The JADE protein family in renal epithelial cells in the context of cystic kidney disease

Nephronophthisis (NPH) is the number one genetic cause of end-stage renal disease in children. Since there are no causative treatment options available, the disease usually leads to dialysis or kidney transplantation by the medium age of 13. By now, several genes (NPHP1-20) have been identified whose mutations lead to NPH. Characteristics for NPH are interstitial fibrosis, tubular basement membrane thickening, and cyst formation in the kidney. Renal cyst formation is a shared feature of NPH and several other inherited (poly)cystic kidney diseases (PKD), as well as von-Hippel-Lindau (VHL) disease. VHL disease is caused by mutations in the VHL gene encoding for the protein pVHL. Moreover, loss of pVHL is also observed in most cases of sporadic renal cell carcinoma (RCC), a very frequent urogenital tumor. Recent groundbreaking studies demonstrated that primary cilia play a pivotal role in the pathogenesis of PKD and cancer biology. As tiny sensory organelles projecting from almost all mammalian cells, primary cilia transmit signals from the environment into the cell and modulate multiple signaling pathways, including Sonic Hedgehog signaling, Hippo signaling, and Wnt signaling, as well as cell cycle progression. The putative E3 ubiquitin ligase JADE1 has been found to interact with various ciliopathy-associated proteins, including pVHL and NPH proteins encoded by the NPHP genes. Thus, JADE1 might be involved in the pathogenesis of both VHL disease and NPH. Importantly, JADE1 forms a protein family with JADE2 and JADE3, the functions of which are still largely unknown. The focus of this work was to unravel the functions of the JADE protein family members, including their shared and distinct role in transcriptional regulation in renal epithelial cells and their impact on the pathogenesis of NPH, VHL disease, and RCC. To this end, two individual loss-of-function cell lines for each of the JADE family members were generated using CRISPR/Cas9-mediated genome engineering. These cell lines were used to study the distinct and mutual functions of Jade1, Jade2, and Jade3 in differentiated renal tubular epithelial cells using unbiased transcriptomic and proteomic approaches followed by comprehensive bioinformatic analyses. Moreover, we generated transgenic mouse models to study the loss of each individual Jade protein in vivo. In addition, NPH mouse models were generated with the intention to resemble the human phenotype of NPH and to gain novel insights into the disease mechanisms. The analysis of the Jade-deficient cell lines provided new insight into the role of Jade proteins in several signaling pathways related to cyst formation and cancer development, including Rap1 signaling, focal adhesion and actin cytoskeleton regulation. In addition, we observed increased expression of proteasomal components and augmented proteasomal activity in all cell lines. Moreover, the newly generated Tmem218emKO/emKO mouse line closely resembles human NPH, which will be a highly valuable preclinical model to study molecular mechanisms of NPH

Disparitäten im Wortschatzerwerb: Zum Einfluss des Arbeitsgedächtnisses und der Anregungsqualität in Kindergarten und Familie auf den Erwerb lexikalischen Wissens

