600 research outputs found
PI3K signaling and Stat92E converge to modulate glial responsiveness to axonal injury
No full textFirst author Johnna Doherty is a doctoral student in the Neuroscience Program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.Glial cells are exquisitely sensitive to neuronal injury but mechanisms by which glia establish competence to respond to injury, continuously gauge neuronal health, and rapidly activate reactive responses remain poorly defined. Here, we show glial PI3K signaling in the uninjured brain regulates baseline levels of Draper, a receptor essential for Drosophila glia to sense and respond to axonal injury. After injury, Draper levels are up-regulated through a Stat92E-modulated, injury-responsive enhancer element within the draper gene. Surprisingly, canonical JAK/STAT signaling does not regulate draper expression. Rather, we find injury-induced draper activation is downstream of the Draper/Src42a/Shark/Rac1 engulfment signaling pathway. Thus, PI3K signaling and Stat92E are critical in vivo regulators of glial responsiveness to axonal injury. We provide evidence for a positive auto-regulatory mechanism whereby signaling through the injury-responsive Draper receptor leads to Stat92E-dependent, transcriptional activation of the draper gene. We propose that Drosophila glia use this auto-regulatory loop as a mechanism to adjust their reactive state following injury.NeuroscienceInterdisciplinary Graduate Progra
The c-Jun kinase signaling cascade promotes glial engulfment activity through activation of draper and phagocytic function
No full textCo-author Johnna Doherty is a student in the Neuroscience program in the Morningside Graduate School of Biomedical Sciences (GSBS) at UMass Medical School, and Jennifer MacDonald is in the MD/PhD program.After neuronal injury or death glial cells become reactive, exhibiting dramatic changes in morphology and patterns of gene expression and ultimately engulfing neuronal debris. Rapid clearance of degenerating neuronal material is thought to be crucial for suppression of inflammation and promotion of functional recovery. Here we demonstrate that Drosophila c-Jun N-terminal kinase (dJNK) signaling is a critical in vivo mediator of glial engulfment activity. In response to axotomy, we find glial dJNK signals through a cascade involving the upstream mitogen-activated protein kinase kinase kinases Slipper and Tak1, the mitogen-activated protein kinase kinase MKK4, and ultimately the Drosophila activator protein 1 (AP-1) transcriptional complex composed of Jra and Kayak to initiate glial phagocytosis of degenerating axons. Interestingly, loss of dJNK also blocked injury-induced upregulation of Draper levels in glia, and glial-specific overexpression of Draper was sufficient to rescue engulfment defects associated with loss of dJNK signaling. This work identifies that the dJNK pathway is a novel mediator of glial engulfment activity and a primary role for the glial Slipper/Tak1short right arrowMKK4short right arrowdJNKshort right arrowdAP-1 signaling cascade appears to be activation of draper expression after axon injury.Cell Death and Differentiation advance online publication, 26 April 2013; doi:10.1038/cdd.2013.30.MD/PhDNeuroscienc
Glial cell biology in Drosophila and vertebrates
No full textGlia are the most abundant cell type in the mammalian nervous system and they have vital roles in neural development, function and health. However our understanding of the biology of glia is in its infancy. How do glia develop and interact with neurons? How diverse are glial populations? What are the primary functions of glia in the mature nervous system? These questions can be addressed incisively in the Drosophila nervous system--this contains relatively few glia, which are well-defined histologically and amenable to powerful molecular-genetic analyses. Here, we highlight several developmental, morphological and functional similarities between Drosophila and vertebrate glia. The striking parallels that emerge from this comparison argue that invertebrate model organisms such as Drosophila have excellent potential to add to our understanding of fundamental aspects of glial biology.Neuroscienc
DRK/DOS/SOS Converge with Crk/Mbc/dCed-12 to Activate Rac1 during Glial Engulfment of Axonal Debris
No full textNervous system injury or disease leads to activation of glia, which govern postinjury responses in the nervous system. Axonal injury in Drosophila results in transcriptional up-regulation of the glial engulfment receptor Draper; there is extension of glial membranes to the injury site (termed activation), and then axonal debris is internalized and degraded. Loss of the small GTPase Rac1 from glia completely suppresses glial responses to injury, but upstream activators remain poorly defined. Loss of the Rac guanine nucleotide exchange factor (GEF) Crk/myoblast city (Mbc)/dCed-12has no effect on glial activation, but blocks internalization and degradation of debris. Here we show that the signaling molecules downstream of receptor kinase (DRK) and daughter of sevenless (DOS) (mammalian homologs, Grb2 and Gab2, respectively) and the GEF son of sevenless (SOS) (mammalian homolog, mSOS) are required for efficient activation of glia after axotomy and internalization/degradation of axonal debris. At the earliest steps of glial activation, DRK/DOS/SOS function in a partially redundant manner with Crk/Mbc/dCed-12, with blockade of both complexes strongly suppressing all glial responses, similar to loss of Rac1. This work identifies DRK/DOS/SOS as the upstream Rac GEF complex required for glialresponses to axonal injury, and demonstrates a critical requirement for multiple GEFs in efficient glial activation after injury and internalization/degradation of axonal debris.NeuroscienceInterdisciplinary Graduate Progra
Distinct molecular pathways mediate glial activation and engulfment of axonal debris after axotomy
