Explore the vast range of titles available.

The proximal tubule is the high-capacity reabsorptive powerhouse of the kidney. Two papers in recent issues of the JCI highlight mechanisms of more delicate effects of the proximal tubule. Yoon et al. demonstrated the intracellular mechanism by which parathyroid hormone (PTH) increases production of 1,25-vitamin D. Activation of PTH receptor 1/cAMP/PKA signaling inhibited salt-inducible kinase 2 (SIK2) and SIK3, which increased CYB27B1 transcription and 1,25-vitamin D production. Replication of these effects with small-molecule SIK inhibitors suggests possible therapeutic applications for patients with disorders characterized by 1,25-vitamin D deficiency. Zhou et al. discovered that proximal tubule glycolysis acts as a phosphate sensor that regulates fibroblast growth factor 23 production in bone. They described several kidney-specific metabolic modifications that enabled glycolysis to be deployed as a phosphate sensor. The provocative results raise intriguing questions with implications for patients with disorders of phosphate homeostasis, including chronic kidney disease.

Vitamin D regulates mineral homeostasis. The most biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is synthesized by CYP27B1 from 25-dihydroxyvitamin D (25D) and is inactivated by CYP24A1. Human monogenic diseases and genome-wide association studies support a critical role for CYP24A1 in regulation of mineral homeostasis, but little is known about its tissue-specific effects. Here, we describe the responses of mice with inducible global deletion, kidney-specific, and intestine-specific deletion of Cyp24a1 to dietary calcium challenge and chronic kidney disease (CKD). Global and kidney-specific Cyp24a1 deletion caused similar syndromes of systemic vitamin D intoxication: elevated circulating 1,25D, 25D, and fibroblast growth factor 23 (FGF23), activation of vitamin D target genes in the kidney and intestine, hypercalcemia, and suppressed parathyroid hormone (PTH). In contrast, mice with intestine-specific Cyp24a1 deletion demonstrated activation of vitamin D target genes exclusively in the intestine, despite no changes in systemic vitamin D levels. In response to a high calcium diet, PTH was suppressed, despite normal serum calcium. In mice with CKD, intestinal Cyp24a1 deletion decreased PTH and FGF23 without precipitating hypercalcemia. These results implicate kidney CYP24A1 in systemic vitamin D regulation while independent local effects of intestinal CYP24A1 could be targeted to treat secondary hyperparathyroidism in CKD.

The protease renin, the key enzyme of the renin–angiotensin–aldosterone system, is mainly produced and secreted by juxtaglomerular cells in the kidney, which are located in the walls of the afferent arterioles at their entrance into the glomeruli. When the body’s demand for renin rises, the renin production capacity of the kidneys commonly increases by induction of renin expression in vascular smooth muscle cells and in extraglomerular mesangial cells. These cells undergo a reversible metaplastic cellular transformation in order to produce renin. Juxtaglomerular cells of the renin lineage have also been described to migrate into the glomerulus and differentiate into podocytes, epithelial cells or mesangial cells to restore damaged cells in states of glomerular disease. More recently, it could be shown that renin cells can also undergo an endocrine and metaplastic switch to erythropoietin-producing cells. This review aims to describe the high degree of plasticity of renin-producing cells of the kidneys and to analyze the underlying mechanisms.

Renal interstitial fibrosis is characterized by the development of myofibroblasts, originating from resident renal and immigrating cells. Myofibroblast formation and extracellular matrix production during kidney damage are triggered by various factors. Among these, endothelins have been discussed as potential modulators of renal fibrosis. Utilizing mouse models of adenine nephropathy (AN) and unilateral ureter occlusion (UUO), this study aimed to investigate the contribution of endothelin signaling in stromal mesenchymal resident renal interstitial cells. We found in controls that adenine feeding and UUO caused marked upregulations of endothelin-1 (ET-1) gene expression in endothelial and in tubular cells and a strong upregulation of ETA-receptor (ETA-R) gene expression in interstitial and mesangial cells, while the gene expression of ETB-receptor (ETB-R) did not change. Conditional deletion of ETA-R and ETB-R gene expression in the FoxD1 stromal cell compartment which includes interstitial cells significantly reduced renal ETA-R gene expression and moderately lowered renal ETB-R gene expression. ET receptor (ET-R) deletion exerted no apparent effects on kidney development nor on kidney function. Adenine feeding and UUO led to similar increases in profibrotic and proinflammatory gene expression in control as well as in ETAflflETBflfl FoxD1Cre+ mice (ET-Ko). In summary, our findings suggest that adenine feeding and UUO activate endothelin signaling in interstitial cells which is due to upregulated ETA-R expression and enhanced renal ET-1 production Our data also suggest that the activation of endothelin signaling in interstitial cells has less impact for the development of experimentally induced fibrosis.

