Sung-Dae Kim

Drosophila Atlastin regulates the stability of muscle microtubules and is required for synapse development.

Hereditary spastic paraplegia (HSP) is an inherited neurological disorder characterized by progressive spasticity and weakness of the lower extremities. The most common early-onset form of HSP is caused by mutations in the human gene that encodes the dynamin-family GTPase Atlastin-1 (Atl-1). Recently, loss of the Drosophila ortholog of Atl-1 (Atl) has been found to induce locomotor impairments from the earliest adult stages, suggesting the developmental role of atlastin-subfamily GTPases. Here, we provide evidence that Atl is required for normal growth of muscles and synapses at the neuromuscular junction (NMJ). Atl protein is highly expressed in larval body-wall muscles. Loss-of-function mutations in the atl gene reduce the size of muscles and increase the number of synaptic boutons. Rescue of these defects is accomplished by muscular, but not neuronal expression of Atl. Loss of Atl also disrupts ER and Golgi morphogenesis in muscles and reduces the synaptic levels of the scaffold proteins Dlg and alpha-spectrin. We also provide evidence that Atl functions with the microtubule-severing protein Spastin to disassemble microtubules in muscles. Finally, we demonstrate that the microtubule-destabilizing drug vinblastine alleviates synapse and muscle defects in atl mutants. Together, our results suggest that Atl controls synapse development and ER and Golgi morphogenesis by regulating microtubule stability.

The Cdc42-selective GAP rich regulates postsynaptic development and retrograde BMP transsynaptic signaling.

Inhibition of Cdc42 by dRich induces postsynaptic release of the BMP ligand Glass bottom boat.

dCIP4 (Drosophila Cdc42-Interacting Protein 4) Restrains Synaptic Growth by Inhibiting the Secretion of the Retrograde Glass Bottom Boat Signal

The bone morphogenetic protein (BMP) ligand Glass bottom boat (Gbb) acts as a retrograde growth signal at the Drosophila neuromuscular junction (NMJ). Endocytic regulation of presynaptic BMP receptors has been proposed to attenuate retrograde BMP signaling. However, it remains unknown whether the Gbb signal is also regulated by postsynaptic mechanisms. Here, we provide evidence that Drosophila Cdc42-interacting protein 4 (dCIP4) functions postsynaptically to inhibit synaptic growth. dCIP4 is localized postsynaptically at NMJs. dcip4 mutations lead to synaptic overgrowth and increased presynaptic phosphorylated mothers against decapentaplegic (Mad) levels, and these defects are rescued by muscle-specific expression of dCIP4. Biochemical and genetic analyses demonstrate that dCIP4 acts downstream of Cdc42 to activate the postsynaptic Wsp–Arp2/3 pathway. We also show that BMP signaling is necessary for synaptic overgrowth in larvae lacking postsynaptic dcip4 or wsp. Finally, dCIP4 and Wsp inhibit Gbb secretion. Thus, we propose that dCIP4 restrains synaptic growth by inhibiting postsynaptic Gbb secretion through the Wsp–Arp2/3 pathway.

Mid-trimester amniotic fluid pro-inflammatory biomarkers predict the risk of spontaneous preterm delivery in twins: a retrospective cohort study

Objective:To evaluate the association between the concentrations of immune-related proteins in mid-trimester amniotic fluid (AF) and the subsequent risk of spontaneous preterm delivery in twins.Study Design:The study population consisted of consecutive women with a twin pregnancy who underwent clinically indicated genetic amniocentesis at 15 to 20 weeks, and had a subsequent spontaneous delivery in the early preterm period (<32 weeks (cases)) or at term (37 to 42 weeks (controls)). AF was analyzed for cytokines (interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13 and IL-15, interferon-γ, tumor necrosis factor-α), matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9 and MMP-12), and chemokines (complement factor-D/Adipsin, Serpin E1/PAI-1, Adiponectin/Acrp30, C-Reactive Protein, CCL2/MCP-1, Leptin, Resistin) using multiplex immunoassay kits. The association between AF protein levels and subsequent early preterm birth were examined.Result:A total of 96 sets of twins were enrolled, including 17 early preterm birth cases and 79 term controls. AF concentrations of IL-6, IL-8, MMP-3, MMP-8 and MMP-9, and CCL2/MCP-1 were significantly higher in cases than controls. Among these analytes, the combination of AF IL-8 and MMP-9 values had the highest predictive value for early preterm birth. The risk was 8% (10/132) for IL-8<1200 pg ml−1 and MMP-9<1000 pg ml−1, 30% (15/50) for IL-8>1200 pg ml−1 or MMP-9>1000 pg ml−1, and 90% (9/10) for IL-8>1200 pg ml−1 and MMP-9>1000 pg ml−1 (P<0.001).Conclusion:High concentrations of IL-8 and MMP-9 in mid-trimester AF in twins predicted well the risk of early preterm birth.

