Trichom-Entwicklung in Arabidopsis thaliana als Modellsystem für de novo Musterbildungsprozesse

Die Trichom-Musterbildung in Arababidopsis thaliana stellt ein etabliertes Modellsystem zur Untersuchung von Musterbildungsprozessen in Pflanzen dar. Die Trichom-Entwicklung wird von bHLH- und MYB-Transkriptionsfaktoren zusammen mit einem WD-40 Protein reguliert. Zu den MYB-Transkriptionsfaktoren zählen die Trichom-Inhibitoren TRY, CPC, ETC1, ETC2 und TCL1 und die Trichom-Aktivatoren GL1 und MYB23. GL3, EGL3 und TTG1, ebenfalls Trichom-Aktivatoren, kodieren für bHLH- Transkriptionsfaktoren bzw. für das WD-40 Protein. Die Trichom-Inhibitoren, auf die sich diese Arbeit konzentriert, regulieren nach der postulierten de novo Trichom-Musterbildung das regelmäßige Abstandsmuster zwischen den Trichomen durch laterale Inhibition, was in dem Aktivator-Inhibitor Modell beschrieben wird. In dieser Arbeit wird gezeigt, dass ein weiteres Gen, ETC3 an der Regulation der Trichom-Musterbildung als Trichom-Inhibitor beteiligt ist. Untersuchungen der Trichom-Inhibitoren auf Proteinebene zeigen neue Aspekte der lateralen Inhibition durch deren Mobilität. Durch Kompetitionsanalysen wird gezeigt, dass die Inhibitoren ETC1, ETC3, CPC und TRY am Mechanismus der lateralen Inhibition durch die Verdrängung von GL1 aus dem Aktivator Komplex beteiligt sind, wohingegen ETC2 keine Kompetitor-Eigenschaft besitzt. Weiterhin wird anhand von CPC und ETC3 gezeigt, dass die Inhibitoren unterschiedliche Signalreichweiten für die laterale Inhibition besitzen, die aufgrund unterschiedlicher Bindungsaffinitäten zu GL3 erklärt werden. Für diese Beobachtung wird ein theoretisches Modell postuliert, nach dem ETC2 die längste Signalreichweite der Inhibitoren besitzt, gefolgt von ETC3 und TRY. CPC und ETC1 haben nach diesem Modell lediglich eine kurze Signalreichweite. Auf Expressionsebene werden Unterschiede zwischen den Promotoren von CPC, TRY und ETC3 aufgezeigt. Weiterhin werden die Inhibitoren CPC und TRY auf eine mögliche posttranslationale Phosphorylierung untersucht um eine eventuelle Regulation der inhibitorischen Aktivität und/oder der Mobilität aufzudecken. Weiterhin wird eine Methode vorgestellt, die es ermöglicht, die Trichom-Musterbildung in Rosettenblättern von der Entstehung der Trichom-initialzellen bis hin zum adulten Stadium in vivo zeitlich zu verfolgen. Daraus ergibt sich einerseits eine neue Möglichkeit, die Musterbildung quantitativ in silico zu analysieren. Außerdem dient diese Methode der in vivo Verfolgung dazu, die postulierte de novo Musterbildung durch Laser-Ablationen zu verifizieren

Two-Dimensional Patterning by a Trapping/Depletion Mechanism: The Role of TTG1 and GL3 in Arabidopsis Trichome Formation

Trichome patterning in Arabidopsis serves as a model system to study how single cells are selected within a field of initially equivalent cells. Current models explain this pattern by an activator–inhibitor feedback loop. Here, we report that also a newly discovered mechanism is involved by which patterning is governed by the removal of the trichome-promoting factor TRANSPARENT TESTA GLABRA1 (TTG1) from non-trichome cells. We demonstrate by clonal analysis and misexpression studies that Arabidopsis TTG1 can act non-cell-autonomously and by microinjection experiments that TTG1 protein moves between cells. While TTG1 is expressed ubiquitously, TTG1–YFP protein accumulates in trichomes and is depleted in the surrounding cells. TTG1–YFP depletion depends on GLABRA3 (GL3), suggesting that the depletion is governed by a trapping mechanism. To study the potential of the observed trapping/depletion mechanism, we formulated a mathematical model enabling us to evaluate the relevance of each parameter and to identify parameters explaining the paradoxical genetic finding that strong ttg1 alleles are glabrous, while weak alleles exhibit trichome clusters

Use of Cis-[18F]Fluoro-Proline for Assessment of Exercise-Related Collagen Synthesis in Musculoskeletal Connective Tissue

Protein turnover in collagen rich tissue is influenced by exercise, but can only with difficulty be studied in vivo due to use of invasive procedure. The present study was done to investigate the possibility of applying the PET-tracer, cis-[18F]fluoro-proline (cis-Fpro), for non-invasive assessment of collagen synthesis in rat musculoskeletal tissues at rest and following short-term (3 days) treadmill running. Musculoskeletal collagen synthesis was studied in rats at rest and 24 h post-exercise. At each session, rats were PET scanned at two time points following injection of cis-FPro: (60 and 240 min p.i). SUV were calculated for Achilles tendon, calf muscle and tibial bone. The PET-derived results were compared to mRNA expression of collagen type I and III. Tibial bone had the highest SUV that increased significantly (p<0.001) from the early (60 min) to the late (240 min) PET scan, while SUV in tendon and muscle decreased (p<0.001). Exercise had no influence on SUV, which was contradicted by an increased gene expression of collagen type I and III in muscle and tendon. The clearly, visible uptake of cis-Fpro in the collagen-rich musculoskeletal tissues is promising for multi-tissue studies in vivo. The tissue-specific differences with the highest basal uptake in bone are in accordance with earlier studies relying on tissue incorporation of isotopic-labelled proline. A possible explanation of the failure to demonstrate enhanced collagen synthesis following exercise, despite augmented collagen type I and III transcription, is that SUV calculations are not sensitive enough to detect minor changes in collagen synthesis. Further studies including kinetic compartment modeling must be performed to establish whether cis-Fpro can be used for non-invasive in-vivo assessment of exercise-induced changes in musculoskeletal collagen synthesis

