Several lines of evidence suggest that gut bacterial microbiota is altered in patients with chronic kidney disease (CKD), though the mechanism of which this dysbiosis takes place is not well understood. Recent studies delineated changes in gut microbiota in both CKD patients and experimental animal models using microarray chips. We present 16S ribosomal RNA gene sequencing of both stool pellets and small bowel contents of C57BL/6J mice that underwent a remnant kidney model and establish that changes in microbiota take place in the early gastrointestinal tract. Increased intestinal urea concentration has been hypothesized as a leading contributor to dysbiotic changes in CKD. We show that urea transporters (UT)-A and UT-B mRNA are both expressed throughout the whole gastrointestinal tract. The noted increase in intestinal urea concentration appears to be independent of UTs' expression. Urea supplementation in drinking water resulted in alteration in bacterial gut microbiota that is quite different than that seen in CKD. This indicates that increased intestinal urea concentration might not fully explain the CKD- associated dysbiosis.
Recent evidence on the transcriptional regulation of the human thymidine kinase (TK) gene raises the possibility that cell-cycle regulatory sequences may be localized within its promoter. A hybrid gene that combines the TK 5' flanking sequence and the coding region of the bacterial neomycin-resistance gene (neo) has been constructed. Upon transfection into a hamster fibroblast cell line K12, the hybrid gene exhibits cell-cycle-dependent expression. Deletion analysis reveals that the region important for cell-cycle regulation is within -441 to -63 nucleotides from the transcriptional initiation site. This region ( -441 to -63) also confers cell-cycle regulation to the herpes simplex virus thymidine kinase (HSVtk) promoter, which is not expressed in a cell-cycle manner. We conclude that the -441 to -63 sequence within the human TK promoter is important for cell-cycle-dependent expression.One approach to understand the control of cell growth on a molecular level is to identify genes whose expression is modulated during the cell cycle and to study the underlying mechanisms of this regulation. The eukaryotic cell cycle has four distinct phases, G1, S, G2, and M (1). There is evidence revealing that several well-studied S-phase-specific genes, such as those encoding the replication-dependent histones, dihydrofolate reductase, and thymidylate synthase, are regulated at multiple control levels (2-4). Recently, it has been shown by DNA-mediated gene transfer that sequences flanking the replication-dependent histone genes can confer transcriptional (5-7) or posttranscriptional control (8) on the heterologous fusion genes, resulting in cell-cycle regulation of their mRNA levels in vivo.Another well-studied cell-cycle-regulated system is the thymidine kinase (TK) gene, which encodes a cytosol enzyme of the pyrimidine salvage pathway catalyzing the phosphorylation of thymidine to form thymidine 5' monophosphate. It has been documented that the activity of the cytosol TK is cell-cycle regulated and the increase in enzyme activity correlates with increases in DNA synthesis (9 (16,17). The implication is that at least part of the determinants of this regulation are contained within the TK mRNA sequence. With the direct demonstration that the half-life of TK mRNA decreases as S phase cells enter quiescence (18), posttranscriptional regulation of the TK transcripts clearly plays an important role in the cell-cycleregulated expression of the TK gene. The less well-understood level of control for the TK gene is at the step of transcriptional regulation. While it has been demonstrated that TK activity is sensitive to actinomycin D (9), the extreme low levels of the TK transcripts and its transient increase of transcriptional activity occurring only at a narrow period at the G1 and S border makes it difficult to directly measure its transcriptional rate. Thus, earlier attempts failed to detect an increase in TK transcriptional activity (19). Highly sensitive techniques have been used to demonstrate that TK gene expression is ...
The properties of two Chinese hamster temperature-sensitive mutants, K12 and H3.5, were examined. Both mutants originated from the same parental cell line, Wg1A, and were isolated as cell cycle mutants arrested in G1. Previously, we had been shown that the H3.5 ts mutation affected the transfer of the oligosaccharide from the lipid carrier to the nascent polypeptide and that the K12 ts mutation regulated the transcription of two glucose/calcium-regulated genes. We report here that these two mutants exhibit almost identical phenotypes at the biochemical level. Furthermore, a genetic complementation test demonstrates that the two ts lesions must be closely related, or even identical. Our results suggest that a specific defect in glycosylation may result in the overproduction of the glucose/calcium-regulated proteins and is capable of activating the promoter of the major glucose-regulated gene.
The impacts of climate change on future river flows are a growing concern. Typically, impacts are simulated by driving hydrological models with climate model ensemble data. The U.K. Climate Projections 2009 (UKCP09) provided probabilistic projections, enabling a risk-based approach to decision-making under climate change. Recently, an update was released-UKCP18-so there is a need for information on how impacts may differ. The probabilistic projections from UKCP18 and UKCP09 are here applied using the change factor method with catchment-based hydrological modelling for 10 catchments across England. Projections of changes in median, mean, high, and low flows are made for the 2050s, using the A1B emissions scenario from UKCP09 and UKCP18 as well as the RCP4.5 and RCP8.5 emissions scenarios from UCKP18. The results show that, in all catchments for all flow measures, the central estimate of change under UKCP18 is similar to that from UKCP09 (A1B emissions).However, the probabilistic uncertainty ranges from UKCP18 are, in all cases, greater than from UKCP09, despite UKCP18 having a smaller ensemble size than UKCP09.Although there are differences between the central estimates of change using UKCP18 RCP4.5, RCP8.5 and A1B emissions, there is considerable overlap in the uncertainty ranges. The results suggest that existing assessments of hydrological impacts remain relevant, though it will be necessary to evaluate sensitive decisions using the latest projections. The analysis will aid development of advice to users of current guidance based on UKCP09 and help make decisions about the prioritization of further hydrological impacts work using UKCP18, which should also apply other products from UKCP18 like the 12-km regional data. K E Y W O R D Sclimate change, hydrological impacts, probabilistic projections, rainfall-runoff, UK Climate Projections 2018, UKCP09, UKCP18
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