Decreased demand for olfactory periglomerular cells impacts on neural precursor cell viability in the rostral migratory stream

The subventricular zone (SVZ) provides a constant supply of new neurons to the olfactory bulb (OB). Different studies have investigated the role of olfactory sensory input to neural precursor cell (NPC) turnover in the SVZ but it was not addressed if a reduced demand specifically for periglomerular neurons impacts on NPC-traits in the rostral migratory stream (RMS). We here report that membrane type-1 matrix metalloproteinase (MT1-MMP) deficient mice have reduced complexity of the nasal turbinates, decreased sensory innervation of the OB, reduced numbers of olfactory glomeruli and reduced OB-size without alterations in SVZ neurogenesis. Large parts of the RMS were fully preserved in MT1-MMP-deficient mice, but we detected an increase in cell death-levels and a decrease in SVZ-derived neuroblasts in the distal RMS, as compared to controls. BrdU-tracking experiments showed that homing of NPCs specifically to the glomerular layer was reduced in MT1-MMP-deficient mice in contrast to controls while numbers of tracked cells remained equal in other OB-layers throughout all experimental groups. Altogether, our data show the demand for olfactory interneurons in the glomerular layer modulates cell turnover in the RMS, but has no impact on subventricular neurogenesis

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition

SummarySmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant

Thermal Modelling of a GaN Bridge Leg Based on non-linear Controller and Observer

Zusammenfassung in englischer SpracheAbweichender Titel nach Übersetzung der Verfasserin/des VerfassersDie vorliegende Arbeit beschäftigt sich mit der thermischen Modellierung einer GaNHalbbrücke mit nichtlinearer Regler- und Beobachterstruktur zu Ermittlung und Regelung der Sperrschichttemperatur. Zu Beginn wird der gesamte Versuchsaufbau und die Eigenschaften sowie Charakteristiken von GaN-Transistoren erläutert. Für eine Verifizierung der entwickelten mathematischen Modelle wird eine NTC-Thermistorschaltung zur Bestimmung der Oberflächentemperaturen entworfen. Das Hauptaugenmerk dieser Arbeit liegt in der mathematischen Modellierung des Kühlsystems sowie der Generierung der thermischen Verluste in den GaN-Transistoren der Halbbrücke. Dafür wird das Kühlsystem mit einem konzentrierten parametrischen Wärmeübertragungsproblem formuliert. Die thermischen Ersatzschaltbilder nach Cauer betrachten das statische sowie dynamische Verhalten des Kühlsystems, mit der Lüfterspannung als Stellgröße und die thermischen Verluste als Eingänge. Zur Regelung der Sperrschichttemperatur bei einem Last- oder Arbeitspunktwechsel wird eine nichtlineare Regler- und Beobachterstruktur mit Trajektorienplanung erstellt. Die Simulations- und Messergebnisse zeigen, dass die Entworfene Regler- und Beobachterstruktur mit Trajektorienplanung auch bei ungenügender Bekanntheit der identifizierten Parametern eine stabile Vorgabe der Sperrschichttemperatur ermöglicht.The presented diploma thesis is focussed on the thermal modelling of a GaN bridge leg using a non-linear controller and observer structure for determination and control of the transistor junction temperature. The thesis starts with a description of the characteristics and basic properties of GaN transistors. Subsequently a test set-up is developed based on a USB-connected PC-AD interface which allows the determination of multiple surface temperatures of the bridge leg sensed by NTC thermistors. The main part of the thesis is the mathematical modelling of the colling system as well as the calculation of the losses generated by the GaN transistors of the bridge leg. For this purpose, the cooling system is formulated as a concentrated parametric heat transfer problem. The Cauer-type thermal equivalent circuit diagrams consider the static and dynamic behaviour of the cooling system, based on the thermal losses as input variables and the van supply voltage representing the control quantity. To control the transistor's junction temperature in case of load and working point variations, a non-linear controller and observer structure with trajectory planning is developed. The simulation and measurement results demonstrate that the developed model in connection with the proposed controller and observer structure achieves a stable and well-damped determination of the junction temperature, even in case the identified system parameters are known merely with uncertainties as being typical for practical converter systems.7

