Double-sieving-defective aminoacyl-tRNA synthetase causes protein mistranslation and affects cellular physiology and development.

Aminoacyl-tRNA synthetases (aaRSs) constitute a family of ubiquitously expressed essential enzymes that ligate amino acids to their cognate tRNAs for protein synthesis. Recently, aaRS mutations have been linked to various human diseases; however, how these mutations lead to diseases has remained unclear. In order to address the importance of aminoacylation fidelity in multicellular organisms, we generated an amino-acid double-sieving model in Drosophila melanogaster using phenylalanyl-tRNA synthetase (PheRS). Double-sieving-defective mutations dramatically misacylate non-cognate Tyr, induce protein mistranslation and cause endoplasmic reticulum stress in flies. Mutant adults exhibit many defects, including loss of neuronal cells, impaired locomotive performance, shortened lifespan and smaller organ size. At the cellular level, the mutations reduce cell proliferation and promote cell death. Our results also reveal the particular importance of the first amino-acid recognition sieve. Overall, these findings provide new mechanistic insights into how malfunctioning of aaRSs can cause diseases

Control of Directed Cell Migration In Vivo by Membrane-to-Cortex Attachment

Analysis of cell migration in vivo combined with biophysical measurements reveals how membrane-to-cortex attachment fine-tunes the type of protrusions formed by cells and, as a consequence, controls directed migration during zebrafish gastrulation

Steering cell migration by alternating blebs and actin-rich protrusions.

BACKGROUND: High directional persistence is often assumed to enhance the efficiency of chemotactic migration. Yet, cells in vivo usually display meandering trajectories with relatively low directional persistence, and the control and function of directional persistence during cell migration in three-dimensional environments are poorly understood. RESULTS: Here, we use mesendoderm progenitors migrating during zebrafish gastrulation as a model system to investigate the control of directional persistence during migration in vivo. We show that progenitor cells alternate persistent run phases with tumble phases that result in cell reorientation. Runs are characterized by the formation of directed actin-rich protrusions and tumbles by enhanced blebbing. Increasing the proportion of actin-rich protrusions or blebs leads to longer or shorter run phases, respectively. Importantly, both reducing and increasing run phases result in larger spatial dispersion of the cells, indicative of reduced migration precision. A physical model quantitatively recapitulating the migratory behavior of mesendoderm progenitors indicates that the ratio of tumbling to run times, and thus the specific degree of directional persistence of migration, are critical for optimizing migration precision. CONCLUSIONS: Together, our experiments and model provide mechanistic insight into the control of migration directionality for cells moving in three-dimensional environments that combine different protrusion types, whereby the proportion of blebs to actin-rich protrusions determines the directional persistence and precision of movement by regulating the ratio of tumbling to run times.This work was supported by the Max Planck Society, the Medical Research Council UK (core funding to the MRC LMCB), and by grants from the Polish Ministry of Science and Higher Education (454/N-MPG/2009/0) to EKP, the Deutsche Forschungsgemeinschaft (HE 3231/6-1 and PA 1590/1-1) to CPH and EKP, a A*Star JCO career development award (12302FG010) to WY and a Damon Runyon fellowship award to ADM (DRG 2157-12). This work was also supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001317), the UK Medical Research Council (FC001317), and the Wellcome Trust (FC001317) to G

Endocytic reawakening of motility in jammed epithelia.

Dynamics of epithelial monolayers has recently been interpreted in terms of a jamming or rigidity transition. How cells control such phase transitions is, however, unknown. Here we show that RAB5A, a key endocytic protein, is sufficient to induce large-scale, coordinated motility over tens of cells, and ballistic motion in otherwise kinetically arrested monolayers. This is linked to increased traction forces and to the extension of cell protrusions, which align with local velocity. Molecularly, impairing endocytosis, macropinocytosis or increasing fluid efflux abrogates RAB5A-induced collective motility. A simple model based on mechanical junctional tension and an active cell reorientation mechanism for the velocity of self-propelled cells identifies regimes of monolayer dynamics that explain endocytic reawakening of locomotion in terms of a combination of large-scale directed migration and local unjamming. These changes in multicellular dynamics enable collectives to migrate under physical constraints and may be exploited by tumours for interstitial dissemination

Fat Body Cells Are Motile and Actively Migrate to Wounds to Drive Repair and Prevent Infection

