Background and Aims: Yes-associated protein (YAP) is a key transcriptional coactivator of cell proliferation and differentiation. In this study, we sought to identify the roles of YAP in colonic ...epithelial regeneration and tumourigenesis. Methods: Murine DSS-induced colitis and YAP overexpression models were constructed via lentiviral intraperitoneal injection. Stable YAP-overexpressing cells, protein immunoprecipitation, and ChIP were used to deeply explore the molecular mechanism. Results: We found that the expression of YAP was dramatically diminished in the colonic crypts during the acute colitis phase, while YAP was strikingly enhanced to initiate tissue repair after DSS withdrawal. Overexpressing YAP in mice drastically accelerated epithelial regeneration, presenting with more intact structural integrity and reduced inflammatory cell infiltration in the mucosa. Further mechanistic studies showed that the expression of YAP in the nucleus was significantly increased by 2 h post-DSS removal, accompanied by upregulated protein levels of activated STAT3. Overexpression of YAP (YAP.sup.WT) elevated the expression of activated STAT3 and its transcriptional targets and strengthened the proliferation and "wound healing" ability of colonic cells. However, these effects were reversed when STAT3 was silenced in YAP.sup.WT cells. Moreover, YAP could directly interact with STAT3 in the nucleus, and c-Myc and CyclinDl were the transcriptional targets. Finally, during colitis-associated cancer (CAC), YAP.sup.WT promoted the progression of CAC, while the phosphomimetic YAP downregulated the expression of STAT3 and inhibited the development and progression of CAC. Conclusion: YAP activates STAT3 signalling to facilitate mucosal regeneration after DSS-induced colitis. However, excessive YAP activation in the colonic epithelium promotes CAC development. Keywords: dextran sodium sulfate, DSS induced colitis, mucosal repair, YAP, STAT3, colitis-associated cancer
The effect of pore water chemistry on the hydro-mechanical behaviour of soft marine clay of Lianyungang was investigated. Field investigation and piezo-cone penetration tests at two sites with 0.56% ...and 4.91% salinity respectively were first performed, and a significant difference was observed in terms of Atterberg's limits (LL and PL), density, net tip resistance, sleeve friction and pore water pressure parameter, suggesting a significant effect of pore water chemistry. To confirm this observation, identification tests were extended to an artificial soil corresponding to a mixture of kaolinite/bentonite with different salinities. The results obtained confirm the significant effect of pore water chemistry. To further clarify this effect, oedometer tests were performed with both site water and deionised water. The results indicated that the compression index, swelling index, and secondary consolidation coefficient are higher in the case of deionised water, whereas the oedometer modulus, consolidation coefficient and hydraulic conductivity are larger in the case of site water. However, the ratio between secondary consolidation coefficient and compression (or swelling) index indicates no significant effect of pore water salinity. After completion of the oedometer tests, the microstructure features were studied by the mercury intrusion porosimetry. The results showed that deionised water led to an increase of porosity, whereas the site water led to a decrease of porosity.
•Field investigation suggests a significant effect of pore water chemistry.•Clays rich in bentonite move toward “A” line when increasing salinity.•A clay with a higher salinity behaves more as a silt.•Clays with higher salinity show less compression and swelling.•Clays with higher salinity show higher permeability.
Inverse modeling of regional CO2 fluxes using atmospheric CO2 data is sensitive to the observational coverage of the observing network. Here we use the GEOS‐Chem adjoint model to examine the ...sensitivity to CO2 fluxes of observations from the in situ surface network, the Total Carbon Column Observing Network (TCCON), the Greenhouse Gases Observing Satellite (GOSAT), and the Orbiting Carbon Observatory (OCO‐2). We find that OCO‐2 has high sensitivity to fluxes throughout the tropics and Southern Hemisphere, while surface observations have high sensitivity to fluxes in the northern extratropics throughout the year. For GOSAT viewing modes, ocean glint data provide the strongest constraints on fluxes in the tropics and Southern Hemisphere during Northern Hemisphere fall and winter relative to other viewing modes. In contrast, GOSAT nadir land data offer the greater sensitivity to fluxes in these regions during Northern Hemisphere spring and summer. For OCO‐2 viewing modes, ocean glint data provided the dominant sensitivity to the surface fluxes in the northern subtropics, tropics, and Southern Hemisphere. We performed a series of inversion analyses using pseudodata and found that the varying sensitivities can result in large differences in regional flux estimates. However, combining measurements from different observing systems to exploit their complementarity may lead to a posteriori flux estimates with improved accuracy.
