Parietal epithelial cell differentiation to a podocyte fate in the aged mouse kidney

Healthy aging is typified by a progressive and absolute loss of podocytes over the lifespan of animals and humans. To test the hypothesis that a subset of glomerular parietal epithelial cell (PEC) progenitors transition to a podocyte fate with aging, dual reporte

Astrocytes promote progression of breast cancer metastases to the brain via a KISS1-mediated autophagy.

Formation of metastases, also known as cancer dissemination, is an important stage of breast cancer (BrCa) development. KISS1 expression is associated with inhibition of metastases development. Recently we have demonstrated that BrCa metastases to the brain exhibit low levels of KISS1 expression at both mRNA and protein levels. By using multicolor immunofluorescence and coculture techniques here we show that normal adult astrocytes in the brain are capable of promoting metastatic transformation of circulating breast cancer cells localized to the brain through secretion of chemokine CXCL12. The latter was found in this study to downregulate KISS1 expression at the post-transcriptional level via induction of microRNA-345 (MIR345). Furthermore, we demonstrated that ectopic expression of KISS1 downregulates ATG5 and ATG7, 2 key modulators of autophagy, and works concurrently with autophagy inhibitors, thereby implicating autophagy in the mechanism of KISS1-mediated BrCa metastatic transformation. We also found that expression of KISS1 in human breast tumor specimens inversely correlates with that of MMP9 and IL8, implicated in the mechanism of metastatic invasion, thereby supporting the role of KISS1 as a potential regulator of BrCa metastatic invasion in the brain. This conclusion is further supported by the ability of KISS1, ectopically overexpressed from an adenoviral vector in MDA-MB-231Br cells with silenced expression of the endogenous gene, to revert invasive phenotype of those cells. Taken together, our results strongly suggest that human adult astrocytes can promote brain invasion of the brain-localized circulating breast cancer cells by upregulating autophagy signaling pathways via the CXCL12-MIR345- KISS1 axis

Learning for Competence through Distance Education

The article focuses on the content components necessary for the formation of a special learning competence for distance-learning students. The authors propose their own interpretation of the constituents of the learning competence with due regard for the specificity of studying foreign languages by means of telecommunication technologies. Such components are to be considered in the context of the learner-centered paradigm. The content of the technology created includes knowledge of the essence and specificity of learning activities in foreign language acquisition. The article demonstrates a big variety of terms in the methodical literature. The authors describe learning skills and say that they are such ways of learning activities that do not directly constitute a mechanism for the formation of a communication competence, but rationalize this process. The article helps to understand that studying foreign languages with the help of telecommunications presents a number of difficulties and it is proved that learning competence remove the difficulties of distance learning. The article gives the important methodological provisions defining a role and the place of learning competence of a context of distance language learning

Learning for Competence through Distance Education

The article focuses on the content components necessary for the formation of a special learning competence for distance-learning students. The authors propose their own interpretation of the constituents of the learning competence with due regard for the specificity of studying foreign languages by means of telecommunication technologies. Such components are to be considered in the context of the learner-centered paradigm. The content of the technology created includes knowledge of the essence and specificity of learning activities in foreign language acquisition. The article demonstrates a big variety of terms in the methodical literature. The authors describe learning skills and say that they are such ways of learning activities that do not directly constitute a mechanism for the formation of a communication competence, but rationalize this process. The article helps to understand that studying foreign languages with the help of telecommunications presents a number of difficulties and it is proved that learning competence remove the difficulties of distance learning. The article gives the important methodological provisions defining a role and the place of learning competence of a context of distance language learning

Additional file 1: Figure S1. of Cells of renin lineage express hypoxia inducible factor 2α following experimental ureteral obstruction

UUO induces kidney fibrosis and reduces vascular density in Ren1cCre mice. (A) Following ureteral obstruction of the right kidney, the ureter is filled with urine. Non-obstructed kidney (contralateral) undergoes hypertrophy. (B) Reduced weight ratio of obstructed/non-obstructed kidney on day 7 and 14 after UUO. (C) Endothelial cells, identified by CD31 staining (green), decrease in the cortex and medulla following UUO on day 7 and 14 compared to sham kidneys. Examples of capillary rarefaction are marked with an asterisk (*). (D) Picrosirius Red staining was examined by polarized light microscopy. Collagen fibers were barely detectable in sham kidneys. Interstitial Picrosirius Red staining was increased on days 3, 7 and 14 following UUO. (E) Fibrosis quantification based on Picrosirius Red staining score shows a gradual increase of fibrosis in UUO. Data are represented as mean ± SEM. (PNG 652 kb