Adipocytes have many functions in various tissues beyond energy storage, including regulating metabolism, growth, and immunity. However, little is known about their role in wound healing. Here we use live imaging of fat body cells, the equivalent of vertebrate adipocytes in Drosophila, to investigate their potential behaviors and functions following skin wounding. We find that pupal fat body cells are not immotile, as previously presumed, but actively migrate to wounds using an unusual adhesion-independent, actomyosin-driven, peristaltic mode of motility. Once at the wound, fat body cells collaborate with hemocytes, Drosophila macrophages, to clear the wound of cell debris; they also tightly seal the epithelial wound gap and locally release antimicrobial peptides to fight wound infection. Thus, fat body cells are motile cells, enabling them to migrate to wounds to undertake several local functions needed to drive wound repair and prevent infections

Denkwerkstatt "Ressourcenknappheit"- Handlungs- und Aktionsfelder II

Vorwort: Non-Profit Manager*innen von heute sind Generalist*innen, die sich initiativ und eigenverantwortlich mit den Herausforderungen unserer Zeit auseinandersetzen und im besten Falle geeignete Lösungen dafür finden und diese auch richtig kommunizieren können. Aus diesem Grunde wird genau diese Fähigkeit bei Studierenden aus den Masterstudiengängen Management in Nonprofit-Organisationen und Soziale Arbeit der Hochschule Osnabrück gefördert. Im Rahmen des Moduls Handlungsfelder II entwickelten rund 30 Studierende im Wintersemester 2020/2021 in einer Denkwerkstatt ihre eigenen Lösungen in Bezug auf Forschung, Produkte / Dienstleistungen und Kommunikation. Die Studierenden wählten in einem partizipativen Prozess ihre eigenen Schwerpunktthemen aus und arbeiteten dann ein Semester lang an den Inhalten. Begleitet wurden sie durch ein Teamteaching von Prof. Dr. Gesa Birnkraut und Marlene Eimterbäumer, die Modelle, Methoden und Coaching zur Unterstützung anboten. Die Modelle und Methoden finden sich in den Beiträgen der Studierenden wieder (unter anderem das socio-ecological model, der Business Model Canvas, der story telling canvas, das design thinking). Am Ende des Semesters stand eine Präsentation vor den Kommiliton*innen und den Lehrenden, aber auch vor externen Gästen, die aus unterschiedlichen Expertisegebieten kamen und dementsprechend Feedback gaben. Das Modul selbst wurde von der Hochschule im Rahmen der Innovativen Lehre an der Fakultät Wirtschafts- und Sozialwissenschaften gefördert. Für die Studierenden stellte das Modul durchaus eine große Herausforderung dar, denn in der Denkwerkstatt musste unter hoher Komplexität stark prozessbezogen gearbeitet werden im Gegensatz zu der sonstigen hohen Ergebnisorientierung. Die durchweg sehr guten Ergebnisse zeigen, dass der Einsatz und das Aushalten der Unsicherheit sich gelohnt haben. Aufgeteilt ist das vorliegende Buch in die zwei Schwerpunktthemen Ressourcenknappheit / Wirtschaft und Wasserknappheit. In diesen beiden Schwerpunktthemen finden Sie jeweils einen Beitrag von den Forscher*innen, den Lösungsfinder*innen und den Kommunikator*innen

Steering cell migration by alternating blebs and actin-rich protrusions.

BACKGROUND: High directional persistence is often assumed to enhance the efficiency of chemotactic migration. Yet, cells in vivo usually display meandering trajectories with relatively low directional persistence, and the control and function of directional persistence during cell migration in three-dimensional environments are poorly understood. RESULTS: Here, we use mesendoderm progenitors migrating during zebrafish gastrulation as a model system to investigate the control of directional persistence during migration in vivo. We show that progenitor cells alternate persistent run phases with tumble phases that result in cell reorientation. Runs are characterized by the formation of directed actin-rich protrusions and tumbles by enhanced blebbing. Increasing the proportion of actin-rich protrusions or blebs leads to longer or shorter run phases, respectively. Importantly, both reducing and increasing run phases result in larger spatial dispersion of the cells, indicative of reduced migration precision. A physical model quantitatively recapitulating the migratory behavior of mesendoderm progenitors indicates that the ratio of tumbling to run times, and thus the specific degree of directional persistence of migration, are critical for optimizing migration precision. CONCLUSIONS: Together, our experiments and model provide mechanistic insight into the control of migration directionality for cells moving in three-dimensional environments that combine different protrusion types, whereby the proportion of blebs to actin-rich protrusions determines the directional persistence and precision of movement by regulating the ratio of tumbling to run times.This work was supported by the Max Planck Society, the Medical Research Council UK (core funding to the MRC LMCB), and by grants from the Polish Ministry of Science and Higher Education (454/N-MPG/2009/0) to EKP, the Deutsche Forschungsgemeinschaft (HE 3231/6-1 and PA 1590/1-1) to CPH and EKP, a A*Star JCO career development award (12302FG010) to WY and a Damon Runyon fellowship award to ADM (DRG 2157-12). This work was also supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001317), the UK Medical Research Council (FC001317), and the Wellcome Trust (FC001317) to G

