Nicotinamide treatment in a murine model of familial tumoral calcinosis reduces serum Fgf23 and raises heart calcium

Mutations in the GALNT3 gene result in familial tumoral calcinosis, characterized by persistent hyperphosphatemia and ectopic calcific masses in soft tissues. Since calcific masses often recur after surgical removal, a more permanent solution to the problem is required. Nicotinamide is reported to lower serum phosphate by decreasing sodium-dependent phosphate co-transporters in the gut and kidney. However, its effectiveness in tumoral calcinosis remains unknown. In this study, we investigated nicotinamide as a potential therapy for tumoral calcinosis, using a murine model of the disease-Galnt3 knockout mice. Initially, five different doses of nicotinamide were given to normal heterozygous mice intraperitoneally or orally. Treatment had no effect on serum phosphate levels, but serum levels of a phosphaturic hormone, fibroblast growth factor 23 (Fgf23), decreased in a dose-dependent manner. Subsequently, high-dose nicotinamide (40mM) was tested in Galnt3 knockout mice fed a high phosphate diet. The radiographic data pre- and post-treatment showed that nicotinamide did not reverse the calcification. However, the treatment retarded calcification growth after 4weeks, while in the untreated animals, calcifications increased in size. The therapy did not affect serum phosphate levels, but intact Fgf23 decreased in the treated mice. The treated mice also had increased calcium in the heart. In summary, nicotinamide did not alter serum phosphate levels, likely due to compensatory decrease in Fgf23 to counteract the phosphate lowering effect of nicotinamide. Although increased calcium accumulation in the heart is a concern, the therapy appears to slow down the progression of ectopic calcifications

Symposium abstracts: Thresholds and permeability in performance

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An Updated Meta-Analysis of Endothelial Nitric Oxide Synthase Gene: Three Well-Characterized Polymorphisms with Hypertension

BACKGROUND: Numerous individually underpowered association studies have been conducted on endothelial nitric oxide synthase (eNOS) genetic variants across different ethnic populations, however, the results are often irreproducible. We therefore aimed to meta-analyze three eNOS widely-evaluated polymorphisms, G894T (rs1799983) in exon 7, 4b/a in intron 4, and T-786C (rs2070744) in promoter region, in association with hypertension from both English and Chinese publications, while addressing between-study heterogeneity and publication bias. METHODS: Data were analyzed using Stata software (version 11.0), and random-effects model was applied irrespective of between-study heterogeneity, which was evaluated by subgroup and meta-regression analyses. Publication bias was weighed using the Egger's test and funnel plot. RESULTS: There were total 19284/26003 cases/controls for G894T, and 6890/6858 for 4b/a, and 5346/6392 for T-786C polymorphism. Overall comparison of allele 894T with 894G in all study populations yielded a 16% increased risk for hypertension (odds ratio [OR] = 1.16; 95% confidence interval [95% CI]: 1.07-1.27; P = 0.001), and particularly a 32% increased risk (95% CI: 1.16-1.52; P<0.0005) in Asians and a 40% increased risk (95% CI: 1.19-1.65; P<0.0005) in Chinese. Further subgroup analyses suggested that published languages accounted for the heterogeneity for G894T polymorphism. The overall OR of allele 4a versus 4b was 1.29 (95% CI: 1.13-1.46; P<0.0005) in all study populations, and this estimate was potentiated in Asians (OR = 1.42; 95% CI: 1.16-1.72; P<0.0005). For T-786C, ethnicity-stratified analyses suggested a significantly increased risk for -786C allele (OR = 1.25; 95% CI: 1.06-1.47; P = 0.007) and -786CC genotype (OR = 1.69; 95% CI: 1.20-2.38; P = 0.003) in Whites. As an aside, the aforementioned risk estimates reached significance after Bonferroni correction. Finally, meta-regression analysis on other study-level covariates failed to provide any significance for all polymorphisms. CONCLUSION: We, via a comprehensive meta-analysis, ascertained the role of eNOS G894T and 4b/a polymorphisms on hypertension in Asians, and T-786C polymorphism in Whites

