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1.
To explore restoration of ovarian function using epigenetically-related, induced pluripotent stem cells (iPSCs), we functionally evaluated the epigenetic memory of novel iPSC lines, derived from mouse and human ovarian granulosa cells (GCs) using c-Myc, Klf4, Sox2 and Oct4 retroviral vectors. The stem cell identity of the mouse and human GC-derived iPSCs (mGriPSCs, hGriPSCs) was verified by demonstrating embryonic stem cell (ESC) antigen expression using immunocytochemistry and RT-PCR analysis, as well as formation of embryoid bodies (EBs) and teratomas that are capable of differentiating into cells from all three germ layers. GriPSCs’ gene expression profiles associate more closely with those of ESCs than of the originating GCs as demonstrated by genome-wide analysis of mRNA and microRNA. A comparative analysis of EBs generated from three different mouse cell lines (mGriPSCs; fibroblast-derived iPSC, mFiPSCs; G4 embryonic stem cells, G4 mESCs) revealed that differentiated mGriPSC-EBs synthesize 10-fold more estradiol (E2) than either differentiated FiPSC- or mESC-EBs under identical culture conditions. By contrast, mESC-EBs primarily synthesize progesterone (P4) and FiPSC-EBs produce neither E2 nor P4. Differentiated mGriPSC-EBs also express ovarian markers (AMHR, FSHR, Cyp19a1, ER and Inha) as well as markers of early gametogenesis (Mvh, Dazl, Gdf9, Boule and Zp1) more frequently than EBs of the other cell lines. These results provide evidence of preferential homotypic differentiation of mGriPSCs into ovarian cell types. Collectively, our data support the hypothesis that generating iPSCs from the desired tissue type may prove advantageous due to the iPSCs’ epigenetic memory.  相似文献   
2.

Trial Design

This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.

Methods

Males aged 5–18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13–17 years), renal function, and glycolipid levels (plasma, urine).

Results

Plasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m2 (range 90.4–161.0 mL/min/1.73 m2) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0–27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.

Conclusions

These data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.

