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Pancreatic stellate cells (PSCs) secrete various factors, which can influence the β-cell function. The identification of stellate cell infiltration into the islets in pancreatic diseases suggests possible existence of cross-talk between these cells. To elucidate the influence of PSCs on β-cell function, mouse PSCs were cocultured with Min6 cells using the Transwell inserts. Glucose-stimulated insulin secretion from Min6 cells in response to PSCs was quantified by enzyme-linked immunosorbent assay and insulin gene expression was measured by quantitative polymerase chain reaction. Upon cytometric identification of IL6 in PSC culture supernatants, Min6 cells were cultured with IL6 to assess its influence on the insulin secretion and gene expression. PLC-IP3 pathway inhibitors were added in the cocultures, to determine the influence of PSC-secreted IL6 on Glucose-stimulated insulin secretion from Min6 cells. Increased insulin secretion with a concomitant decrease in total insulin content was noticed in PSC-cocultured Min6 cells. Although increased GSIS was noted from IL6-treated Min6 cells, no change in the total insulin content was noted. Coculture of Min6 cells with PSCs or their exposure to IL6 did not alter either the expression of β-cell-specific genes or that of miRNA-375. PSC-cocultured Min6 cells, in the presence of PLC-IP3 pathway inhibitors (U73122, Neomycin, and Xestospongin C), did not revoke the observed increase in GSIS. In conclusion, the obtained results indicate that augmented insulin secretion from Min6 cells in response to PSC secretions is independent of IL6-mediated PLC-IP3 pathway.  相似文献   
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Four bacterial and one yeast species, cultured and identified as Stenotrophomonas maltophilia, Acinetobacter sp., Pseudomonas sp. and Ochrobactrum sp. and the yeast as Metschnikowia reukaufii, were isolated from the internal organs of four collections of field-sourced egg parasitoid, Trichogramma chilonis, obtained as parasitised Helicoverpa armigera eggs. Bacteria were identified through 16 rRNA amplification and sequencing. The single species of yeast was identified through internal transcribed spacer sequences. A single bacterial species could be isolated from each of the four T. chilonis collections; however, all four T. chilonis collections yielded the yeast, M. reukaufii. In order to study the influence of the association of each of the bacterial species and the yeast, microbe-free laboratory-bred populations of T. chilonis were fed with the individual cultures and fitness parameters as parasitisation vigour and female bias were studied in T. chilonis over 10 generations. T. chilonis fed with either S. maltophilia or Acinetobacter sp. and Pseudomonas sp. showed a mean percent increase in female ratio of 26.2%, 30% and 30.3% and mean percent parasitisation of H. armigera eggs significantly increased by 38%, 32.2% and 31.3%, respectively. However, T. chilonis fed with Acinetobacter sp. did not positively influence the two T. chilonis fitness factors. The ubiquitous yeast, M. reukaufii, which could be isolated from all four collections of T. chilonis, could significantly increase both female count and percent parasitism ratio by 22% and 65%, respectively. This study has opened the possibility of modulating the parasitisation fitness of laboratory-bred T. chilonis, prior to field release, using microbes associated with them in the wild.  相似文献   
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Janus kinases (JAKs) are critical regulators of cytokine pathways and attractive targets of therapeutic value in both inflammatory and myeloproliferative diseases. Although the crystal structures of active JAK1 and JAK2 kinase domains have been reported recently with the clinical compound CP-690550, the structures of both TYK2 and JAK3 with CP-690550 have remained outstanding. Here, we report the crystal structures of TYK2, a first in class structure, and JAK3 in complex with PAN-JAK inhibitors CP-690550 ((3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile) and CMP-6 (tetracyclic pyridone 2-t-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-one), both of which bind in the ATP-binding cavities of both JAK isozymes in orientations similar to that observed in crystal structures of JAK1 and JAK2. Additionally, a complete thermodynamic characterization of JAK/CP-690550 complex formation was completed by isothermal titration calorimetry, indicating the critical role of the nitrile group from the CP-690550 compound. Finally, computational analysis using WaterMap further highlights the critical positioning of the CP-690550 nitrile group in the displacement of an unfavorable water molecule beneath the glycine-rich loop. Taken together, the data emphasize the outstanding properties of the kinome-selective JAK inhibitor CP-690550, as well as the challenges in obtaining JAK isozyme-selective inhibitors due to the overall structural and sequence similarities between the TYK2, JAK1, JAK2 and JAK3 isozymes. Nevertheless, subtle amino acid variations of residues lining the ligand-binding cavity of the JAK enzymes, as well as the global positioning of the glycine-rich loop, might provide the initial clues to obtaining JAK-isozyme selective inhibitors.  相似文献   
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Key message

Seed weight QTL identified in different populations were synthesized into consensus QTL which were shown to harbor candidate genes by in silico mapping. Allelic variation inferred would be useful in breeding B. juncea lines with high seed weight.

