Phosphate Metabolism in CKD Stages 3–5: Dietary and Pharmacological Control

When compared to the available information for patients on dialysis (CKD stage 5D), data on the epidemiology and appropriate treatment of calcium and phosphate metabolism in the predialysis stages of chronic kidney disease (CKD) are quite limited. Perceptible derangements of calcium and phosphate levels start to become apparent when GFR falls below 30 mL/min in some, but not all, patients. However, hyperphosphatemia may be a significant morbidity and mortality risk predictor in predialysis CKD stages. The RIND study, evaluating progression of coronary artery calcification in incident hemodialysis patients, indirectly demonstrated that vascular calcification processes start to manifest in CKD patients prior to the dialysis stage, which may be closely linked to early and invisible derangements in calcium and phosphate homeostasis. Novel insights into the pathophysiology of calcium and phosphate handling such as the discovery of FGF23 and other phosphatonins suggest that a more complex assessment of phosphate balance is warranted, possibly including measurements of fractional phosphate excretion and phosphatonin levels in order to appropriately evaluate disordered metabolism in earlier stages of kidney disease. As a consequence, early and preventive treatment approaches may have to be developed for patients in CKD stages 3-5 to halt progression of CKD-MBD

A new age in functional genomics using CRISPR/Cas9 in arrayed library screening

CRISPR technology has rapidly changed the face of biological research, such that precise genome editing has now become routine for many labs within several years of its initial development. What makes CRISPR/Cas9 so revolutionary is the ability to target a protein (Cas9) to an exact genomic locus, through designing a specific short complementary nucleotide sequence, that together with a common scaffold sequence, constitute the guide RNA bridging the protein and the DNA. Wild-type Cas9 cleaves both DNA strands at its target sequence, but this protein can also be modified to exert many other functions. For instance, by attaching an activation domain to catalytically inactive Cas9 and targeting a promoter region, it is possible to stimulate the expression of a specific endogenous gene. In principle, any genomic region can be targeted, and recent efforts have successfully generated pooled guide RNA libraries for coding and regulatory regions of human, mouse and Drosophila genomes with high coverage, thus facilitating functional phenotypic screening. In this review, we will highlight recent developments in the area of CRISPR-based functional genomics and discuss potential future directions, with a special focus on mammalian cell systems and arrayed library screening

Epitaxial Iron Oxide Growth on Vicinal Pt(111): Well-defined defective model systems?

Heterogeneous catalysts consist often of metals in contact with oxides and the activity depends on the interaction between them. In addition, the defect structure of the surface is of high importance for the catalytic activity. The common electron-based surface science techniques allow the characterization of model catalyst surfaces with atomic precision. Studied model catalyst systems include single crystal surfaces, epitaxial compound films, or well-defined particles deposited on single-crystalline supports. However, real catalysts contains a defect structure which is difficult to model in a well-defined manner. In order to study the controlled introduction of defects into iron oxide model catalysts for the dehydrogenation of ethylbenzene to styrene, we have grown different iron oxide phases on a stepped Pt(9 11 11) single crystal surface. The hope was that this may provide a way to introduce well-defined step defects into the epitaxially grown films. For coverages below 1 ML, FeO(111) films wet the vicinal Pt substrate. The step structure changes under formation of doubled and triplicated terrace widths and step heights. Further cycles of iron deposition and oxidation lead to a Stranski-Krastanov-type growth of Fe3O4(111) islands which initially are elongated along the edge direction. However, the morphology of a coalesced closed film is almost unaffected by the underlying substrate step morphology. High pressure oxidation of Fe3O4 films results in poorly defined Fe2O3(0001). Although FeO films grown on the vicinal Pt surface may serve as model systems for systematic studies of well-defined defective oxide surfaces, the catalytically more relevant Fe3O4 and Fe2O3 phases could not be obtained reproducibly with a well-defined defect structure