Endoreplication Controls Cell Fate Maintenance

Cell-fate specification is typically thought to precede and determine cell-cycle regulation during differentiation. Here we show that endoreplication, also known as endoreduplication, a specialized cell-cycle variant often associated with cell differentiation but also frequently occurring in malignant cells, plays a role in maintaining cell fate. For our study we have used Arabidopsis trichomes as a model system and have manipulated endoreplication levels via mutants of cell-cycle regulators and overexpression of cell-cycle inhibitors under a trichome-specific promoter. Strikingly, a reduction of endoreplication resulted in reduced trichome numbers and caused trichomes to lose their identity. Live observations of young Arabidopsis leaves revealed that dedifferentiating trichomes re-entered mitosis and were re-integrated into the epidermal pavement-cell layer, acquiring the typical characteristics of the surrounding epidermal cells. Conversely, when we promoted endoreplication in glabrous patterning mutants, trichome fate could be restored, demonstrating that endoreplication is an important determinant of cell identity. Our data lead to a new model of cell-fate control and tissue integrity during development by revealing a cell-fate quality control system at the tissue level

INSIGHT MM: a large, global, prospective, non-interventional, real-world study of patients with multiple myeloma

With the introduction of new drugs with different mechanisms of action, multiple myeloma (MM) patients’ outcomes have improved. However, the efficacy seen in clinical trials is often not seen in real-world settings and data on the effectiveness of MM therapies are needed. INSIGHT MM is a prospective, global, non-interventional, observational study that is enrolling approximately 4200 patients with newly diagnosed or relapsed/refractory MM, making it the largest study of its kind to date. The study aims to describe contemporary, real-world patterns of patient characteristics, clinical disease presentation, therapies chosen, clinical outcomes (response, treatment duration, time-to-next-therapy, progression-free and overall survival), safety, healthcare resource utilization and quality of life. One interim analysis has been conducted to date; current accrual is approximately 3094 patients

Room-Temperature Micropillar Growth of Lithium–Titanate–Carbon Composite Structures by Self-Biased Direct Current Magnetron Sputtering for Lithium Ion Microbatteries

Here, an unidentified type of micropillar growth is described at room temperature during conventional direct-current magnetron sputtering (DC-MS) deposition from a Li4Ti5O12+graphite sputter target under negative substrate bias and high operating pressure. These fabricated carbon–Li2O–TiO2 microstructures consisting of various Li4Ti5O12/Li2TiO3/Lix TiO2 crystalline phases are demonstrated as an anode material in Li-ion microbatteries. The described micropillar fabrication method is a low-cost, substrate independent, single-step, room-temperature vacuum process utilizing a mature industrial complementary metal–oxide–semiconductor (CMOS)-compatible technology. Furthermore, tentative consideration is given to the effects of selected deposition parameters and the growth process, as based on extensive physical and chemical characterization. Additional studies are, however, required to understand the exact processes and interactions that form the micropillars. If this facile method is further extended to other similar metal oxide–carbon systems, it could offer alternative low-cost fabrication routes for microporous high-surface area materials in electrochemistry and microelectronics.Peer reviewe

Room-Temperature Micropillar Growth of Lithium–Titanate–Carbon Composite Structures by Self-Biased Direct Current Magnetron Sputtering for Lithium Ion Microbatteries

Here, an unidentified type of micropillar growth is described at room temperature during conventional direct-current magnetron sputtering (DC-MS) deposition from a Li4Ti5O12+graphite sputter target under negative substrate bias and high operating pressure. These fabricated carbon–Li2O–TiO2 microstructures consisting of various Li4Ti5O12/Li2TiO3/Lix TiO2 crystalline phases are demonstrated as an anode material in Li-ion microbatteries. The described micropillar fabrication method is a low-cost, substrate independent, single-step, room-temperature vacuum process utilizing a mature industrial complementary metal–oxide–semiconductor (CMOS)-compatible technology. Furthermore, tentative consideration is given to the effects of selected deposition parameters and the growth process, as based on extensive physical and chemical characterization. Additional studies are, however, required to understand the exact processes and interactions that form the micropillars. If this facile method is further extended to other similar metal oxide–carbon systems, it could offer alternative low-cost fabrication routes for microporous high-surface area materials in electrochemistry and microelectronics.Peer reviewe

Perspective of αβ-Integrin Imaging for Clinical Management of Pancreatic Carcinoma and Its Precursor Lesions

ß 6 -integrin immunohistochemistry analysis of a large number of pancreatic ductal adenocarcinoma (PDAC, 383 primary tumors, 7 lymph node, and 8 distant metastases) and 34 pancreatic intraepithelial neoplasia (PanIN) specimens revealed a high prevalence of α v ß 6 -integrin expression in PDAC primaries (88%) and in almost all metastases, as well as in PanIN (57%). These findings underscore the high potential of a novel α v ß 6 -integrin targeting positron emission tomography (PET) radiopharmaceutical, Ga-68-Avebehexin, for early diagnosis of pancreatic cancer