Academic discussions have frequently examined the interrelation between regional employment growth and firm locations. Two growth patterns emerge: employment growth induced through new firm locations or vice versa, where firms locate in areas experiencing employment supply growth. The specific causal relationship responsible for regional employment growth in Germany remains uncertain. In the German context, however, more research is needed to identify contributors to employment growth, as most existing studies rely on highly aggregated data or focus on specific case studies. This paper aims to approach this subject by using a uniquely matched dataset of firm locations and the individual employment of 480 multi-locational firms in the knowledge economy and comparing it to total employment in Germany. We assume that a change in knowledge-intensive firms' employment may affect regional employment growth. The study uses longitudinal historical employment data at the functional urban area (FUA) level from 1999 to 2019, aggregated to knowledge-intensive high-tech and advanced producer services (APS) sectors. The analysis employs aggregated and individual Granger causality tests, evaluating the relationship between employment in knowledge-intensive sectors and overall employment change. Results are spatialised using GIS to provide evidence of where the Granger causalities occur at the FUA level in Germany. Findings indicate that, in general, knowledge-intensive employment growth Granger causes total employment growth in a few economically more active FUAs. In contrast, for a greater number of FUAs, total employment Granger causes knowledge-intensive employment.

In Germany, employment is becoming increasingly concentrated in urban areas, largely driven by knowledge-intensive firms competing to attract the most qualified and appropriate labour. Therefore, this paper addresses where knowledge workers relocate to and how relocation patterns vary across spatial distances. Using an innovative origin-destination analysis, we examine job-related employment relocations across 186 functional urban areas in Germany from 2012 to 2021, using official employment data for 480 multi-locational firms, classified into one of three knowledge bases: analytical, synthetic and symbolic. This classification helps explain how firms create and use knowledge in their innovation process and allows us to differentiate workers' relocation patterns. Our findings reveal a nuanced, multi-scalar perspective on the German knowledge economy. Between 2012 and 2021, knowledge-intensive employment has primarily relocated towards the largest functional urban areas, such as Munich or Frankfurt. However, relocation patterns diverge by knowledge base, and we can reveal the underlying dynamics driving this concentration. Workers in synthetic knowledge bases predominantly relocate on a large scale to and between these largest functional areas and between more decentralised functional areas, suggesting that spatial proximity plays a subordinate role in job-related relocations. In contrast, workers in analytical and symbolic knowledge bases exhibit less frequent relocations to other functional urban areas, instead relocating on a regional scale, mostly between neighbouring or spatially closer functional urban areas. In Deutschland konzentriert sich die Beschäftigung in der Wissensökonomie zunehmend auf urbane Räume, vor allem durchdort angesiedelte Unternehmen, die um die qualifiziertesten und am besten geeigneten Arbeitskräfte konkurrieren. Dieser Beitrag befasst sich mit dem Umzugsverhalten von Wissensarbeiterinnen und Wissensarbeitern und wie sich Umzugsmuster auf unterschiedlichen räumlichen Ebenen unterscheiden. Mit einer innovativen Herkunft-Ziel-Analyse untersuchen wir arbeitsplatzbezogene Beschäftigtenumzüge zwischen 186 funktionalen urbanen Räumen in Deutschland im Zeitraum von 2012 bis 2021. Hierfür nutzen wir offizielle Beschäftigungsdaten von 480 Mehrbetriebsunternehmen, die einer von drei Wissensbasen zugeordnet werden: analytisch, synthetisch und symbolisch. Diese Klassifizierung hilft zu erklären, wie Unternehmen Wissen in ihren Innovationsprozessen erzeugen und nutzen, und ermöglicht uns, die Umzugsmuster der Beschäftigten zu differenzieren. Unsere Ergebnisse liefern eine detaillierte, multiskalare Perspektive auf die deutsche Wissensökonomie: Zwischen 2012 und 2021 hat sich die räumli-che Verteilung wissensintensiver Beschäftigung stärker aufdie größten funktionalen urbanen Räume wie München oder Berlin konzentriert. Allerdings unterscheiden sich die Umzugsmuster je nach Wissensbasis, weshalb wir die zugrundeliegende Dynamik dieser Konzentration aufdecken können. Arbeitskräfte in synthetischen Wissensbasen ziehen überwiegend in großem Maßstab in die größten Funktionsbereiche sowie zwischen diesen und dezentraleren funktionalen urbanen Räumen um. Dies deutet darauf hin, dass die räumliche Nähe bei arbeitsplatzbezogenen Umzügen möglicherweise eine untergeordnete Rolle spielt. Im Gegensatz dazu ziehen Beschäftigte in analytischen und symbolischen Wissensbasen seltener in andere funktionale urbane Räume. Sie ziehenstattdessen auf kleinräumigerer Ebene um, meist zwischenbenachbarten oder räumlich näher gelegenen funktionalenurbanen Räumen.

