Drugs in Clinical Development to Treat Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst formation that ultimately leads to kidney failure in most patients. Approximately 10% of patients who receive kidney replacement therapy suffer from ADPKD. To date, a vasopressin V2 receptor antagonist (V2RA) is the only drug that has been proven to attenuate disease progression. However, aquaresis-related adverse events limit its widespread use. Data on the renoprotective effects of somatostatin analogues differ largely between studies and medications. This review discusses new drugs that are investigated in clinical trials to treat ADPKD, such as cystic fibrosis transmembrane conductance regulator (CFTR) modulators and micro RNA inhibitors, and drugs already marketed for other indications that are being investigated for off-label use in ADPKD, such as metformin. In addition, potential methods to improve the tolerability of V2RAs are discussed, as well as methods to select patients with (likely) rapid disease progression and issues regarding the translation of preclinical data into clinical practice. Since ADPKD is a complex disease with a high degree of interindividual heterogeneity, and the mechanisms involved in cyst growth also have important functions in various physiological processes, it may prove difficult to develop drugs that target cyst growth without causing major adverse events. This is especially important since long-standing treatment is necessary in this chronic disease. This review therefore also discusses approaches to targeted therapy to minimize systemic side effects. Hopefully, these developments will advance the treatment of ADPKD

BMP2 Is Essential for Post Natal Osteogenesis but Not for Recruitment of Osteogenic Stem Cells

The effects of BMP2 on bone marrow stromal cell differentiation and bone formation after bone marrow ablation were determined using C57 BL/6J (B6) mice. Inhibition of BMP2 expression with lentiviral BMP2 shRNA prevented both mineralized nodule formation in vitro and bone formation in vivo, and blocked the expression of Runx2 and osterix, transcriptional determinants of terminal osteogenic differentiation. No effect was observed on the expression of Sox9, a transcription factor, which is the one of the first transcriptional determinant to be expressed in committed chondroprogenitor and osteoprogenitor cells. In vitro studies showed that exogenously added BMP7 rescued the expression of osterix and enhanced the expression of Sox9, but had no effect on the expression of Runx2, while it only partially recovered the development of mineral deposition in the cultures. On the other hand, the exogenous addition of BMP2 rescued both Runx2 and osterix expression, did not enhance the expression of Sox9, but fully recovered the inhibition of mineral deposition in the cultures. Using antibodies against CD146 and Sox9, immunohistological examination of the cell populations found in the medullary space three days after bone marrow ablation, showed qualitatively equal numbers of cells expressing these skeletal progenitor and stem cell markers in control and BMP2 shRNA treated animals. Fluorescence Activated Cell Sorting (FACS) analysis of the cells found with the marrow cavities at three days after marrow ablation using CD146 antibody showed near equal numbers of immunopositive cells in both control and shRNA treated animals. In summary, the differences observed in vitro for BMP2 and BMP7 on osteogenic gene expression and mineralization suggest that they have differing effects on bone cell differentiation. These results further demonstrate that in vivo BMP2 is a central morphogenetic regulator of post natal osteoprogenitor differentiation, but does not affect recruitment of progenitors to the osteoblastic lineage

Spontaneously broken abelian Chern-Simons theories

A detailed analysis of Chern-Simons (CS) theories in which a compact abelian direct product gauge group U(1)^k is spontaneously broken down to a direct product H of (finite) cyclic groups is presented. The spectrum features global H charges, vortices carrying flux labeled by the elements of H and dyonic combinations. Due to the Aharonov-Bohm effect these particles exhibit toplogical interactions. The remnant of the U(1)^k CS term in the discrete H gauge theory describing the effective long distance physics of such a model is shown to be a 3-cocycle for H summarizing the nontrivial topological interactions cast upon the magnetic vortices by the U(1)^k CS term. It is noted that there are in general three types of 3-cocycles for a finite abelian gauge group H: one type describes topological interactions among vortices carrying flux w.r.t. the same cyclic group in the direct product H, another type gives rise to topological interactions between vortices carrying flux w.r.t. two different cyclic factors of H and a third type leading to topological interactions between vortices carrying flux w.r.t. three different cyclic factors. Among other things, it is demonstrated that only the first two types can be obtained from a spontaneously broken U(1)^k CS theory. The 3-cocycles that can not be reached in this way turn out to be the most interesting. They render the theory nonabelian and in general lead to dualities with planar theories with a nonabelian finite gauge group. In particular, the CS theory with finite gauge group H = Z_2 x Z_2 x Z_2 defined by such a 3-cocycle is shown to be dual to the planar discrete D_4 gauge theory with D_4 the dihedral group of order 8.Comment: 72+2 pages, LaTeX, 10 eps figures uuencoded. Postscript version also available at http://parthe.lpthe.jussieu.fr/~mdwp

High Throughput Determination of TGFβ1/SMAD3 Targets in A549 Lung Epithelial Cells