Materials for Diabetes Therapeutics

This review is focused on the materials and methods used to fabricate closed-loop systems for type 1 diabetes therapy. Herein, we give a brief overview of current methods used for patient care and discuss two types of possible treatments and the materials used for these therapies–(i) artificial pancreases, comprised of insulin producing cells embedded in a polymeric biomaterial, and (ii) totally synthetic pancreases formulated by integrating continuous glucose monitors with controlled insulin release through degradable polymers and glucose-responsive polymer systems. Both the artificial and the completely synthetic pancreas have two major design requirements: the device must be both biocompatible and be permeable to small molecules and proteins, such as insulin. Several polymers and fabrication methods of artificial pancreases are discussed: microencapsulation, conformal coatings, and planar sheets. We also review the two components of a completely synthetic pancreas. Several types of glucose sensing systems (including materials used for electrochemical, optical, and chemical sensing platforms) are discussed, in addition to various polymer-based release systems (including ethylene-vinyl acetate, polyanhydrides, and phenylboronic acid containing hydrogels).Juvenile Diabetes Research Foundation International (17-2007-1063)Leona M. and Harry B. Helmsley Charitable Trust (09PG-T1D027)United States. National Institutes of Health (F32 EB011580-01

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Paratext in Contemporary Theatre Practice

This thesis, Paratext in Contemporary Theatre Practice, proposes a ‘paratextual model’ as a new model of analysis for contemporary theatre practice, applying the concept of ‘paratextuality’ established by Gérard Genette. This analytical model enables us to flexibly schematise the central/marginal and the textual/paratextual in the audience’s appreciation of the work, capturing boundary-crossing acts within a performance work, whether this is explicitly aimed at by the practitioners or not. Such slippages and fluidity of focus within the work are observed particularly in contemporary performance practice that demands a more directly immersed, participatory role for the audience members. Chapter 1 details the concept of paratextuality by Genette, discussing its departure from a solely literary concept to an analytical vehicle with a wider applicability beyond literature. Chapter 2 establishes the paratextual approach offers a new way to understand and examine theatrical experiments with marginality. Case studies in later chapters illustrate the manifestation of the paratextual across contemporary performance works of diverse forms, ranging from devised performance and site-specific performance to immersive theatre. The primarily spatial concept of paratext is tested through the case studies of selected performance examples that take diverse formats and situated in disparate physical spaces. The thesis as a whole demonstrates that a paratextual approach usefully supplements the existing critical discourses on the contemporary theatre practice by providing the vocabulary to discuss seemingly marginal elements of performance that are actually integral to the meaning-making process for theatre makers and their audiences. Beginning from the originally literary concept of paratext, the thesis reinterprets and adapts Genette’s paratextual model to offer a valuable perspective which enables us to address both text-based theatre and creative experimentation which are often beyond the verbal, potentially bridging the gap between the performance forms

Effects of truncations in the N‐ and C‐terminal domains of filensin on filament formation with phakinin in cell‐free conditions and cultured cells

Filensin and phakinin are lens fiber cell‐specific proteins that constitute the beaded filaments (BFs) that are critical for maintaining lens transparency. In the Shumiya cataract rat, filensin 94 kDa undergoes N‐ and C‐terminal proteolytic processing to give a transient 50 kDa fragment and a final 38 kDa fragment, just before opacification. To characterize the effects of this processing on filensin function, recombinant proteins representing the two filensin fragments, termed Fil(30–416) and Fil(30–369), respectively, were examined. Fil(30–416) lacks the N‐terminal 29 amino acids and the C‐terminal 248 amino acids. Fil(30–369) lacks the N‐terminal 29 residues and the C‐terminal 295 residues. In cell‐free assembly characterized by electron microscopy, filensin and Fil(30–416) co‐polymerized with phakinin and formed rugged, entangled filaments, whereas Fil(30–369) formed only aggregates. In cultured SW‐13 and MCF‐7 cells expressing fluorescent fusion proteins, filensin and Fil(30–416) co‐polymerized with phakinin and formed cytoplasmic sinuous filaments with different widths, while Fil(30–369) gave aggregates. Therefore, while truncation of the N‐terminal 29 amino acids did not affect filament formation, truncation of the C‐terminal 295 but not the 248 residues resulted in failure of filament formation. These results indicate that the tail B region (residues 370–416) of rat filensin is essential for filament formation with phakinin. Truncation of the tail B region by proteolytic processing in the cataract rat lens might interfere with BF formation and thereby contribute to opacification