Vor dem Hintergrund der Bedeutung von Sprache und Spracherwerb für die kindliche Entwicklung und für die Ausbildung sozialer Disparitäten in Schulleistungen und Bildungskarrieren werden innere und äußere Einflussvariablen auf die Wortschatzentwicklung bei 428 monolingual deutschsprachigen Vorschulkindern der BiKS-3-10 Studie untersucht. Die Entwicklung des im Alter von 3, 4 und 5 Jahren längsschnittlich erhobenen rezeptiven Wortschatzes der Kinder wurde mittels latenter linearer Wachstumsmodelle analysiert. Speziell geprüft wurde der relative Einfluss von Personvariablen (phonologisches Arbeitsgedächtnis) sowie von strukturellen und prozessbezogenen Merkmalen der Kindergartenqualität und familiärer Variablen (sozioökonomischer Status, Bildung der Mutter, „literacy“ Anregung) auf die Wortschatzentwicklung von Kindern mit vergleichsweise besserem versus schlechterem Sprachstand zu Beginn der Studie. Die Ergebnisse zeigen einen signifikanten Einfluss der phonologischen Arbeitsgedächtniskapazität, die sich bei der Gruppe der sprachlich schwächeren Kinder als besonders bedeutsam für die Wortschatzentwicklung erweist. Die Qualität und Varianz der „literacy“ Anregung im Kindergarten erwies sich insgesamt als eher niedrig; bedeutsame Effekte auf den Wortschatzanstieg waren nicht nachweisbar. Die Effekte der „literacy“ Förderung im Elternhaus variieren in Abhängigkeit vom Sprachstand der Kinder zu Beginn der Studie. Die Ergebnisse werden hinsichtlich ihrer theoretischen und praktischen Implikationen diskutiert.Language competencies are important for child development in general and have been suggested to play a major role for the emergence of social disparities in educational careers. Therefore, the aim of the present study is to investigate the impact of internal (phonological working memory) and external variables (measures of preschool quality, home learning environment, and family background) on vocabulary development in preschool children with relatively restricted or more advanced language competencies at the beginning of the study. A subsample of 428 monolingual German children (who took part in the larger BiKS-3-10 study) was tested for receptive vocabulary at three successive measurement points (age 3, 4, and 5). Using latent growth curve models the relative impact of phonological working memory capacity and various measures of preschool quality and home background (SES, mother’s educational level, literacy stimulation) was evaluated. The results show that the capacity of phonological working memory has a strong impact on vocabulary development in preschool children, especially in children with less advanced language competencies. The observed quality of and variance in literacy stimulation in preschool (domain specific preschool quality) proved to be rather low and had no significant impact on vocabulary growth. Home learning environment in the sense of literacy stimulation showed different effects depending on the child’s language status. The results are discussed with respect to developmental and educational consequences

Strategieoptionen zur Realisierung einer 100%igen Biofütterung bei Monogastriern im ökologischen Landbau

Die Umstellung auf 100%ige Biofütterung innerhalb der nächsten drei Jahre stellt eine große Herausforderung in der Monogastrierfütterung dar. Die in diesem Dossier vorgestellten Lösungsoptionen sind hinsichtlich ihrer Implementierungsmöglichkeit sehr unterschiedlich zu bewerten: Manche Optionen, wie beispielsweise die bakterielle Aminosäureherstellung, setzen noch erhebliche Forschungsarbeiten voraus, andere, wie die Verfütterung von bestimmten Silagen, sind bereits bewerte Praxis bei der Fütterung von Wiederkäuern, müssen allerdings erst noch auf Monogastrier angepasst werden. Während für die bakterielle Aminosäureherstellung entsprechende Bakterienstämme in ihrer Leistungsfähigkeit optimiert und geeignete Biosubstrate gefunden werden müssen, müssen bei der Silagebereitung und -verfütterung vor allem noch verbesserte technische Lösungen gefunden und installiert werden, damit das darin vorhandene Potenzial zur Entfaltung kommt

Leistungsprüfung offen-abblühender Maispopulationen

Auf modernem Zuchtmaterial basierende, offen-abblühende Maispopulationen könnten vor allem für ökologische und Low-Input Anbausysteme eine alternative zu Hybriden darstellen. Im Rahmen des zeitlich befristeten Experiments 2014/150/EU der EU-Kommission wurden 2016 fünf moderne Maispopulationen vom Bundessortenamt zugelassen. In einem BÖLN-Projekt wurden in 2017 und 2018 Leistungsprüfungen aller zugelassenen Maispopulationen (mit Hybriden als Referenzsorten) unter konventionellen und  ökologischen Anbaubedingungen durchgeführt. Wir stellen die Ergebnisse dieser Leistungsprüfungen vor, ziehen Schlussfolgerungen über das agronomische Potential von Maispopulationen und diskutieren zukünftige Perspektiven

Übersicht über die Ergebnisse des Vorhabens „Zuchtmethoden, Leistungs- und Adaptionsfähigkeit von Maispopulationen“

In einem Projekt im Rahmen des Bundesprogramms Ökologischer Landbau (BÖL) wurden von 2017-2022 Ertragsleistung, Ertragsstabilität, Anpassungsfähigkeit und Zuchtmethoden von Maispopulationen untersucht. Im Durchschnitt erreichten die Populationen max. 80 % Kornertrag im Vergleich zu Hybridsorten

Live attenuated virus vaccine protects against SARS-CoV-2 variants of concern B.1.1.7 (Alpha) and B.1.351 (Beta).