Key Points
Large spatiotemporal differences in sensitivity to surface fluxes between observing systems
OCO‐2 has the highest sensitivity to surface fluxes throughout the tropics and Southern Hemisphere
Surface observations have the highest sensitivity to surface fluxes in the northern extratropics
Vitamin D catabolizing enzymes, along with vitamin D receptor (VDR) and vitamin D binding protein (DBP) are expressed in the decidua and placenta during pregnancy and capable of synthesizing active ...vitamin D. Vitamin D plays roles in immunoregulation and trophoblast invasion, key features of a successful pregnancy. Epidemiological data suggests that vitamin D deficiency is associated with both spontaneous and recurrent miscarriage but few studies have investigated the expression of the key vitamin D catabolizing enzymes in miscarriage.
Placenta and decidua were collected after termination of apparently normal pregnancies (controls, n = 22) or spontaneous miscarriage (n = 20). Immunohistochemical staining, Western Blot and qRT-PCR were performed for CYP27B1, CYP24A1, CYP2R1, VDR and DBP (not qRT-PCR). HTR-8/SVneo cells were cultured in CoCL2 (hypoxic mimetic) or LPS (bacterial infection mimetic) for 24 h, RNA extracted and qRT-PCR performed for CYP27B1, CYP24A1, CYP2R1 and VDR.
In spontaneous miscarriage, placental and decidual expression of CYP27B1 was reduced, while expression of CYP24A1, VDR and DBP was increased. When a trophoblast cell line was treated with CoCL2 expression of CYP27B1 was increased and CYP24A1 was reduced, while LPS induced expression of VDR.
This is the first report of altered utero-placental vitamin D catabolism in spontaneous miscarriage. It is becoming accepted that women who are undergoing assisted reproductive technologies should ensure they have sufficient vitamin D levels prior to pregnancy, these data support that all women should ensure they are vitamin D replete before planning to get pregnant.
•Placental/decidual levels of vitamin D are decreased in spontaneous miscarriage.•CYP enzyme expression changes may be linked to hyperoxia.•VDR expression changes may be linked to infection.
Two experiments were conducted to evaluate the effects of Bacillus subtilis natto, which was initially isolated from fermented soybeans on milk production, rumen fermentation and ruminal microbiome ...in dairy cows. In Experiment 1, 36 early lactation Chinese Holstein dairy cows (56 ± 23 days in milk) were randomly assigned to three groups: Control, cows were fed total mixed ration (TMR); BSNLOW, TMR plus 0.5 × 10¹¹ colony-forming units (cfu) of B. subtilis natto/cow per day; and BSNHIGH, TMR plus 1.0 × 10¹¹ cfu of B. subtilis natto/cow per day. During the 70-day treatment period, daily milk production and daily milk composition were determined in individual cows. The results showed that supplementing dairy cows with 0.5 × 10¹¹ and 1.0 × 10¹¹ cfu of B. subtilis natto linearly increased (P < 0.01) milk production (25.2 and 26.4 kg/day v. 23.0 kg/day), 4% fat-corrected milk (27.3 and 28.1 kg/day v. 24.2 kg/day), energy-corrected milk (27.3 and 28.2 kg/day v. 24.2 kg/day), as well as milk fat (1.01 and 1.03 kg/day v. 0.88 kg/day), protein (0.77 and 0.82 kg/day v. 0.69 kg/day) and lactose yield (1.16 and 1.22 kg/day v. 1.06 kg/day) but decreased milk somatic cell counts (SCC) by 3.4% to 5.5% (P < 0.01) in BSNLOW and BSNHIGH treatments compared with Control. In Experiment 2, four rumen-cannulated dairy cows were fed the basal diet from 1 to 7 days (pre-trial period) and rumen samples were collected on days 6 and 7; the same cows then were fed 1.0 × 10¹¹ cfu/day B. subtilis natto from days 8 to 21 (trial period) and rumen samples were collected on days 20 and 21. B. subtilis natto was discontinued from days 22 to 28 (post-trial period) and rumen samples were collected on days 27 and 28. Compared with the pre- and post-periods, ruminal pH decreased by 2.7% to 3.0% during the trial period (P < 0.01), whereas ammonia nitrogen (NH₃-N), total volatile fatty acids and molar proportion of propionate (P < 0.01) and valerate (P < 0.05) increased. Molar proportion of acetate decreased and the acetate to propionate ratio was lower (P < 0.01) during the trial period. However, no differences for 24-h in sacco dry matter digestibility were detected among different periods (treatments) though NDF digestibility was reduced in the trial and post-trial periods (P < 0.01). Compared with pre-trial period, total ruminal bacteria, proteolytic and amylolytic bacteria in rumen enumerated by culture methods increased by 15.0%, 16.2% and 11.7%, respectively (P < 0.01) but protozoa decreased to 5.35 log₁₀ cfu/ml (P < 0.01) during the trial period. These results demonstrate that B. subtilis natto improves milk production and milk components yield, decreases SCC and promotes the growth of total ruminal bacteria, proteolytic and amylolytic bacteria, which indicate that B. subtilis natto has potential to be applied as a probiotic for dairy cows.
