Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. Foxd1 is required during kidney development and its inactivation results in ...failure of nephron progenitor cell differentiation. Foxd1 is expressed in interstitial cells adjacent to nephron progenitor cells, suggesting an essential role for the progenitor cell niche in nephrogenesis. To better understand how cortical interstitial cells in general, and FOXD1 in particular, influence the progenitor cell niche, we examined the differentiation states of two progenitor cell subtypes in Foxd1(-/-) tissue. We found that although nephron progenitor cells are retained in a primitive CITED1-expressing compartment, cortical interstitial cells prematurely differentiate. To identify pathways regulated by FOXD1, we screened for target genes by comparison of Foxd1 null and wild-type tissues. We found that the gene encoding the small leucine-rich proteoglycan decorin (DCN) is repressed by FOXD1 in cortical interstitial cells, and we show that compound genetic inactivation of Dcn partially rescues the failure of progenitor cell differentiation in the Foxd1 null. We demonstrate that DCN antagonizes BMP/SMAD signaling, which is required for the transition of CITED1-expressing nephron progenitor cells to a state that is primed for WNT-induced epithelial differentiation. On the basis of these studies, we propose a mechanism for progenitor cell retention in the Foxd1 null in which misexpressed DCN produced by prematurely differentiated interstitial cells accumulates in the extracellular matrix, inhibiting BMP7-mediated transition of nephron progenitor cells to a compartment in which they can respond to epithelial induction signals.
Embryonic nephron progenitor cells are segregated in molecularly distinct compartments of unknown function. Our study reveals an integral role for bone morphogenetic protein-SMAD in promoting ...transition of progenitors from the primitive Cbp/p300-interacting transactivator 1 expressing (CITED1+) compartment to the uniquely sine oculis-related homeobox 2 expressing (SIX2-only) compartment where they become inducible by wingless-type mouse mammary tumor virus integration site family member (WNT)/β-catenin signaling. Significantly, CITED1 ⁺ cells are refractory to WNT/β-catenin induction. We propose a model in which the primitive CITED1 ⁺ compartment is refractory to induction by WNT9b/β-catenin, ensuring maintenance of undifferentiated progenitor cells for future nephrogenesis. Bone morphogenetic protein 7-SMAD is then required for transition to a distinct compartment in which cells become inducible by WNT9b/β-catenin, allowing them to progress toward epithelialization.
The iterative formation of nephrons during embryonic development relies on continual replenishment of progenitor cells throughout nephrogenesis. Defining molecular mechanisms that maintain and ...regulate this progenitor pool is essential to understanding nephrogenesis in developmental and regenerative contexts. Maintenance of nephron progenitors is absolutely dependent on BMP7 signaling, and Bmp7-null mice exhibit rapid loss of progenitors. However, the signal transduction machinery operating downstream of BMP7 as well as the precise target cell remain undefined. Using a novel primary progenitor isolation system, we have investigated signal transduction and biological outcomes elicited by BMP7. We find that BMP7 directly and rapidly activates JNK signaling in nephron progenitors resulting in phosphorylation of Jun and ATF2 transcription factors. This signaling results in the accumulation of cyclin D3 and subsequent proliferation of PAX2(+) progenitors, inversely correlating with the loss of nephron progenitors seen in the Bmp7-null kidney. Activation of Jun and ATF2 is severely diminished in Bmp7-null kidneys, providing an important in vivo correlate. BMP7 thus promotes proliferation directly in nephron progenitors by activating the JNK signaling circuitry.
We investigated the dynamics of seroconversion in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. During March 29-May 22, 2020, we collected serum samples and associated ...clinical data from 177 persons in London, UK, who had SARS-CoV-2 infection. We measured IgG against SARS-CoV-2 and compared antibody levels with patient outcomes, demographic information, and laboratory characteristics. We found that 2.0%-8.5% of persons did not seroconvert 3-6 weeks after infection. Persons who seroconverted were older, were more likely to have concurrent conditions, and had higher levels of inflammatory markers. Non-White persons had higher antibody concentrations than those who identified as White; these concentrations did not decline during follow-up. Serologic assay results correlated with disease outcome, race, and other risk factors for severe SARS-CoV-2 infection. Serologic assays can be used in surveillance to clarify the duration and protective nature of humoral responses to SARS-CoV-2 infection.
