLH112 share partially redundant functions in the regulation of abiotic stress responses but have opposite functions to control flowering in Arabidopsis, presumably due to the evolutionary functional divergence of homolog-encoded proteins.

Comparative Transcriptome Analysis of Shoots and Roots of TNG67 and TCN1 Rice Seedlings under Cold Stress and Following Subsequent Recovery: Insights into Metabolic Pathways, Phytohormones, and Transcription Factors.

Cold stress affects rice growth, quality and yield. The investigation of genome-wide gene expression is important for understanding cold stress tolerance in rice. We performed comparative transcriptome analysis of the shoots and roots of 2 rice seedlings (TNG67, cold-tolerant; and TCN1, cold-sensitive) in response to low temperatures and restoration of normal temperatures following cold exposure. TNG67 tolerated cold stress via rapid alterations in gene expression and the re-establishment of homeostasis, whereas the opposite was observed in TCN1, especially after subsequent recovery. Gene ontology and pathway analyses revealed that cold stress substantially regulated the expression of genes involved in protein metabolism, modification, translation, stress responses, and cell death. TNG67 takes advantage of energy-saving and recycling resources to more efficiently synthesize metabolites compared with TCN1 during adjustment to cold stress. During recovery, expression of OsRR4 type-A response regulators was upregulated in TNG67 shoots, whereas that of genes involved in oxidative stress, chemical stimuli and carbohydrate metabolic processes was downregulated in TCN1. Expression of genes related to protein metabolism, modification, folding and defense responses was upregulated in TNG67 but not in TCN1 roots. In addition, abscisic acid (ABA)-, polyamine-, auxin- and jasmonic acid (JA)-related genes were preferentially regulated in TNG67 shoots and roots and were closely associated with cold stress tolerance. The TFs AP2/ERF were predominantly expressed in the shoots and roots of both TNG67 and TCN1. The TNG67-preferred TFs which express in shoot or root, such as OsIAA23, SNAC2, OsWRKY1v2, 24, 53, 71, HMGB, OsbHLH and OsMyb, may be good candidates for cold stress tolerance-related genes in rice. Our findings highlight important alterations in the expression of cold-tolerant genes, metabolic pathways, and hormone-related and TF-encoding genes in TNG67 rice during cold stress and recovery. The cross-talk of hormones may play an essential role in the ability of rice plants to cope with cold stress.

A novel function of abscisic acid in the regulation of rice (Oryza sativa L.) root growth and development.

Plant roots retain developmental plasticity and respond to environmental stresses or exogenous plant growth regulators by undergoing profound morphological and physiological alteration. In this study, we investigated the effects of exogenous ABA on root growth and development in Taichung native 1 (TN1) rice. Exogenous application of 10 microM ABA leads to swelling, root hair formation and initiation of lateral root primodia in the tips of young, seminal rice roots. Cortex cells increased in size and were irregularly shaped. ABA treatment significantly increased 2, 3, 5-triphenyl tetrazolium chloride (TTC) reductase ability in the root tips and the exudation rate of xylem sap. In addition, the K(+) ion content in xylem sap increased nearly 2-fold, but not that of Ca(2+) or Mg(2+). Analysis of proteins expressed in the root tips identified several ABA-induced or -repressed proteins, including actin depolymerization factor (ADF), late embryo abundant protein (LEA), putative steroid membrane-binding protein, ferredoxin thionine reductase and calcium-binding protein. The effects of ABA on root morphogenesis change were Ca(2+) dependent and required the participation of calmodulin and de novo protein synthesis. A model is presented that illustrates how ABA acts through a potential cellular and signal transduction mechanism to induce morphological and physiological changes in rice roots.