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Goblet cell metaplasia and mucus hypersecretion are observed in many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the regulation of goblet cell differentiation remains unclear. Here, we identify a regulator of this process in an N-ethyl-N-nitrosourea (ENU) screen for modulators of postnatal lung development; Ryk mutant mice exhibit lung inflammation, goblet cell hyperplasia, and mucus hypersecretion. RYK functions as aWNT coreceptor, and, in the developing lung, we observed high RYK expression in airway epithelial cells and moderate expression in mesenchymal cells as well as in alveolar epithelial cells. From transcriptomic analyses and follow-up studies, we found decreased WNT/β-catenin signaling activity in the mutant lung epithelium. Epithelial-specific Ryk deletion causes goblet cell hyperplasia and mucus hypersecretion but not inflammation, while club cell-specific Ryk deletion in adult stages leads to goblet cell hyperplasia and mucus hypersecretion during regeneration. We also found that the airway epithelium of COPD patients often displays goblet cell metaplastic foci, as well as reduced RYK expression. Altogether, our findings reveal that RYK plays important roles in maintaining the balance between airway epithelial cell populations during development and repair, and that defects in RYK expression or function may contribute to the pathogenesis of human lung diseases.

Impaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10 . Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is downregulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema. Abnormal alveolar development and homeostasis are common features of pulmonary disease. Here the authors show that Myh10 expression is reduced in emphysema patients, and that Myh10 loss of function impairs alveolar formation and lung morphogenesis via upregulation of matrix metalloproteinase activity and altered matrix remodeling.

Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13- mutant trachea phenotypes. These results provide insight into the role of ion homeostasis in cytoskeletal organization during tubulogenesis. Tubulogenesis is required for the formation of many internal structures including the trachea. Here, the authors show that the potassium channel KCNJ13 regulates tracheal tube formation, with shorter tracheas forming in mutant mice due in part to changes in actin organization in tracheal smooth muscle cells.

Tubulogenesis is essential for the formation and function of internal organs. One such organ is the trachea, which allows gas exchange between the external environment and the lungs. However, the cellular and molecular mechanisms underlying tracheal tube development remain poorly understood. Here, we show that the potassium channel KCNJ13 is a critical modulator of tracheal tubulogenesis. We identify Kcnj13 in an ethylnitrosourea forward genetic screen for regulators of mouse respiratory organ development. Kcnj13 mutants exhibit a shorter trachea as well as defective smooth muscle (SM) cell alignment and polarity. KCNJ13 is essential to maintain ion homeostasis in tracheal SM cells, which is required for actin polymerization. This process appears to be mediated, at least in part, through activation of the actin regulator AKT, as pharmacological increase of AKT phosphorylation ameliorates the Kcnj13 mutant trachea phenotypes. These results provide insights into the role of ion homeostasis in cytoskeletal organization during tubulogenesis.

Impaired alveolar formation and maintenance are features of many pulmonary diseases that are associated with significant morbidity and mortality. In a forward genetic screen for modulators of mouse lung development, we identified the non-muscle myosin II heavy chain gene, Myh10. Myh10 mutant pups exhibit cyanosis and respiratory distress, and die shortly after birth from differentiation defects in alveolar epithelium and mesenchyme. From omics analyses and follow up studies, we find decreased Thrombospondin expression accompanied with increased matrix metalloproteinase activity in both mutant lungs and cultured mutant fibroblasts, as well as disrupted extracellular matrix (ECM) remodeling. Loss of Myh10 specifically in mesenchymal cells results in ECM deposition defects and alveolar simplification. Notably, MYH10 expression is down-regulated in the lung of emphysema patients. Altogether, our findings reveal critical roles for Myh10 in alveologenesis at least in part via the regulation of ECM remodeling, which may contribute to the pathogenesis of emphysema.

