243 research outputs found
Directed polymer in a random medium of dimension 1+1 and 1+3: weights statistics in the low-temperature phase
We consider the low-temperature disorder-dominated phase of the
directed polymer in a random potentiel in dimension 1+1 (where )
and 1+3 (where ). To characterize the localization properties of
the polymer of length , we analyse the statistics of the weights of the last monomer as follows. We numerically compute the probability
distributions of the maximal weight , the probability distribution of the parameter as well as the average values of the higher order
moments . We find that there exists a
temperature such that (i) for , the distributions
and present the characteristic Derrida-Flyvbjerg
singularities at and for . In particular, there
exists a temperature-dependent exponent that governs the main
singularities and as well as the power-law decay of the moments . The exponent grows from the value
up to . (ii) for , the
distribution vanishes at some value , and accordingly the
moments decay exponentially as in . The
histograms of spatial correlations also display Derrida-Flyvbjerg singularities
for . Both below and above , the study of typical and
averaged correlations is in full agreement with the droplet scaling theory.Comment: 13 pages, 29 figure
High-throughput mutational screening adds clinically important information in myelodysplastic syndromes and secondary or therapy-related acute myeloid leukemia
Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109769/1/cptclpt201378.pd
Pathways and Management of Phosphorus in urban areas
Due to the finite nature of mineral phosphorus reserves, effective management of anthropogenic
phosphorus flows is currently under investigation by the international research
community. This article emphasizes the importance of urban phosphorus flows, which are
often marginalized due to the greater magnitude of agricultural phosphorus flows. A study
on phosphorus flows in Gothenburg, Sweden, points out the potential role of solid waste in
nutrient management, as the amounts of phosphorus in solid waste and in wastewater were
found to be equal. Importation of food commodities accounts for 50% of the total inflow
of phosphorus, and food waste is a major contributor of phosphorus to solid waste. The
results suggest that solid waste incineration residues represent a large underestimated sink
of phosphorus. Focusing on wastewater as the sole source of recovered phosphorus is not
sufficient. The Swedish national goal on phosphorus recycling, which is limited to sewage
sludge, targets only a part of the total phosphorus flow that can potentially be recovered.
In contrast to previous studies, agricultural flows in Gothenburg were marginal compared
to flows related to the urban waste management infrastructure. We emphasize the need
for debate on preferable routes for disposal of waste with a high phosphorus content. Both
recovery potential and usefulness of the recovered product for agricultural purposes have
to be considered. Impacts of five waste management strategies on phosphorus flows were
evaluated: incineration of all the waste, comprehensive food waste separation, installation
of kitchen grinders, urine diversion, and separation of blackwater and food waste
In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug–Drug Interactions
An HPLC-UV method for the measurement of permeability of marker drugs in the Caco-2 cell assay
Combined mutation screening of NKX2-5, GATA4, and TBX5 in congenital heart disease: multiple heterozygosity and novel mutations
Background: Variants of several genes encoding transcription modulators, signal transduction, and structural proteins are known to cause Mendelian congenital heart disease (CHD). NKX2-5 and GATA4 were the first CHD-causing genes identified by linkage analysis in large affected families. Mutations of TBX5 cause Holt–Oram syndrome, which includes CHD as a clinical feature. All three genes have a well-established role in cardiac development.
Design: In order to investigate the possible role of multiple mutations in CHD, a combined mutation screening was performed in NKX2-5, GATA4, and TBX5 in the same patient cohort. Samples from a cohort of 331 CHD patients were analyzed by polymerase chain reaction, double high-performance liquid chromatography and sequencing in order to identify changes in the NKX2-5, GATA4, and TBX5 genes.
Results: Two cases of multiple heterozygosity of putative disease-causing mutations were identified. One patient was found with a novel L122P NKX2-5 mutation in combination with the private A1443D mutation of MYH6. A patient heterozygote for a D425N GATA4 mutation carries also a private mutation of the MYH6 gene (V700M).
Conclusions: In addition to reporting two novel mutations of NKX2-5 in CHD, we describe families where multiple individual mutations seem to have an additive effect over the pathogenesis of CHD. Our findings highlight the usefulness of multiple gene mutational analysis of large CHD cohorts
Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver
Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism. This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed
Extra-Renal Elimination of Uric Acid via Intestinal Efflux Transporter BCRP/ABCG2
Urinary excretion accounts for two-thirds of total elimination of uric acid and the remainder is excreted in feces. However, the mechanism of extra-renal elimination is poorly understood. In the present study, we aimed to clarify the mechanism and the extent of elimination of uric acid through liver and intestine using oxonate-treated rats and Caco-2 cells as a model of human intestinal epithelium. In oxonate-treated rats, significant amounts of externally administered and endogenous uric acid were recovered in the intestinal lumen, while biliary excretion was minimal. Accordingly, direct intestinal secretion was thought to be a substantial contributor to extra-renal elimination of uric acid. Since human efflux transporter BCRP/ABCG2 accepts uric acid as a substrate and genetic polymorphism causing a decrease of BCRP activity is known to be associated with hyperuricemia and gout, the contribution of rBcrp to intestinal secretion was examined. rBcrp was confirmed to transport uric acid in a membrane vesicle study, and intestinal regional differences of expression of rBcrp mRNA were well correlated with uric acid secretory activity into the intestinal lumen. Bcrp1 knockout mice exhibited significantly decreased intestinal secretion and an increased plasma concentration of uric acid. Furthermore, a Bcrp inhibitor, elacridar, caused a decrease of intestinal secretion of uric acid. In Caco-2 cells, uric acid showed a polarized flux from the basolateral to apical side, and this flux was almost abolished in the presence of elacridar. These results demonstrate that BCRP contributes at least in part to the intestinal excretion of uric acid as extra-renal elimination pathway in humans and rats
Cardiac Alpha-Myosin (MYH6) Is the Predominant Sarcomeric Disease Gene for Familial Atrial Septal Defects
Secundum-type atrial septal defects (ASDII) account for approximately 10% of all congenital heart defects (CHD) and are associated with a familial risk. Mutations in transcription factors represent a genetic source for ASDII. Yet, little is known about the role of mutations in sarcomeric genes in ASDII etiology. To assess the role of sarcomeric genes in patients with inherited ASDII, we analyzed 13 sarcomeric genes (MYH7, MYBPC3, TNNT2, TCAP, TNNI3, MYH6, TPM1, MYL2, CSRP3, ACTC1, MYL3, TNNC1, and TTN kinase region) in 31 patients with familial ASDII using array-based resequencing. Genotyping of family relatives and control subjects as well as structural and homology analyses were used to evaluate the pathogenic impact of novel non-synonymous gene variants. Three novel missense mutations were found in the MYH6 gene encoding alpha-myosin heavy chain (R17H, C539R, and K543R). These mutations co-segregated with CHD in the families and were absent in 370 control alleles. Interestingly, all three MYH6 mutations are located in a highly conserved region of the alpha-myosin motor domain, which is involved in myosin-actin interaction. In addition, the cardiomyopathy related MYH6-A1004S and the MYBPC3-A833T mutations were also found in one and two unrelated subjects with ASDII, respectively. No mutations were found in the 11 other sarcomeric genes analyzed. The study indicates that sarcomeric gene mutations may represent a so far underestimated genetic source for familial recurrence of ASDII. In particular, perturbations in the MYH6 head domain seem to play a major role in the genetic origin of familial ASDII
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