Folding and unfolding characteristics of short beta strand peptides under different environmental conditions and starting configurations

We analyze the effect of different environmental conditions, sequence lengths and starting configurations on the folding and unfolding pathways of small peptides exhibiting beta turns. We use chignolin and a sequence of peptide G as examples. A variety of different analysis tools allows us to characterize the changes in the folding pathways. It is observed that different harmonic modes dominate not only for different conditions but also for different starting points. The modes remain essentially very similar but their relative importance varies. A detailed analysis from diverse viewpoints including the influence of the particular amino acid sequence, conformational aspects as well as the associated motions yields a global picture that is consistent with experimental evidence and theoretical studies published elsewhere. Patterns of modes that remain stable over a range of temperatures might serve as an additional diagnostic to identify conformations that have reliably adopted a native fold. This could aid in reconstructing the folding process of a complete protein by identifying conformationally determined regions

Plexin-B2 controls the development of cerebellar granule cells

Cerebellar granule cell progenitors proliferate postnatally in the upper part of the external granule cell layer (EGL) of the cerebellum. Postmitotic granule cells differentiate and migrate, tangentially in the EGL and then radially through the molecular and Purkinje cell layers. The molecular control of the transition between proliferation and differentiation in cerebellar granule cells is poorly understood. We show here that the transmembrane receptor Plexin-B2 is expressed by proliferating granule cell progenitors. To study Plexin-B2 function, we generated a targeted mutation of mouse Plexin-B2. Most Plexin-B2−/− mutants die at birth as a result of neural tube closure defects. Some mutants survive but their cerebellum cytoarchitecture is profoundly altered. This is correlated with a disorganization of the timing of granule cell proliferation and differentiation in the EGL. Many differentiated granule cells migrate inside the cerebellum and keep proliferating. These results reveal that Plexin-B2 controls the balance between proliferation and differentiation in granule cells.This work was supported by National Institutes of Mental Health Grant RO1MH60612 (Identifying Brain Wiring Mechanisms by Gene Trapping) and from National Heart, Lung, and Blood Institute (NHLBI) Grant U01HL66600 (the NHLBI–Bay Area Functional Genomics Consortium) (M.T.-L. and S. K. McConnell). A.C. was supported by the Fondation pour la Recherche sur le Cerveau and the Association pour la Recherche sur le Cancer, R.H.F was supported by the Deutsche Forschungsgemeinschaft, U.S. was supported by a fellowship from the Dr. Mildred-Scheel-Stiftung für Krebsforschung, and C.S. was supported by Spanish Ministry of Education and Science Grant SAF2004-07990).Peer reviewe

The C-terminal domain of RNA polymerase II is modified by site-specific methylation.

The carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII) in mammals undergoes extensive posttranslational modification, which is essential for transcriptional initiation and elongation. Here, we show that the CTD of RNAPII is methylated at a single arginine (R1810) by the coactivator-associated arginine methyltransferase 1 (CARM1). Although methylation at R1810 is present on the hyperphosphorylated form of RNAPII in vivo, Ser2 or Ser5 phosphorylation inhibits CARM1 activity toward this site in vitro, suggesting that methylation occurs before transcription initiation. Mutation of R1810 results in the misexpression of a variety of small nuclear RNAs and small nucleolar RNAs, an effect that is also observed in Carm1−/− mouse embryo fibroblasts. These results demonstrate that CTD methylation facilitates the expression of select RNAs, perhaps serving to discriminate the RNAPII-associated machinery recruited to distinct gene types

Tyrosine phosphorylation of RNA polymerase II CTD is associated with antisense promoter transcription and active enhancers in mammalian cells

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