Novel high capacitance materials: BaTiO3:La and CaCu3Ti4O12 WEST, Anthony R; ADAMS, Timothy B; MORRISON, Finlay D ...
Journal of the European Ceramic Society,
2004, 2004-1-00, 20040101, Letnik:
24, Številka:
6
Conference Proceeding, Journal Article
Recenzirano
A review is given of the origins of high permittivity in two groups of materials, La-doped BaTiO3 and a new barrier layer capacitor material, CaCu3Ti4O12. Factors that influence permittivity include: ...dopant, doping mechanism, processing conditions and grain size. La-doped BaTiO3 has high permittivity due to its ferroelectric nature at low temperatures and a novel doping mechanism: A-site substitution linked to the creation of B-site vacancies for charge compensation. Permittivities of 25,000 have been achieved, which can be increased further to ~36,000 by additional doping with Zr. The value of impedance spectroscopy to characterize materials that have heterogeneous electrical microstructures is illustrated with the example of CaCu3Ti4O12; the high permittivity is not a bulk effect, as widely stated in the literature, but is a thin layer effect typical of a barrier layer capacitor. By attention to processing conditions to achieve large grain sizes, effective permittivities as high as 300,000 have been obtained.
Long-term pulse chase experiments previously identified a sizable population of BrdU-retaining cells within the renal papilla. The origin of these cells has been unclear, and in this work we test the ...hypothesis that they become quiescent early during the course of kidney development and organ growth. Indeed, we find that BrdU-retaining cells of the papilla can be labeled only by pulsing with BrdU from embryonic (E) day 11.25 to postnatal (P) day 7, the approximate period of kidney development in the mouse. BrdU signal in the cortex and outer medulla is rapidly diluted by cellular proliferation during embryonic development and juvenile growth, whereas cells within the papilla differentiate and exit the cell cycle during organogenesis. Indeed, by E17.5, little or no active proliferation can be seen in the distal papilla, indicating maturation of this structure in a distal-to-proximal manner during organogenesis. We conclude that BrdU-retaining cells of the papilla represent a population of cells that quiesce during embryonic development and localize within a region of the kidney that matures early. We therefore propose that selective papillary retention of BrdU arises through a combination of regionalized slowing of, and exit from, the cell cycle within the papilla during the period of ongoing kidney development, and extensive proliferative growth of the juvenile kidney resulting in dilution of BrdU below the detection level in extra-papillary regions.
► Age and geographic location were the main influences on plasma PFC concentrations in dolphins. ► ∑PFCs, ∑PFCAs and ∑PFSAs declined significantly with age. ► Site-specific exposures with ...significantly higher plasma PFCs levels in SC than FL dolphins.
Plasma PFCs were measured in 157 bottlenose dolphins (Tursiops truncatus) sampled from two US southeast Atlantic sites (Charleston (CHS), SC and Indian River Lagoon (IRL), FL) during 2003–2005. ∑PFCs, perfluoroalkyl carboxylates (∑PFCAs), perfluoroalkyl sulfonates (∑PFSAs) and individual compounds were significantly higher in CHS dolphins for all age/sex categories compared to IRL dolphins. Highest ∑PFCs concentrations occurred in CHS juvenile dolphins (2340ng/g w.w.); significantly higher than found in adults (1570ng/g w.w. males; 1330ng/g w.w. females). ∑PFCAs were much greater in CHS dolphins (∼21%) compared to IRL dolphins (∼7%); ∑PFSAs were 79% in CHS dolphins versus 93% in IRL dolphins. PFOS, the dominant compound, averaged 72% and 84%, respectively, in CHS and IRL dolphins. Decreasing PFC levels occurred with age on the bioaccumulation of PFCs in both sites. These observations suggest PFC accumulation in these two dolphin populations are influenced by site-specific exposures with significantly higher levels in CHS dolphins.