Piccolo is one of the largest cytomatrix proteins present at active zones of chemical synapses, where it is suggested to play a role in recruiting and integrating molecules relevant for both synaptic vesicle exo- and endocytosis. Here we examined the retina of a Piccolo-mutant mouse with a targeted deletion of exon 14 in the Pclo gene. Piccolo deficiency resulted in its profound loss at conventional chemical amacrine cell synapses but retinal ribbon synapses were structurally and functionally unaffected. This led to the identification of a shorter, ribbon-specific Piccolo variant, Piccolino, present in retinal photoreceptor cells, bipolar cells, as well as in inner hair cells of the inner ear. By RT-PCR analysis and the generation of a Piccolino-specific antibody we show that non-splicing of intron 5/6 leads to premature translation termination and generation of the C-terminally truncated protein specifically expressed at active zones of ribbon synapse containing cell types. With in situ proximity ligation assays we provide evidence that this truncation leads to the absence of interaction sites for Bassoon, Munc13, and presumably also ELKS/CAST, RIM2, and the L-type Ca(2) (+) channel which exist in the full-length Piccolo at active zones of conventional chemical synapses. The putative lack of interactions with proteins of the active zone suggests a function of Piccolino at ribbon synapses of sensory neurons different from Piccolo's function at conventional chemical synapses.

The DBA/2J mouse is a commonly used animal model in glaucoma research. The eyes of DBA/2J mice show severe age-related changes that finally lead to the degeneration of retinal ganglion cells and the optic nerve. Recent electroretinogram studies identified functional deficits, which suggest that also photoreceptor cells are involved in the pathological processes occurring in the DBA/2J mouse retina. In a comparative study, we examined anatomical and molecular changes in the retinae of DBA/2J and C57BL/6 control mice with light and electron microscopy and with PCR analyses. In the retina of the DBA/2J mouse, we found a thinning of the outer plexiform layer, the first synaptic layer in the transfer of visual signals, and age-dependent and progressive degenerative structural changes at rod photoreceptor ribbon synapses. The structural ribbon changes represent a photoreceptor synaptic phenotype that has not yet been described in this animal model of secondary angle-closure glaucoma. Furthermore, genes of the classical complement cascade were upregulated in the photoreceptor cells of aging DBA/2J mice, suggesting a putative link between ribbon synapse degradation and the innate immune system.

We examine job creation and destruction in Eastern and Western Germany for the period of 2000 to 2006, using a comprehensive dataset that enables us to capture precisely gross job flows. Our analysis clearly states that pronounced differences between the two parts of Germany exist only in terms of the magnitude, but not in the composition of gross job gains and losses. This finding holds independently of the observed sector or size class of plants. Considering interaction effects between all variables, this first econometric analysis on gross job flows for Germany shows that job creation and destruction can be explained to a large part by plant characteristics. The pattern found in descriptive studies for other countries that job reallocation rates diminish with firm size is similarly true for Germany. The creation of jobs attenuates with plant age, while regional characteristics are only important for job destruction.