Trial Registration

ClinicalTrials.gov NCT00701415  相似文献   
3.
Despite many advances and optimization in colon cancer treatment, tumor recurrence and metastases make the development of new therapies necessary. Colon cancer stem cells (CCSCs) are considered as the main triggering factor of cancer progression, recurrence, and metastasis. CCSCs as a result of accumulated genetic and epigenetic alterations and also complex interconnection with the tumor microenvironment (TME) can evolve and convert to full malignant cells. Mounting evidence suggests that in cancer therapy both CCSCs and non-CCSCs in TME have to be regarded to break through the limitation of current therapies. In this regard, stem cell capabilities of some non-CCSCs may arise inside the TME condition. Therefore, a deep knowledge of regulatory mechanisms, heterogeneity, specific markers, and signaling pathways of CCSCs and their interconnection with TME components is needed to improve the treatment of colorectal cancer and the patient's life quality. In this review, we address current different targeted therapeutic options that target cell surface markers and signaling pathways of CCSCs and other components of TME. Current challenges and future perspectives of colon cancer personalized therapy are also provided here. Taken together, based on the deep understanding of biology of CCSCs and using three-dimensional culture technologies, it can be possible to reach successful colon cancer eradication and improvise combination targeted therapies against CCSCs and TME.  相似文献   
4.
5.
Upon phosphorus (P) deficiency, marine phytoplankton reduce their requirements for P by replacing membrane phospholipids with alternative non-phosphorus lipids. It was very recently demonstrated that a SAR11 isolate also shares this capability when phosphate starved in culture. Yet, the extent to which this process occurs in other marine heterotrophic bacteria and in the natural environment is unknown. Here, we demonstrate that the substitution of membrane phospholipids for a variety of non-phosphorus lipids is a conserved response to P deficiency among phylogenetically diverse marine heterotrophic bacteria, including members of the Alphaproteobacteria and Flavobacteria. By deletion mutagenesis and complementation in the model marine bacterium Phaeobacter sp. MED193 and heterologous expression in recombinant Escherichia coli, we confirm the roles of a phospholipase C (PlcP) and a glycosyltransferase in lipid remodelling. Analyses of the Global Ocean Sampling and Tara Oceans metagenome data sets demonstrate that PlcP is particularly abundant in areas characterized by low phosphate concentrations. Furthermore, we show that lipid remodelling occurs seasonally and responds to changing nutrient conditions in natural microbial communities from the Mediterranean Sea. Together, our results point to the key role of lipid substitution as an adaptive strategy enabling heterotrophic bacteria to thrive in the vast P-depleted areas of the ocean.  相似文献   
6.
Although winter conditions play a major role in determining the productivity of the western Antarctic Peninsula (WAP) waters for the following spring and summer, a few studies have dealt with the seasonal variability of microorganisms in the WAP in winter. Moreover, because of regional warming, sea-ice retreat is happening earlier in spring, at the onset of the production season. In this context, this study describes the dynamics of the marine microbial community in the Melchior Archipelago (WAP) from fall to spring 2006. Samples were collected monthly to biweekly at four depths from the surface to the aphotic layer. The abundance and carbon content of bacteria, phytoplankton and microzooplankton were analyzed using flow cytometry and inverted microscopy, and bacterial richness was examined by PCR–DGGE. As expected, due to the extreme environmental conditions, the microbial community abundance and biomass were low in fall and winter. Bacterial abundance ranged from 1.2 to 2.8 × 105 cells ml?1 showing a slight increase in spring. Phytoplankton biomass was low and dominated by small cells (<2 μm) in fall and winter (average chlorophyll a concentration, Chl-a, of, respectively, 0.3 and 0.13 μg l?1). Phytoplankton biomass increased in spring (Chl-a up to 1.13 μg l?1), and, despite potentially adequate growth conditions, this rise was small and phytoplankton was still dominated by small cells (2–20 μm). In addition, the early disappearing of sea-ice in spring 2006 let the surface water exposed to ultraviolet B radiations (UVBR, 280–320 nm), which seemed to have a negative impact on the microbial community in surface waters.  相似文献   
7.
Molecular Biology Reports - Combination therapy has been considered as a potential method to overcome the BC chemoresistance. MicroRNAs (miRs) have been suggested as a therapeutic factor in the...  相似文献   
8.
Plant Cell, Tissue and Organ Culture (PCTOC) - Globular androgenic haploid embryos of TV21 and TV19 cultivars of Camellia ssp., obtained on embryo induction medium (EIM), Murashige and Skoog medium...  相似文献   
9.

Peatlands have accumulated vast quantities of organic carbon over thousands of years but it is unclear how these sensitive ecosystems will respond to future climate change. If emissions of methane from peatlands increase, then they may contribute increasingly towards climatic warming due to the higher greenhouse warming potential of this gas. We investigated the radiocarbon concentration of methane emissions from a temperate bog over 1.5 years, which we supported with measurements of the surface flux of methane and carbon dioxide. The radiocarbon content of methane emissions varied greatly, from modern (i.e. fixed from the atmosphere within recent decades) to ~ 1400 years BP. Flux rates of methane were spatially and temporally highly variable. A vegetation clipping experiment showed that plants had a great influence on the carbon isotope composition and flux of methane emitted from the peat surface, consistent with earlier studies showing the key role of plants in peatland methane emissions. When plants were absent, emission rates were 70–94% lower and the radiocarbon age of methane emissions was much younger and less variable. Our radiocarbon measurements show that at this peatland, plant-associated methane emissions contain carbon originally fixed from the atmosphere up to hundreds of years earlier, consistent with a contribution from plant mediated transport of methane sourced from sub-surface layers.

  相似文献   
10.
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