Stimulation of the bone morphogenetic protein (BMP) pathway protects the kidney from acute and chronic injury. Numerous regulators in the kidney control BMP signaling, offering many targets for ...therapeutic manipulation. Here, we screened for modulators of BMP signaling in the ischemia-sensitive S3 segment and found that Chordin-like 1 is expressed in this segment of both the mouse and human nephron. Chordin-like 1 specifically antagonizes BMP7, which is expressed in the neighboring distal nephron, and this depends on the presence of the protein Twisted gastrulation. Upon ischemia-induced degeneration of the S3 segment, we observed a reduction in Chordin-like 1 expression coincident with intense BMP signaling in tubules of the recovering kidney. Restored expression accompanied proximal tubule epithelia redifferentiation, again coincident with decreased BMP signaling. We propose that Chordin-like 1 reduces BMP7 signaling in healthy proximal tubules, and the loss of this activity upon sloughing of injured epithelia promotes BMP7 signaling in repopulating, dedifferentiated epithelia. As regenerating epithelia differentiate, Chordin-like 1 is again expressed, antagonizing BMP7. These data suggest a mechanism for dynamic regulation of renoprotective BMP7 signaling in the S3 segment of the proximal tubule.
Decomposition Reactions in CaCu3Ti4O12 Ceramics Adams, Timothy B.; Sinclair, Derek C.; West, Anthony R.
Journal of the American Ceramic Society,
September 2006, Letnik:
89, Številka:
9
Journal Article
Recenzirano
CaCu3Ti4O12 (CCTO) ceramics sintered in air at 1115°C for 3 and 24 h have been heat treated in N2 at 1000°C. Surface layers develop on the outer regions of the ceramics, and a combination of X‐ray ...diffraction and analytical electron microscopy has been used to establish the phase content of the layers. A model to explain the formation of the surface layers is proposed based on decomposition of CCTO into a mixture of CaTiO3, TiO2, and Cu2O. The role of limited decomposition in the development of electrically inhomogeneous CCTO ceramics prepared at elevated temperatures in air is discussed.
Bone morphogenetic proteins (BMPs) regulate essential processes during organogenesis, and a functional understanding of these secreted proteins depends on identification of their target cells. In ...this study, we generate a transgenic reporter for organogenesis studies that we use to define BMP pathway activation in the developing kidney.
Mouse strains reporting on BMP pathway activation were generated by transgenically expressing beta-galactosidase under the control of BMP responsive elements from Id1. Reporter expression corresponds well with immunoassays for pathway activation in all organs studied, validating the model. Using these reporters we have generated a detailed map of cellular targets of BMP signaling in the developing kidney. We find that SMAD dependent BMP signaling is active in collecting duct trunks, but not tips. Furthermore, glomerular endothelial cells, and proximal nephron tubules from the renal vesicle stage onward show pathway activation. Surprisingly, little activation is detected in the nephrogenic zone of the kidney, and in organ culture BMP treatment fails to activate SMAD dependent BMP signaling in nephron progenitor cells. In contrast, signaling is efficiently induced in collecting duct tips.
Transgenic reporters driven by control elements from BMP responsive genes such as Id1 offer significant advantages in sensitivity and consistency over immunostaining for studies of BMP pathway activation. They also provide opportunities for analysis of BMP signaling in organ and primary cell cultures subjected to experimental manipulation. Using such a reporter, we made the surprising finding that SMAD dependent BMP signaling is inactive in nephron progenitors, and that these cells are refractory to activation by applied growth factors. Furthermore, we find that the BMP pathway is not normally active in collecting duct tips, but that it can be ectopically activated by BMP treatment, offering a possible explanation for the inhibitory effects of BMP treatment on collecting duct growth and branching.
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