Additional file 2: Figure S2. of Cells of renin lineage express hypoxia inducible factor 2α following experimental ureteral obstruction

Renin staining is limited to labeled CoRL in JG and afferent arterioles. Red fluorescent protein staining identified CoRL (red), renin staining indicates renin-producing cells (green). DAPI (blue) staining labels nuclei. At 7 days post UUO, (A) in the cortex, renin staining was detected in classical JG location (arrow) (B) in the medulla there was no renin staining found, interstitial CoRL were negative for renin. (PNG 431 kb

Tamoxifen overrides autophagy inhibition in Beclin-1-deficient glioma cells and their resistance to adenovirus-mediated oncolysis via upregulation of PUMA and BAX.

Autophagy is an evolutionarily conserved process regulating cellular homeostasis via digestion of dysfunctional proteins and whole cellular organelles by mechanisms, involving their enclosure into double-membrane vacuoles that are subsequently fused to lysosomes. Glioma stem cells utilize autophagy as a main mechanism of cell survival and stress response. Most recently, we and others demonstrated induction of autophagy in gliomas in response to treatment with chemical drugs, such as temozolomide (TMZ) or oncolytic adenoviruses (Ads). As autophagy has been implicated in the mechanism of Ad-mediated cell killing, autophagy deficiency in some glioma tumors could be the reason for their resistance to oncolysis. Despite the observed connection, the exact relationship between autophagy-activating cell signaling and adenoviral infection remains unclear. Here, we report that inhibition of autophagy in target glioma cells induces their resistance to killing by oncolytic agent CRAd-S-5/3. Furthermore, we found that downregulation of autophagy inducer Beclin-1 inhibits replication-competent Ad-induced oncolysis of human glioma by suppressing cell proliferation and inducing premature senescence. To overcome the autophagy-deficient state of such glioma cells and restore their susceptibility to oncolytic Ad infection, we propose treating glioma tumors with an anticancer drug tamoxifen (TAM) as a means to induce apoptosis in Ad-targeted cancer cells via upregulation of BAX/PUMA genes. In agreement with the above hypothesis, our data suggest that TAM improves susceptibility of Beclin-1-deficient glioma cells to CRAd-S-5/3 oncolysis by means of activating autophagy and pro-apoptotic signaling pathways in the target cancer cells

Tracking the stochastic fate of cells of the renin lineage after podocyte depletion using multicolor reporters and intravital imaging

<div><p>Podocyte depletion plays a major role in focal segmental glomerular sclerosis (FSGS). Because cells of the renin lineage (CoRL) serve as adult podocyte and parietal epithelial cell (PEC) progenitor candidates, we generated <i>Ren1cCre/R26R-ConfettiTG/WT</i> and <i>Ren1dCre/R26R-ConfettiTG/WT</i> mice to determine CoRL clonality during podocyte replacement. Four CoRL reporters (GFP, YFP, RFP, CFP) were restricted to cells in the juxtaglomerular compartment (JGC) at baseline. Following abrupt podocyte depletion in experimental FSGS, all four CoRL reporters were detected in a subset of glomeruli at day 28, where they co-expressed de novo four podocyte proteins (podocin, nephrin, WT-1 and p57) and two glomerular parietal epithelial cell (PEC) proteins (claudin-1, PAX8). To monitor the precise migration of a subset of CoRL over a 2w period following podocyte depletion, intravital multiphoton microscopy was used. Our findings demonstrate direct visual support for the migration of single CoRL from the JGC to the parietal Bowman’s capsule, early proximal tubule, mesangium and glomerular tuft. In summary, these results suggest that following podocyte depletion, multi-clonal CoRL migrate to the glomerulus and replace podocyte and PECs in experimental FSGS.</p></div