No full textGlial cells efficiently recognize and clear cellular debris after nervous system injury to maintain brain homeostasis, but pathways governing glial responses to neural injury remain poorly defined. We identify the Drosophila melanogaster guanine nucleotide exchange factor complex Crk/Mbc/dCed-12 and the small GTPase Rac1 as modulators of glial clearance of axonal debris. We found that Crk/Mbc/dCed-12 and Rac1 functioned in a non-redundant fashion with the Draper transmembrane receptor pathway: loss of either pathway fully suppressed clearance of axonal debris. Draper signaling was required early during glial responses, promoting glial activation, which included increased Draper and dCed-6 expression and extension of glial membranes to degenerating axons. In contrast, the Crk/Mbc/dCed-12 complex functioned at later phases, promoting glial phagocytosis of axonal debris. Our work identifies new components of the glial engulfment machinery and shows that glial activation, phagocytosis of axonal debris and termination of responses to injury are genetically separable events mediated by distinct signaling pathways.Neuroscienc
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Through the Lens of Color: An Interview with Gareth Doherty, Author of Paradoxes of Green: Landscapes of a City-State
No full textThis interview by Mark Tirpak with Gareth Doherty of Harvard University Graduate School of Design, focuses on his Paradoxes of Green: Landscapes of a City-State (University of California Press, 2017). With Paradoxes of Green (2017) and via the interview, Doherty recounts some of the findings of his ethnographic fieldwork in the Kingdom of Bahrain and describes tensions arising from differing conceptions of what ‘green’ means or signifies within this growing and predominantly arid region. An argument that Doherty makes in Paradoxes of Green (2017) is that color and form are interlinked, and that color deserves deeper consideration by policy-makers and other formal shapers of cities. The interview draws from Paradoxes of Green (2017) to discuss some of Doherty’s findings as well as his latest work on the intersections between landscape architecture and anthropology.Version of Recor
Through the Lens of Color: An Interview with Gareth Doherty, Author of Paradoxes of Green: Landscapes of a City-State
No full textThis interview by Mark Tirpak with Gareth Doherty of Harvard University Graduate School of Design, focuses on his Paradoxes of Green: Landscapes of a City-State (University of California Press, 2017). With Paradoxes of Green (2017) and via the interview, Doherty recounts some of the findings of his ethnographic fieldwork in the Kingdom of Bahrain and describes tensions arising from differing conceptions of what ‘green’ means or signifies within this growing and predominantly arid region. An argument that Doherty makes in Paradoxes of Green (2017) is that color and form are interlinked, and that color deserves deeper consideration by policy-makers and other formal shapers of cities. The interview draws from Paradoxes of Green (2017) to discuss some of Doherty’s findings as well as his latest work on the intersections between landscape architecture and anthropology
Helping children think: Gaze aversion and teaching
No full textLooking away from an interlocutor's face during demanding cognitive activity can help adults answer challenging arithmetic and verbal-reasoning questions (Glenberg, Schroeder, & Robertson, 1998). However, such `gaze aversion' (GA) is poorly applied by 5-year-old school children (Doherty-Sneddon, Bruce, Bonner, Longbotham, & Doyle, 2002). In Experiment 1 we trained ten 5-year-old children to use GA while thinking about answers to questions. This trained group performed significantly better on challenging questions compared with 10 controls given no GA training. In Experiment 2 we found significant and monotonic age-related increments in spontaneous use of GA across three cohorts of ten 5-year-old school children (mean ages: 5;02, 5;06 and 5;08). Teaching and encouraging GA during challenging cognitive activity promises to be invaluable in promoting learning, particularly during early primary years
Wideband Digital Intensive Doherty Concepts
No full textMany applications require wide bandwidth transmitters, but unfortunately, they usually have way less than 50% average drain efficiency for their modulated signals. This low efficiency is a significant drawback in all wireless applications, both for battery power devices and base stations. The Doherty radio frequency (RF) power amplifier architecture is widely used to enhance the average efficiency for modulated signals in base stations. Its popularity is due to its relatively cheap and simple hardware and its suitability to handle high-power wideband modulated signals. However, even Doherty amplifiers often have less than 50% average efficiency and are restricted in their RF bandwidth.This thesis reviews recent research on the Doherty power amplifier (DPA) topology and discusses possible power and bandwidth efficiency improvements. In the second part of the thesis, another topology is introduced, which also provides Doherty-like behavior. That topology is called a Pseudo Doherty Load Modulated Balanced Amplifier (PD-LMBA). The performance of PD-LMBA is compared with “conventional” DPAs. Circuit design examples of DPA and PD-LMBA are given. The thesis concludes with a PD-LMBA prototype design, which appears to be very promising in its wideband performance.Electrical Engineering | Microelectronic
A Wideband Two-Way Digital Doherty Transmitter in 40nm CMOS
No full textA 40nm CMOS wideband digital Cartesian push-pull inverted Doherty operating in class-E is presented. Wideband Doherty operation is achieved over a 1.9-to-3GHz frequency band, using an off-chip power combining network. The fully digital transmitter (DTX) provides 25.3dBm peak power with a drain/DTX line-up efficiency (DE/SE) of 58.7%/44.9%, respectively, at 2.4GHz. When operated with a 160MHz 256-QAM OFDM signal, it achieves 46.1%/32.7% average DE/SE, with an ACLR and EVM better than −40.6dBc and −33.9dB, respectively, using a simple memory-less digital pre-distortion (DPD).Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Electronic
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