The phosphoinositide phosphatase Sac1 is required for midline axon guidance

Sac1 phosphoinositide (PI) phosphatases are important regulators of PtdIns(4)P turnover at the ER, Golgi, and plasma membrane (PM) and are involved in diverse cellular processes including cytoskeletal organization and vesicular trafficking. Here, we present evidence that Sac1 regulates axon guidance in the embryonic CNS of Drosophila. Sac1 is expressed on three longitudinal axon tracts that are defined by the cell adhesion molecule Fasciclin II (Fas II). Mutations in the sac1 gene cause ectopic midline crossing of Fas II-positive axon tracts. This phenotype is rescued by neuronal expression of wild-type Sac1 but not by a catalytically-inactive mutant. Finally, sac1 displays dosage-sensitive genetic interactions with mutations in the genes that encode the midline repellent Slit and its axonal receptor Robo. Taken together, our results suggest that Sac1-mediated regulation of PIs is critical for Slit/Robo-dependent axon repulsion at the CNS midline.

Graf regulates hematopoiesis through GEEC endocytosis of EGFR

GTPase regulator associated with focal adhesion kinase 1 (GRAF1) is an essential component of the GPI-enriched endocytic compartment (GEEC) endocytosis pathway. Mutations in the human GRAF1 gene are associated with acute myeloid leukemia, but its normal role in myeloid cell development remains unclear. We show that Graf, the Drosophila ortholog of GRAF1, is expressed and specifically localizes to GEEC endocytic membranes in macrophage-like plasmatocytes. We also find that loss of Graf impairs GEEC endocytosis, enhances EGFR signaling and induces a plasmatocyte overproliferation phenotype that requires the EGFR signaling cascade. Mechanistically, Graf-dependent GEEC endocytosis serves as a major route for EGFR internalization at high, but not low, doses of the predominant Drosophila EGFR ligand Spitz (Spi), and is indispensable for efficient EGFR degradation and signal attenuation. Finally, Graf interacts directly with EGFR in a receptor ubiquitylation-dependent manner, suggesting a mechanism by which Graf promotes GEEC endocytosis of EGFR at high Spi. Based on our findings, we propose a model in which Graf functions to downregulate EGFR signaling by facilitating Spi-induced receptor internalization through GEEC endocytosis, thereby restraining plasmatocyte proliferation. Summary: During Drosophila hematopoiesis, Graf promotes downregulation of EGFR through GEEC-mediated endocytosis to restrain Spitz-dependent plasmatocyte proliferation. Defective EGFR downregulation may contribute to the development of a subset of myeloid malignancies.

Study on listmode OSEM reconstruction including image-space resolution recovery techniques for Compton camera

Although Compton camera may has a great potential as next generation imaging modality comparing to SPECT and PET, its fully three-dimensional image reconstruction requires the considerable computational burden and the spatial resolution is suffered from the various physical phenomena arising during detection process. In this study, we investigated the accelerated statistical image reconstruction in which system matrix included a resolution recovery (RR) technique. We considered 3D Gaussian resolution model for the integrated angular and geometric uncertainties. The angular uncertainty is closely related to the limited energy resolution of the Compton camera and Doppler broadening and the geometric uncertainty is due to the segmented detectors. For RR, the 3D Gaussian resolution model is incorporated into listmode OSEM (LMOSEM) using image-space convolution operation. We investigated two different RR approaches: one (denoted by LMOSEM-RRF) is when the convolution is only performed in forward projection step, and the other (denoted by LMOSEM-RRFB) is when it is performed in both forward and backward projection steps. The simulation results showed that both RR approaches gave an improvement on spatial resolution for the resolution-degraded data due to both angular and geometric uncertainties. Although LMOSEM-RRF provided better resolution than LMOSEM-RRFB, LMOSEM-RRFB could still useful for low counting statistics in measurement.

OP23.06: Measurement of fetal urine production in predicting adverse perinatal outcome in patients with uteroplacental insufficiency

GA at measurement (weeks) 35.3 ± 3.7 NS 35.7 ± 3.8 NS 34.2 ± 3.5 NS NS Estimated fetal weight (gm) 2540 ± 689 NS 2326 ± 744 < 0.05 1578 ± 587 < 0.005 < 0.005 Amniotic fluid index 13.9 ± 4.4 < 0.01 10.8 ± 3.8 < 0.05 7.1 ± 4.8 < 0.005 < 0.001 UPR (ml/hr) 49.2 ± 35.6 NS 38.6 ± 17.1 < 0.005 15.0 ± 8.8 < 0.005 < 0.005 UPR SD −0.07 ± 1.06 NS −0.45 ± 0.42 < 0.005 −1.17 ± 0.40 < 0.005 < 0.005 UPR/Wt (ml/hr/gm) 18.3 ± 11.8 NS 16.4 ± 4.9 < 0.05 9.9 ± 5.6 < 0.05 0.074 Cerebroplacental ratio 1.91 ± 0.59 NS 1.81 ± 0.66 < 0.05 1.10 ± 0.49 < 0.05 0.067 GA at delivery (weeks) 39.9 ± 1.2 < 0.001 37.9 ± 1.5 NS 35.5 ± 3.8 < 0.005 < 0.001 Birthweight 3343 ± 341 < 0.001 2727 ± 537 < 0.005 1693 ± 613 < 0.001 < 0.001