Intracellular Spatial Localization Regulated by the Microtubule Network

The commonly recognized mechanisms for spatial regulation inside the cell are membrane-bounded compartmentalization and biochemical association with subcellular organelles. We use computational modeling to investigate another spatial regulation mechanism mediated by the microtubule network in the cell. Our results demonstrate that the mitotic spindle can impose strong sequestration and concentration effects on molecules with binding affinity for microtubules, especially dynein-directed cargoes. The model can recapitulate the essence of three experimental observations on distinct microtubule network morphologies: the sequestration of germ plasm components by the mitotic spindles in the Drosophila syncytial embryo, the asymmetric cell division initiated by the time delay in centrosome maturation in the Drosophila neuroblast, and the diffusional block between neighboring energids in the Drosophila syncytial embryo. Our model thus suggests that the cell cycle-dependent changes in the microtubule network are critical for achieving different spatial regulation effects. The microtubule network provides a spatially extensive docking platform for molecules and gives rise to a “structured cytoplasm”, in contrast to a free and fluid environment

A Precise Bicoid Gradient Is Nonessential during Cycles 11–13 for Precise Patterning in the Drosophila Blastoderm

Background: During development, embryos decode maternal morphogen inputs into highly precise zygotic gene expression. The discovery of the morphogen Bicoid and its profound effect on developmental programming in the Drosophila embryo has been a cornerstone in understanding the decoding of maternal inputs. Bicoid has been described as a classical morphogen that forms a concentration gradient along the antero-posterior axis of the embryo by diffusion and initiates expression of target genes in a concentration-dependent manner in the syncytial blastoderm. Recent work has emphasized the stability of the Bicoid gradient as a function of egg length and the role of nuclear dynamics in maintaining the Bicoid gradient. Bicoid and nuclear dynamics were observed but not modulated under the ideal conditions used previously. Therefore, it has not been tested explicitly whether a temporally stable Bicoid gradient prior to cellularization is required for precise patterning. Principal Findings: Here, we modulate both nuclear dynamics and the Bicoid gradient using laminar flows of different temperature in a microfluidic device to determine if stability of the Bicoid gradient prior to cellularization is essential for precise patterning. Dramatic motion of both cytoplasm and nuclei was observed prior to cellularization, and the Bicoid gradient was disrupted by nuclear motion and was highly abnormal as a function of egg length. Despite an abnormal Bicoid gradient during cycles 11–13, Even-skipped patterning in these embryos remained precise. Conclusions: These results indicate that the stability of the Bicoid gradient as a function of egg length is nonessential during syncytial blastoderm stages. Further, presumably no gradient formed by simple diffusion on the scale of egg length could be responsible for the robust antero-posterior patterning observed, as severe cytoplasmic and nuclear motion would disrupt such a gradient. Additional mechanisms for how the embryo could sense its dimensions and interpret the Bicoid gradient are discussed

The Toll→NFκB Signaling Pathway Mediates the Neuropathological Effects of the Human Alzheimer's Aβ42 Polypeptide in Drosophila

Alzheimer's (AD) is a progressive neurodegenerative disease that afflicts a significant fraction of older individuals. Although a proteolytic product of the Amyloid precursor protein, the Αβ42 polypeptide, has been directly implicated in the disease, the genes and biological pathways that are deployed during the process of Αβ42 induced neurodegeneration are not well understood and remain controversial. To identify genes and pathways that mediated Αβ42 induced neurodegeneration we took advantage of a Drosophila model for AD disease in which ectopically expressed human Αβ42 polypeptide induces cell death and tissue degeneration in the compound eye. One of the genes identified in our genetic screen is Toll (Tl). It encodes the receptor for the highly conserved Tl→NFkB innate immunity/inflammatory pathway and is a fly homolog of the mammalian Interleukin-1 (Ilk-1) receptor. We found that Tl loss-of-function mutations dominantly suppress the neuropathological effects of the Αβ42 polypeptide while gain-of-function mutations that increase receptor activity dominantly enhance them. Furthermore, we present evidence demonstrating that Tl and key downstream components of the innate immunity/inflammatory pathway play a central role in mediating the neuropathological activities of Αβ42. We show that the deleterious effects of Αβ42 can be suppressed by genetic manipulations of the Tl→NFkB pathway that downregulate signal transduction. Conversely, manipulations that upregulate signal transduction exacerbate the deleterious effects of Aβ42. Since postmortem studies have shown that the Ilk-1→NFkB innate immunity pathway is substantially upregulated in the brains of AD patients, the demonstration that the Tl→NFkB signaling actively promotes the process of Αβ42 induced cell death and tissue degeneration in flies points to possible therapeutic targets and strategies

ATLAS pixel detector electronics and sensors

The silicon pixel tracking system for the ATLAS experiment at the Large Hadron Collider is described and the performance requirements are summarized. Detailed descriptions of the pixel detector electronics and the silicon sensors are given. The design, fabrication, assembly and performance of the pixel detector modules are presented. Data obtained from test beams as well as studies using cosmic rays are also discussed

Particle identification with the Silicon Transition Radiation Detector (SiTRD): State of art and future perspectives

We are developing a novel Transition Radiation Detector (SiTRD) based on silicon strip detectors (SSDs) operated in a magnetic field region. In this way the trajectory of the radiating particle is deflected with respect to the Transition Radiation X-rays that are absorbed in a detector region far away from the particle track. The SiTRD combines the particle identification performance of a traditional TRD with the high-precision tracking capability of SSDs, and it can be suitable for both accelerator and cosmic ray experiments, whenever particle identification and momentum reconstruction are required. In this paper we will show the experimental results obtained with a reduced scale SiTRD prototype exposed to an electron-pion beam. (c) 2006 Elsevier B.V. All rights reserved

MEASUREMENT OF W-PRODUCTION AND Z-PRODUCTION PROPERTIES AT THE CERN PBARP COLLIDER

A study has been made of the production characteristics of W and Z bosons produced at the CERN pp Collider. The event sample consists of 251 W→ev decays, and 39 Z→e+e- decays, identified by the UA2 detector, and corresponds to an integrated luminosity of 142 nb-1 at √s = 546 GeV, and 768 nb-1 at √s = 630 GeV. Measurements of W and Z production cross sections, of longitudinal and transverse momentum distributions, and of associated jet production, are presented. These measurements are compared with theoretical expectations, which include higher order QCD effects. © 1987