Abstract

Seed weight is an important yield influencing trait in oilseed Brassicas and is a multigenic trait. Among the oilseed Brassicas, Brassica juncea harbors the maximum phenotypic variation wherein thousand seed weight varies from around 2.0 g to more than 7.0 g. In this study, we have undertaken quantitative trait locus/quantitative trait loci (QTL) analysis of seed weight in B. juncea using four bi-parental doubled-haploid populations. These four populations were derived from six lines (three Indian and three east European lines) with parental phenotypic values for thousand seed weight ranging from 2.0 to 7.6 g in different environments. Multi-environment QTL analysis of the four populations identified a total of 65 QTL ranging from 10 to 25 in each population. Meta-analysis of these component QTL of the four populations identified six ‘consensus’ QTL (C-QTL) in A3, A7, A10 and B3 by merging 33 of the 65 component Tsw QTL from different bi-parental populations. Allelic diversity analysis of these six C-QTL showed that Indian lines, Pusajaikisan and Varuna, hold the most positive allele in all the six C-QTL. In silico mapping of candidate genes with the consensus QTL localized 11 genes known to influence seed weight in Arabidopsis thaliana and also showed conserved crucifer blocks harboring seed weight QTL between the A subgenomes of B. juncea and B. rapa. These findings pave the way for a better understanding of the genetics of seed weight in the oilseed crop B. juncea and reveal the scope available for improvement of seed weight through marker-assisted breeding.
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Elevated plasma triglyceride (TG) levels are an established risk factor for type-2 diabetes (T2D). However, recent studies have hinted at the possibility that genetic risk for TG may paradoxically protect against T2D. In this study, we examined the association of genetic risk for TG with incident T2D, and the interaction of baseline TG with TG genetic risk on incident T2D in 13,247 European-Americans (EA) and 3,238 African-Americans (AA) from three prospective cohort studies. A TG genetic risk score (GRS) was calculated based on 31 validated single nucleotide polymorphisms (SNPs). We considered several baseline covariates, including body- mass index (BMI) and lipid traits. Among EA and AA, we find, as expected, that baseline levels of TG are strongly positively associated with incident T2D (p<2 x 10-10). However, the TG GRS is negatively associated with T2D (p=0.013), upon adjusting for only race, in the full dataset. Upon additionally adjusting for age, sex, BMI, high-density lipoprotein cholesterol and TG, the TG GRS is significantly and negatively associated with T2D incidence (p=7.0 x 10-8), with similar trends among both EA and AA. No single SNP appears to be driving this association. We also find a significant statistical interaction of the TG GRS with TG (pinteraction=3.3 x 10-4), whereby the association of TG with incident T2D is strongest among those with low genetic risk for TG. Further research is needed to understand the likely pleiotropic mechanisms underlying these findings, and to clarify the causal relationship between T2D and TG.  相似文献   
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Genome stability is jeopardized by imbalances of the dNTP pool; such imbalances affect the rate of fork progression. For example, cytidine deaminase (CDA) deficiency leads to an excess of dCTP, slowing the replication fork. We describe here a novel mechanism by which pyrimidine pool disequilibrium compromises the completion of replication and chromosome segregation: the intracellular accumulation of dCTP inhibits PARP-1 activity. CDA deficiency results in incomplete DNA replication when cells enter mitosis, leading to the formation of ultrafine anaphase bridges between sister-chromatids at “difficult-to-replicate” sites such as centromeres and fragile sites. Using molecular combing, electron microscopy and a sensitive assay involving cell imaging to quantify steady-state PAR levels, we found that DNA replication was unsuccessful due to the partial inhibition of basal PARP-1 activity, rather than slower fork speed. The stimulation of PARP-1 activity in CDA-deficient cells restores replication and, thus, chromosome segregation. Moreover, increasing intracellular dCTP levels generates under-replication-induced sister-chromatid bridges as efficiently as PARP-1 knockdown. These results have direct implications for Bloom syndrome (BS), a rare genetic disease combining susceptibility to cancer and genomic instability. BS results from mutation of the BLM gene, encoding BLM, a RecQ 3’-5’ DNA helicase, a deficiency of which leads to CDA downregulation. BS cells thus have a CDA defect, resulting in a high frequency of ultrafine anaphase bridges due entirely to dCTP-dependent PARP-1 inhibition and independent of BLM status. Our study describes previously unknown pathological consequences of the distortion of dNTP pools and reveals an unexpected role for PARP-1 in preventing DNA under-replication and chromosome segregation defects.  相似文献   
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