Transforming growth factor beta 1 (TGFβ1) plays a major role in many lung diseases including lung cancer, pulmonary hypertension, and pulmonary fibrosis. TGFβ1 activates a signal transduction cascade that results in the transcriptional regulation of genes in the nucleus, primarily through the DNA-binding transcription factor SMAD3. The objective of this study is to identify genome-wide scale map of SMAD3 binding targets and the molecular pathways and networks affected by the TGFβ1/SMAD3 signaling in lung epithelial cells. We combined chromatin immunoprecipitation with human promoter region microarrays (ChIP-on-chip) along with gene expression microarrays to study global transcriptional regulation of the TGFβ1/SMAD3 pathway in human A549 alveolar epithelial cells. The molecular pathways and networks associated with TGFβ1/SMAD3 signaling were identified using computational approaches. Validation of selected target gene expression and direct binding of SMAD3 to promoters were performed by quantitative real time RT-PCR and electrophoretic mobility shift assay on A549 and human primary lung epithelial cells. Known TGFβ1 target genes such as SERPINE1, SMAD6, SMAD7, TGFB1 and LTBP3, were found in both ChIP-on-chip and gene expression analyses as well as some previously unrecognized targets such as FOXA2. SMAD3 binding of FOXA2 promoter and changed expression were confirmed. Computational approaches combining ChIP-on-chip and gene expression microarray revealed multiple target molecular pathways affected by the TGFβ1/SMAD3 signaling. Identification of global targets and molecular pathways and networks associated with TGFβ1/SMAD3 signaling allow for a better understanding of the mechanisms that determine epithelial cell phenotypes in fibrogenesis and carcinogenesis as does the discovery of the direct effect of TGFβ1 on FOXA2

Large scale enzyme based xenobiotic identification for exposomics.

Advances in genomics have revealed many of the genetic underpinnings of human disease, but exposomics methods are currently inadequate to obtain a similar level of understanding of environmental contributions to human disease. Exposomics methods are limited by low abundance of xenobiotic metabolites and lack of authentic standards, which precludes identification using solely mass spectrometry-based criteria. Here, we develop and validate a method for enzymatic generation of xenobiotic metabolites for use with high-resolution mass spectrometry (HRMS) for chemical identification. Generated xenobiotic metabolites were used to confirm identities of respective metabolites in mice and human samples based upon accurate mass, retention time and co-occurrence with related xenobiotic metabolites. The results establish a generally applicable enzyme-based identification (EBI) for mass spectrometry identification of xenobiotic metabolites and could complement existing criteria for chemical identification

Higher spin AdS_3 holography with extended supersymmetry

We propose a holographic duality between a higher spin AdS_3 gravity with so(p) extended supersymmetry and a large N limit of a 2-dimensional Grassmannian-like model with a specific critical level k=N and a non-diagonal modular invariant. As evidence, we show the match of one-loop partition functions. Moreover, we construct symmetry generators of the coset model for low spins which are dual to gauge fields in the supergravity. Further, we discuss a possible relation to superstring theory by noticing an N=3 supersymmetry of critical level model at finite k,N. In particular, we examine BPS states and marginal deformations. Inspired by the supergravity side, we also propose and test another large N CFT dual obtained as a Z_2 automorphism truncation of a similar coset model, but at a non-critical level.Comment: 44 pages, published versio

The success of the Montreal Protocol in mitigating interactive effects of stratospheric ozone depletion and climate change on the environment

The Montreal Protocol and its Amendments have been highly effective in protecting the stratospheric ozone layer, preventing global increases in solar ultraviolet-B radiation (UV-B; 280-315 nm) at Earth's surface, and reducing global warming. While ongoing and projected changes in UV-B radiation and climate still pose a threat to human health, food security, air and water quality, terrestrial and aquatic ecosystems, and construction materials and fabrics, the Montreal Protocol continues to play a critical role in protecting Earth's inhabitants and ecosystems by addressing many of the United Nations Sustainable Development Goals.Non peer reviewe

Comparison of measured and modelled uv indices for the assessment of health risks

The World Health Organisation (WHO) and the World Meteorological Organisation (WMO) have jointly recommended that the UV Index (UVI) should be used to inform the public about possible health risks due to overexposure to solar radiation, especially skin damage. To test the current operational status of measuring and modelling techniques used in providing the public with UVI information, this article compares cloudless sky UVIs (measured using five instruments at four locations with different latitudes and climate) with the results of 13 models used in UVI forecasting schemes. For the models, only location, total ozone and solar zenith angle were provided as input parameters. In many cases the agreement is acceptable, i.e. less than 0.5 UVI. Larger differences may originate from instrumental errors and shortcomings in the models and their input parameters. A possible explanation for the differences between models is the treatment of the unknown input parameters, especially aerosols

Aerosol optical depth in the ultraviolet range: a new product in EUBREWNET

Póster elaborado para el Quadrennial Ozone Symposium celebrado en Edinburgh los días 4–9 de septiembre de 2016The AERONET sun photometers at the Izaña station have been calibrated within the AERONET Europe TNA, supported by the European Community-Research Infrastructure Action under the FP7 ACTRIS grant agreement no. 262254