[Figure: see text]

Asteroid 2008 TC3, not a polymict ureilitic but a polymict C1 chondrite parent body? Survey of 249 Almahata Sitta fragments

On October 7, 2008, the asteroid 2008 TC3 exploded as it entered the Earth’s atmosphere, producing significant dust (in the atmosphere) and delivering thousands of stones in a strewn field in Sudan, collectively known as the Almahata Sitta (AhS) stones. About 600 fragments were officially recovered in 2008 and 2009. Further rocks were collected since the fall event by local people. From these stones, 249 were classified at the Institut für Planetologie in Münster (MS) known as MS‐xxx or MS‐MU‐xxx AhS subsamples. Most of these rocks are ureilitic in origin (168; 67%): 87 coarse‐grained ureilites, 60 fine‐grained ureilites, 15 ureilites with variable texture/mineralogy, four trachyandesites, and two polymict breccias. We identified 81 non‐ureilitic fragments, corresponding to 33% of the recovered samples studied in Münster. These included chondrites, namely 65 enstatite chondrites (43 EL; 22 EH), 11 ordinary chondrites (OC), one carbonaceous chondrite, and one unique R‐like chondrite. Furthermore, three samples represent a unique type of enstatite achondrite. Since all AhS stones must be regarded as individual specimens independent from each other, the number of fresh ureilite and enstatite chondrite falls in our meteorite collections has been increased by several hundred percent. Overall, the samples weigh between <1 and 250 g and have a mean mass of ~15 g. If we consider—almost 15 years after the fall—the mass calculations, observations during and after the asteroid entered the atmosphere, the mineralogy of the C1 stones AhS 91A and AhS 671, and the experimental work on fitting the asteroid spectrum (e.g., Goodrich et al., 2019; Jenniskens et al., 2010; Shaddad et al., 2010), the main portion of the meteoroid was likely made of the fine‐grained (carbonaceous) dust and was mostly lost in the atmosphere. In particular, the fact that C1 materials were found has important implications for interpreting asteroid 2008 TC3's early spectroscopic results. Goodrich et al. (2019) correctly suggested that if scientists had not recovered the “water‐free” samples (e.g., ureilites, enstatites, and OC) from the AhS strewn field, 2008 TC3 would have been assumed to be a carbonaceous chondrite meteoroid. Considering that the dominating mass of the exploding meteoroid consisted of carbonaceous materials, asteroid 2008 TC3 cannot be classified as a polymict ureilite; consequently, we state that the asteroid was a polymict carbonaceous chondrite breccia, specifically a polymict C1 object that may have formed by late accretion at least 50–100 Ma after calcium–aluminum‐rich inclusions

Separation of atomic and molecular ions by ion mobility with an RF carpet

Gas-filled stopping cells are used at accelerator laboratories for the thermalization of high-energy radioactive ion beams. Common challenges of many stopping cells are a high molecular background of extracted ions and limitations of extraction efficiency due to space-charge effects. At the FRS Ion Catcher at GSI, a new technique for removal of ionized molecules prior to their extraction out of the stopping cell has been developed. This technique utilizes the RF carpet for the separation of atomic ions from molecular contaminant ions through their difference in ion mobility. Results from the successful implementation and test during an experiment with a 600~MeV/u $^{124}$Xe primary beam are presented. Suppression of molecular contaminants by three orders of magnitude has been demonstrated. Essentially background-free measurement conditions with less than $1~\%$ of background events within a mass-to-charge range of 25 u/e have been achieved. The technique can also be used to reduce the space-charge effects at the extraction nozzle and in the downstream beamline, thus ensuring high efficiency of ion transport and highly-accurate measurements under space-charge-free conditions.Comment: 8 pages, 4 figure

Agronomic Performance Of Heterogeneous Cereal Populations

Results from comparative field trials of heterogeneous winter wheat and maize populations marketed in Germany under the temporary experiment 2014/150 of the European Commission are presented. Winter wheat populations were tested across 16 environments (four locations x four years) and eight maize populations were tested in six environments (three locations x two years) under organic conditions. In terms of yield and quality parameters both the wheat and maize populations indicated good agronomic performance. The wheat populations demonstrated yield levels and baking quality characteristics comparable to pure line varieties ranked in the highest German quality category (E). The maize populations yielded up to 85% of the hybrid reference varieties. An important future perspective will be the design of field trials for populations in order to test and quantify their special characteristics, e.g. adaptive capacity and suitability for low input conditions