Since March 2021, Germany has been providing cost-free severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen tests, and many day-to-day activities following the lockdown have required negative test results. Yet it remains unclear how tests have been used and whether there are patterns connected to mitigation measures. We analyzed over 50,000 anonymized records from eight test centers in a typical medium-sized city, with one of them remaining open continuously from March until December 2021. The centers exhibit distinct patterns of visitor types, with the majority tested only once in the investigated period. Individuals who underwent repeated testing tended to favor the same location. A preference for spontaneous testing grew in proportion to the availability of spare tests. Visitors aged 18 to 30 years were distinctly overrepresented compared to the local demographic. A negative binominal model showed that implemented mitigation measures had an impact on the number of tests conducted. Cost-free testing in private facilities was implemented into the German complementary screening strategy, aiming to achieve weekly population-wide testing. This study demonstrates these facilities were rarely used for regular testing but rather for meeting requirements of certified tests. The results should aid authorities in making future decisions regarding infection control.

During the third wave of the COVID-19 (coronavirus disease 2019) pandemic in Germany, free SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) point-of-care (PoC) antigen tests were offered to citizens at least once a week to prevent spreading by asymptomatic infected individuals. This study investigated user groups, timing, frequency, and test center locations in a typical medium-sized European city. We analyzed 27,369 pseudonymized datasets from eight centers over 12 weeks. Those were evaluated according to age, residence, appointment, and potential repeated test occurrence. The centers were visited by different groups; some centers were preferred by a predominantly younger demographic, whereas a mobile option attracted an older age group by reaching districts with few other testing possibilities. Elderly individuals were tested more spontaneously than younger individuals, and a test center at a ‘park and ride’ had more spontaneous visitors from outside of the city compared to other test locations. Only a small proportion of less than 4% came for testing more than five times. To preferably address many people for voluntary antigen testing, it is crucial to offer different test opportunities accounting for individual behavioral patterns, despite this requiring more complex and costly design than conventional forms.

This biophysical study aimed to determine fitting parameters for the Lyman–Kutcher–Burman (LKB) dose–response model for normal tissue complication probability (NTCP) calculations of acute side effects and to investigate the impact of reduced radiation doses on the probability of their occurrence in supradiaphragmatic non-Hodgkin lymphoma (NHL) irradiation. A cohort of 114 patients with NHL in the cervicothoracic region, treated between 2015 and 2021 at the University Hospitals of Münster, Hamburg, and Essen, with involved site radiation therapy (ISRT), were included. Among them, 68 patients with aggressive NHL (a-NHL) received consolidative radiation therapy with 24–54 Gy following (R-)CHOP chemotherapy. Additionally, 46 patients with indolent NHL (i-NHL) underwent radiotherapy with 22.5–45.0 Gy. Two treatment plans were prospectively created for each patient (a-NHL: 30.0/40.0 Gy; i-NHL: 24.0/30.0 Gy). NTCP were then calculated using the optimized LKB model. The adapted dose–response models properly predicted the patient’s probability of developing acute side effects when receiving doses ≤ 50 Gy. In addition, it was shown that reduced radiation doses can influence the NTCP of acute side effects depending on the aggressiveness of NHL significantly. This study provided a foundation to prospectively assess the probability of adverse side effects among today’s reduced radiation doses in the treatment of NHL.

The KArlsruhe TRItium Neutrino experiment (KATRIN) aims to measure the effective electron anti-neutrino mass with an unprecedented sensitivity of \\(0.2\\,\\mathrm{eV}/\\mathrm{c}^2\\), using \\(\\beta\\)-electrons from tritium decay. The electrons are guided magnetically by a system of superconducting magnets through a vacuum beamline from the windowless gaseous tritium source through differential and cryogenic pumping sections to a high resolution spectrometer and a segmented silicon pin detector. At the same time tritium gas has to be prevented from entering the spectrometer. Therefore, the pumping sections have to reduce the tritium flow by more than 14 orders of magnitude. This paper describes the measurement of the reduction factor of the differential pumping section performed with high purity tritium gas during the first measurement campaigns of the KATRIN experiment. The reduction factor results are compared with previously performed simulations, as well as the stringent requirements of the KATRIN experiment.