A Nanoprinted Model of Interstitial Cancer Migration Reveals a Link between Cell Deformability and Proliferation

Metastatic progression of tumors requires the coordinated dissemination of cancerous cells through interstitial tissues and their replication in distant body locations. Despite their importance in cancer treatment decisions, key factors, such as cell shape adaptation and the role it plays in dense tissue invasion by cancerous cells, are not well understood. Here, we employ a 3D electrohydrodynamic nanoprinting technology to generate vertical arrays of topographical pores that mimic interstitial tissue resistance to the mesenchymal migration of cancerous cells, in order to determine the effect of nuclear size, cell deformability, and cell-to-substrate adhesion on tissue invasion efficiency. The high spatial and temporal resolution of our analysis demonstrates that the ability of cells to deform depends on the cell cycle phase, peaks immediately after mitosis, and is key to the invasion process. Increased pore penetration efficiency by cells in early G1 phase also coincided with their lower nuclear volume and higher cell deformability, compared with the later cell cycle stages. Furthermore, artificial decondensation of chromatin induced an increase in cell and nuclear deformability and improved pore penetration efficiency of cells in G1. Together, these results underline that along the cell cycle cells have different abilities to dynamically remodel their actin cytoskeleton and induce nuclear shape changes, which determines their pore penetration efficiency. Thus, our results support a mechanism in which cell proliferation and pore penetration are functionally linked to favor the interstitial dissemination of metastatic cells

A Nanoprinted Model of Interstitial Cancer Migration Reveals a Link between Cell Deformability and Proliferation

Metastatic progression of tumors requires the coordinated dissemination of cancerous cells through interstitial tissues and their replication in distant body locations. Despite their importance in cancer treatment decisions, key factors, such as cell shape adaptation and the role it plays in dense tissue invasion by cancerous cells, are not well understood. Here, we employ a 3D electrohydrodynamic nanoprinting technology to generate vertical arrays of topographical pores that mimic interstitial tissue resistance to the mesenchymal migration of cancerous cells, in order to determine the effect of nuclear size, cell deformability, and cell-to-substrate adhesion on tissue invasion efficiency. The high spatial and temporal resolution of our analysis demonstrates that the ability of cells to deform depends on the cell cycle phase, peaks immediately after mitosis, and is key to the invasion process. Increased pore penetration efficiency by cells in early G1 phase also coincided with their lower nuclear volume and higher cell deformability, compared with the later cell cycle stages. Furthermore, artificial decondensation of chromatin induced an increase in cell and nuclear deformability and improved pore penetration efficiency of cells in G1. Together, these results underline that along the cell cycle cells have different abilities to dynamically remodel their actin cytoskeleton and induce nuclear shape changes, which determines their pore penetration efficiency. Thus, our results support a mechanism in which cell proliferation and pore penetration are functionally linked to favor the interstitial dissemination of metastatic cells

A Nanoprinted Model of Interstitial Cancer Migration Reveals a Link between Cell Deformability and Proliferation

Metastatic progression of tumors requires the coordinated dissemination of cancerous cells through interstitial tissues and their replication in distant body locations. Despite their importance in cancer treatment decisions, key factors, such as cell shape adaptation and the role it plays in dense tissue invasion by cancerous cells, are not well understood. Here, we employ a 3D electrohydrodynamic nanoprinting technology to generate vertical arrays of topographical pores that mimic interstitial tissue resistance to the mesenchymal migration of cancerous cells, in order to determine the effect of nuclear size, cell deformability, and cell-to-substrate adhesion on tissue invasion efficiency. The high spatial and temporal resolution of our analysis demonstrates that the ability of cells to deform depends on the cell cycle phase, peaks immediately after mitosis, and is key to the invasion process. Increased pore penetration efficiency by cells in early G1 phase also coincided with their lower nuclear volume and higher cell deformability, compared with the later cell cycle stages. Furthermore, artificial decondensation of chromatin induced an increase in cell and nuclear deformability and improved pore penetration efficiency of cells in G1. Together, these results underline that along the cell cycle cells have different abilities to dynamically remodel their actin cytoskeleton and induce nuclear shape changes, which determines their pore penetration efficiency. Thus, our results support a mechanism in which cell proliferation and pore penetration are functionally linked to favor the interstitial dissemination of metastatic cells