Summary Osteoporosis is a major public health problem characterized by low bone mineral density (BMD). This replication study confirmed 38 single-nucleotide polymorphisms (SNPs) out of 139 SNPs ...previously reported in three recent genome-wide association studies (GWASs) in an independent US white sample. Ten SNPs achieved combined p < 3.6 × 10⁻⁴. Introduction BMD is under strong genetic control. This study aims to verify the potential associations between BMD and candidate genes/loci reported by GWAS of FHS100K, Icelandic deCODE, and UK-NL. Methods Eight promising (at the genome-wide significant level after Bonferroni correction) and 131 available sub-promising (at the most stringent p value, p < 5.5 × 10⁻⁵ in the three GWASs reports) SNPs were selected. By using genotypic information from Affymetrix 500 K SNP arrays, we tested their associations with BMD in 1,000 unrelated US whites. Fisher's combined probability method was used to quantify the overall evidence of association. BMD was measured by dual energy X-ray absorptiometry. Results Two promising SNPs, rs3762397 and rs3736228, were replicated in the current study with p < 0.05. Besides, 36 sub-promising SNPs were replicated at the same significant level. Ten SNPs achieved significant combined p < 3.6 × 10⁻⁴ (0.05/139 SNPs, corrected for multiple testing). Conclusions Osteoporosis susceptibility of 38 SNPs was replicated in 1,000 unrelated US whites. This study showed promise for replication of some initial genome-wide association signals.
Recombinant adenoviruses are one of the most common vehicles for efficient in vitro and in vivo gene deliveries. Here, we investigate whether exogenous precursor terminal protein (pTP) expression in ...293 cells improves the efficiency of adenovirus packaging and amplification. We used a piggyBac transposon-based vector and engineered a stable 293 line that expresses high level of Ad5 pTP, designated as 293pTP. Using the AdBMP6-GLuc that expresses green fluorescent protein (GFP), BMP6 and Gaussia luciferase, we found that the infectivity of AdBMP6-GLuc viral samples packaged in 293pTP cells was titrated up to 19.3 times higher than that packaged in parental 293 cells. AdBMP6-GLuc viral samples packaged in 293pTP cells exhibited significantly higher transduction efficiency in 143B and immortalized mouse embryonic fibroblast (iMEF) cells, as assessed by fluorescence-activated cell sorting analysis of GFP-positive cells, the luciferase activity assay and BMP6-induced osteogenic marker alkaline phosphatase activities in iMEFs. When adenovirus amplification efficiency was analyzed, we found that 293pTP cells infected with AdBMP6-GLuc yielded up to 12.6 times higher titer than that in parental 293 cells, especially at lower multiplicities of infection. These results strongly suggest that exogenous pTP expression may accelerate the packaging and amplification of recombinant adenoviruses. Thus, the engineered 293pTP cells should be a superior packaging line for efficient adenovirus production.
Aims. We investigate the dependence of galaxy properties on the local environment. Methods. Member galaxies of compact groups (CGs) and isolated galaxies are located at both extremes of density, ...which are identified from the volume-limited Main galaxy sample of the Sixth Data Release of the Sloan Digital Sky Survey(SDSS DR6), while the volume-limited Main galaxy sample represents the mean density. We perform comparative studies of distributions of various physical properties among member galaxies of CGs, isolated galaxies, and the volume-limited Main galaxy sample. Results. We find that physical properties of galaxies, such as luminosity, size, colors, concentration index, and morphology strongly depend on the local environment: luminous, red, and early-type galaxies exist preferentially in the densest regions of the universe (e.g., in groups), while faint, blue, and late-type galaxies are located preferentially in low-density regions.
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