On ATG4B as Drug Target for Treatment of Solid Tumours-The Knowns and the Unknowns

Autophagy is an evolutionary conserved stress survival pathway that has been shown to play an important role in the initiation, progression, and metastasis of multiple cancers; however, little progress has been made to date in translation of basic research to clinical application. This is partially due to an incomplete understanding of the role of autophagy in the different stages of cancer, and also to an incomplete assessment of potential drug targets in the autophagy pathway. While drug discovery efforts are on-going to target enzymes involved in the initiation phase of the autophagosome, e.g., unc51-like autophagy activating kinase (ULK)1/2, vacuolar protein sorting 34 (Vps34), and autophagy-related (ATG)7, we propose that the cysteine protease ATG4B is a bona fide drug target for the development of anti-cancer treatments. In this review, we highlight some of the recent advances in our understanding of the role of ATG4B in autophagy and its relevance to cancer, and perform a critical evaluation of ATG4B as a druggable cancer targe

Interface-dependence of Nucleation and Self-Assembly of Ultrathin Iron Oxide Films

The interface-dependence of heteroepitaxial growth of iron oxide films is investigated by scanning tunneling microscopy (STM) and low-energy electron diffraction (LEED). We show that the different chemical affinity to the metal substrate (Ru vs. Pt) and the step density (basal vs. vicinal Pt) significantly influence nucleation, heteroepitaxial crystal growth, and adhesion. Repeated Fe deposition-oxidation cycles lead to a Stranski-Krastanov growth mode on all substrates. On Ru(0001), metastable FeO(111) layers with strongly expanded lattice constants with a thickness up to 4 monolayers (ML) can be obtained by one-minute oxidation of the corresponding amount of Fe. Homogeneous nucleation of self-assembled, periodic Fe3O4(111) nanodomains embedded in an ultrathin FeO(111) film occurs on Ru(0001) in ~4 ML thick FeO(111) films. Nucleation of Fe3O4(111) islands below 4 ML on Ru(0001) occurs preferentially at substrate step edges while on Pt(111), no influence of surface defects was observed. On a vicinal Pt substrate, the terrace width and step height triplicates under influence of the wetting FeO(111) film. Differences in the growth behavior are discussed in terms of the involved surface and interface free energies

Targeting Deubiquitinating Enzymes (DUBs) That Regulate Mitophagy via Direct or Indirect Interaction with Parkin

The quality control of mitochondria is critical for the survival of cells, and defects in the pathways required for this quality control can lead to severe disease. A key quality control mechanism in cells is mitophagy, which functions to remove damaged mitochondria under conditions of various stresses. Defective mitophagy can lead to a number of diseases including neurodegeneration. It has been proposed that an enhancement of mitophagy can improve cell survival, enhance neuronal function in neurodegeneration and extend health and lifespans. In this review, we highlight the role of deubiquitinating enzymes (DUBs) in the regulation of mitophagy. We summarise the current knowledge on DUBs that regulate mitophagy as drug targets and provide a list of small molecule inhibitors that are valuable tools for the further development of therapeutic strategies targeting the mitophagy pathway in neurodegeneration

Качество воды в водных объектах природно-исторического парка "Покровское-Стрешнево"

В статье представлен материал выполненного анализа данных показателей качества родника «Царевна-Лебедь» и реки Химки за многолетний период для выявления закономерностей в изменении содержания загрязняющих веществ в условиях трансформации антропогенной нагрузки. По результатам проведённых исследований выявлено, что по некоторым показателям качество воды не соответствует нормативам, предъявляемым к водным объектам в зоне рекреации.In an article presents the material of the аnalysis and general conclusions of indicators of the quality of the source «The Swan Princess» and the river Khimki during the year to identify patterns of change in the content of pollutants in the conditions of transformation of anthropogenic load. The results of the research revealed that some indicators the quality of water in water bodies does not match the standards for to water bodies in the recreation area